Systemic inflammatory markers in ageing, Alzheimer's disease and other dementias.

Systemic inflammation with alterations in inflammatory markers is involved in aging and Alzheimer's disease. However, few studies have investigated the longitudinal trajectories of systemic inflammatory markers during aging and Alzheimer's disease, and specific markers contributing to Alzheimer's disease remain undetermined. In this study, a longitudinal cohort (cohort 1: n = 290; controls, 136; preclinical Alzheimer's disease, 154) and a cross-sectional cohort (cohort 2: n = 351; controls, 62; Alzheimer's disease, 63; vascular dementia, 58; Parkinson's disease dementia, 56; behavioural variant frontotemporal dementia, 57; dementia with Lewy bodies, 55) were included. Plasma levels of inflammatory markers were measured every 2 years during a 10-year follow-up in the longitudinal cohort and once in the cross-sectional cohort. The study demonstrated that the inflammatory markers significantly altered during both aging and the development of Alzheimer's disease. However, only complement C3, interleukin-1ß, and interleukin-6 exhibited significant changes in participants with preclinical Alzheimer's disease, and their longitudinal changes were significantly associated with the development of Alzheimer's disease compared to controls over the 10-year follow-up. In the cross-sectional cohort, complement C3 demonstrates specificity to Alzheimer's disease, while interleukin-1ß and interleukin-6 were also altered in other dementias. The study provides a new perspective on the involvement of inflammatory markers in the aging process and the development of Alzheimer's disease, implying that regulating inflammation may have a pivotal role in promoting successful aging and in the prevention and treatment of Alzheimer's disease.

Nicotinate-curcumin improves NASH by inhibiting the AKR1B10/ACCα-mediated triglyceride synthesis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a prevalent chronic liver condition. However, the potential therapeutic benefits and underlying mechanism of nicotinate-curcumin (NC) in the treatment of NASH remain uncertain. METHODS: A rat model of NASH induced by a high-fat and high-fructose diet was treated with nicotinate-curcumin (NC, 20, 40 mg·kg- 1), curcumin (Cur, 40 mg·kg- 1) and metformin (Met, 50 mg·kg- 1) for a duration of 4 weeks. The interaction between NASH, Cur and Aldo-Keto reductase family 1 member B10 (AKR1B10) was filter and analyzed using network pharmacology. The interaction of Cur, NC and AKR1B10 was analyzed using molecular docking techniques, and the binding energy of Cur and NC with AKR1B10 was compared. HepG2 cells were induced by Ox-LDL (25 µg·ml- 1, 24 h) in high glucose medium. NC (20µM, 40µM), Cur (40µM) Met (150µM) and epalrestat (Epa, 75µM) were administered individually. The activities of ALT, AST, ALP and the levels of LDL, HDL, TG, TC and FFA in serum were quantified using a chemiluminescence assay. Based on the changes in the above indicators, score according to NAS standards. The activities of Acetyl-CoA and Malonyl-CoA were measured using an ELISA assay. And the expression and cellular localization of AKR1B10 and Acetyl-CoA carboxylase (ACCα) in HepG2 cells were detected by Western blotting and immunofluorescence. RESULTS: The results of the animal experiments demonstrated that NASH rat model induced by a high-fat and high-fructose diet exhibited pronounced dysfunction in liver function and lipid metabolism. Additionally, there was a significant increase in serum levels of FFA and TG, as well as elevated expression of AKR1B10 and ACCα, and heightened activity of Acetyl-CoA and Malonyl-CoA in liver tissue. The administration of NC showed to enhance liver function in rats with NASH, leading to reductions in ALT, AST and ALP levels, and decrease in blood lipid and significant inhibition of FFA and TG synthesis in the liver. Network pharmacological analysis identified AKR1B10 and ACCα as potential targets for NASH treatment. Molecular docking studies revealed that both Cur and NC are capable of binding to AKR1B10, with NC exhibiting a stronger binding energy to AKR1B10. Western blot analysis demonstrated an upregulation in the expression of AKR1B10 and ACCα in the liver tissue of NASH rats, accompanied by elevated Acetyl-CoA and Malonyl-CoA activity, and increased levels of FFA and TG. The results of the HepG2 cell experiments induced by Ox-LDL suggest that NC significantly inhibited the expression and co-localization of AKR1B10 and ACCα, while also reduced levels of TC and LDL-C and increased level of HDL-C. These effects are accompanied by a decrease in the activities of ACCα and Malonyl-CoA, and levels of FFA and TG. Furthermore, the impact of NC appears to be more pronounced compared to Cur. CONCLUSION: NC could effectively treat NASH and improve liver function and lipid metabolism disorder. The mechanism of NC is related to the inhibition of AKR1B10/ACCα pathway and FFA/TG synthesis of liver.

Targeting HDL in tumor microenvironment: New hope for cancer therapy.

Epidemiological studies have shown that plasma HDL-C levels are closely related to the risk of prostate cancer, breast cancer, and other malignancies. As one of the key carriers of cholesterol regulation, high-density lipoprotein (HDL) plays an important role in tumorigenesis and cancer development through anti-inflammation, antioxidation, immune-modulation, and mediating cholesterol transportation in cancer cells and noncancer cells. In addition, the occurrence and progression of cancer are closely related to the alteration of the tumor microenvironment (TME). Cancer cells synthesize and secrete a variety of cytokines and other factors to promote the reprogramming of surrounding cells and shape the microenvironment suitable for cancer survival. By analyzing the effect of HDL on the infiltrating immune cells in the TME, as well as the relationship between HDL and tumor-associated angiogenesis, it is suggested that a moderate increase in the level of HDL in vivo with consequent improvement of the function of HDL in the TME and induction of intracellular cholesterol efflux may be a promising strategy for cancer therapy.

The APOE ε4 exerts differential effects on familial and other subtypes of Alzheimer's disease.

INTRODUCTION: The genetic risk effects of apolipoprotein E (APOE) on familial Alzheimer's disease (FAD) with or without gene mutations, sporadic AD (SAD), and normal controls (NC) remain unclear in the Chinese population. METHODS: In total, 15 119 subjects, including 311 FAD patients without PSEN1, PSEN2, APP, TREM2, and SORL1 pathogenic mutations (FAD [unknown]); 126 FAD patients with PSENs/APP mutations (FAD [PSENs/APP]); 7234 SAD patients; and 7448 NC were enrolled. The risk effects of APOE ε4 were analyzed across groups. RESULTS: The prevalence of the APOE ε4 genotype in FAD (unknown), FAD (PSENs/APP), SAD, and NC groups was 56.27%, 26.19%, 36.23%, and 19.54%, respectively. Further, the APOE ε4 positive genotype had predictive power for FAD (unknown) risk (odds ratio: 4.51, 95% confidence interval: 3.57-5.45, P < .001). DISCUSSION: APOE ε4 positive genotype may cause familial aggregation, and the investigation of multiple interventions targeting APOE pathological function to reduce the risk for this disease warrants attention.

Exploration of cultivable fungal communities in deep coal-bearing sediments from ∼1.3 to 2.5 km below the ocean floor.

Although subseafloor sediments are known to harbour a vast number of microbial cells, the distribution, diversity, and origins of fungal populations remain largely unexplored. In this study, we cultivated fungi from 34 of 47 deep coal-associated sediment samples collected at depths ranging from 1289 to 2457 m below the seafloor (mbsf) off the Shimokita Peninsula, Japan (1118 m water depth). We obtained a total of 69 fungal isolates under strict contamination controls, representing 61 Ascomycota (14 genera, 23 species) and 8 Basidiomycota (4 genera, 4 species). Penicillium and Aspergillus relatives were the most dominant genera within the Ascomycetes, followed by the members of genera Cladosporium, Hamigera, Chaetomium, Eutypella, Acremonium, Aureobasidium, Candida, Eurotium, Exophiala, Nigrospora, Bionectria and Pseudocercosporella. Four Basidiomycota species were identified as genera Schizophyllum, Irpex, Bjerkandera and Termitomyces. Among these isolates, Cladosporium sphaerospermum and Aspergillus sydowii relatives were isolated from a thin lignite coal-sandstone formation at 2457 mbsf. Our results indicate that these cultivable fungal populations are indigenous, originating from past terrigenous environments, which have persisted, possibly as spores, through ∼20 million years of depositional history.

Polygalacic acid attenuates cognitive impairment by regulating inflammation through PPARγ/NF-κB signaling pathway.

AIMS: We aimed to explore the role and molecular mechanism of polygalacic acid (PA) extracted from traditional Chinese medicine Polygala tenuifolia in the treatment of Alzheimer's disease (AD). METHODS: The network pharmacology analysis was used to predict the potential targets and pathways of PA. Molecular docking was applied to analyze the combination between PA and core targets. Aß42 oligomer-induced AD mice model and microglia were used to detect the effect of PA on the release of pro-inflammatory mediators and its further mechanism. In addition, a co-culture system of microglia and neuronal cells was constructed to assess the effect of PA on activating microglia-mediated neuronal apoptosis. RESULTS: We predict that PA might regulate inflammation by targeting PPARγ-mediated pathways by using network pharmacology. In vivo study, PA could attenuate cognitive deficits and inhibit the expression levels of inflammation-related factors. In vitro study, PA can also decrease the production of activated microglia-mediated inflammatory cytokines and reduce the apoptosis of N2a neuronal cells. PPARγ inhibitor GW9662 inversed the neuroprotective effect of PA. Both in vivo and in vitro studies showed PA might attenuate the inflammation through the PPARγ/NF-κB pathway. CONCLUSIONS: PA is expected to provide a valuable candidate for new drug development for AD in the future.

The role of N-methyl-D-aspartate glutamate receptors in Alzheimer's disease: From pathophysiology to therapeutic approaches.

N-Methyl-D-aspartate glutamate receptors (NMDARs) are involved in multiple physiopathological processes, including synaptic plasticity, neuronal network activities, excitotoxic events, and cognitive impairment. Abnormalities in NMDARs can initiate a cascade of pathological events, notably in Alzheimer's disease (AD) and even other neuropsychiatric disorders. The subunit composition of NMDARs is plastic, giving rise to a diverse array of receptor subtypes. While they are primarily found in neurons, NMDAR complexes, comprising both traditional and atypical subunits, are also present in non-neuronal cells, influencing the functions of various peripheral tissues. Furthermore, protein-protein interactions within NMDAR complexes has been linked with Aß accumulation, tau phosphorylation, neuroinflammation, and mitochondrial dysfunction, all of which potentially served as an obligatory relay of cognitive impairment. Nonetheless, the precise mechanistic link remains to be fully elucidated. In this review, we provided an in-depth analysis of the structure and function of NMDAR, investigated their interactions with various pathogenic proteins, discussed the current landscape of NMDAR-based therapeutics, and highlighted the remaining challenges during drug development.

A 19-Year-Old Adolescent with Probable Alzheimer's Disease.

Alzheimer's disease (AD) primarily affects older adults. In this report, we present the case of a 19-year-old male with gradual memory decline for 2 years and World Health Organization-University of California Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT) results also showing memory impairment. Positron emission tomography-magnetic resonance imaging with 18F fluorodeoxyglucose revealed atrophy of the bilateral hippocampus and hypometabolism in the bilateral temporal lobe. Examination of the patient's cerebrospinal fluid showed an increased concentration of p-tau181 and a decreased amyloid-ß 42/40 ratio. However, through whole-genome sequencing, no known gene mutations were identified. Considering the above, the patient was diagnosed with probable AD.

Shared and unique effects of ApoEε4 and pathogenic gene mutation on cognition and imaging in preclinical familial Alzheimer's disease.

BACKGROUND: Neuropsychology and imaging changes have been reported in the preclinical stage of familial Alzheimer's disease (FAD). This study investigated the effects of APOEε4 and known pathogenic gene mutation on different cognitive domains and circuit imaging markers in preclinical FAD. METHODS: One hundred thirty-nine asymptomatic subjects in FAD families, including 26 APOEε4 carriers, 17 APP and 20 PS1 mutation carriers, and 76 control subjects, went through a series of neuropsychological tests and MRI scanning. Test scores and imaging measures including volumes, diffusion indices, and functional connectivity (FC) of frontostriatal and hippocampus to posterior cingulate cortex pathways were compared between groups and analyzed for correlation. RESULTS: Compared with controls, the APOEε4 group showed increased hippocampal volume and decreased FC of fronto-caudate pathway. The APP group showed increased recall scores in auditory verbal learning test, decreased fiber number, and increased radial diffusivity and FC of frontostriatal pathway. All three genetic groups showed decreased fractional anisotropy of hippocampus to posterior cingulate cortex pathway. These neuropsychological and imaging measures were able to discriminate genetic groups from controls, with areas under the curve from 0.733 to 0.837. Circuit imaging measures are differentially associated with scores in various cognitive scales in control and genetic groups. CONCLUSIONS: There are neuropsychological and imaging changes in the preclinical stage of FAD, some of which are shared by APOEε4 and known pathogenic gene mutation, while some are unique to different genetic groups. These findings are helpful for the early identification of Alzheimer's disease and for developing generalized and individualized prevention and intervention strategies.

Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective cohort study.

OBJECTIVE: To identify an optimal lifestyle profile to protect against memory loss in older individuals. DESIGN: Population based, prospective cohort study. SETTING: Participants from areas representative of the north, south, and west of China. PARTICIPANTS: Individuals aged 60 years or older who had normal cognition and underwent apolipoprotein E (APOE) genotyping at baseline in 2009. MAIN OUTCOME MEASURES: Participants were followed up until death, discontinuation, or 26 December 2019. Six healthy lifestyle factors were assessed: a healthy diet (adherence to the recommended intake of at least 7 of 12 eligible food items), regular physical exercise (≥150 min of moderate intensity or ≥75 min of vigorous intensity, per week), active social contact (≥twice per week), active cognitive activity (≥twice per week), never or previously smoked, and never drinking alcohol. Participants were categorised into the favourable group if they had four to six healthy lifestyle factors, into the average group for two to three factors, and into the unfavourable group for zero to one factor. Memory function was assessed using the World Health Organization/University of California-Los Angeles Auditory Verbal Learning Test, and global cognition was assessed via the Mini-Mental State Examination. Linear mixed models were used to explore the impact of lifestyle factors on memory in the study sample. RESULTS: 29 072 participants were included (mean age of 72.23 years; 48.54% (n=14 113) were women; and 20.43% (n=5939) were APOE ε4 carriers). Over the 10 year follow-up period (2009-19), participants in the favourable group had slower memory decline than those in the unfavourable group (by 0.028 points/year, 95% confidence interval 0.023 to 0.032, P<0.001). APOE ε4 carriers with favourable (0.027, 95% confidence interval 0.023 to 0.031) and average (0.014, 0.010 to 0.019) lifestyles exhibited a slower memory decline than those with unfavourable lifestyles. Among people who were not carriers of APOE ε4, similar results were observed among participants in the favourable (0.029 points/year, 95% confidence interval 0.019 to 0.039) and average (0.019, 0.011 to 0.027) groups compared with those in the unfavourable group. APOE ε4 status and lifestyle profiles did not show a significant interaction effect on memory decline (P=0.52). CONCLUSION: A healthy lifestyle is associated with slower memory decline, even in the presence of the APOE ε4 allele. This study might offer important information to protect older adults against memory decline. TRIAL REGISTRATION: ClinicalTrials.gov NCT03653156.

Open Reduction of Displaced Radial Neck Fractures in Children by Internal Fixation Techniques: Comparison of Percutaneous Kirschner Wiring and Elastic Stable Intramedullary Nailing.

Background: Although most paediatric radial neck fractures can be treated with closed reduction, some severely displaced fractures require open reduction. The purpose of this study is to compare the effects of ESIN and KW fixation in open reduction of radial neck fracture in children. Methods: Twenty-four patients with mean age of 8.5 years were included. Four of the patients had a Judet type III fracture and 20 had a Judet type IV fracture. Ten patients who underwent percutaneous KW fixation were assigned to group A, while 14 patients who underwent ESIN fixation were assigned to group B. Variables of interest included age, sex, fracture type, associated lesions, surgical time, fracture reduction, cost, follow-up, healing time, X-rays, clinical outcomes, and complications. Results: There were no significant between-group differences in sex, age, additional injuries, fracture type, and quality of reduction. Costs were significantly lower in Group A. Fracture healing was achieved in 23 of 24 patients (10/10 in group A and 13/14 in group B). In a postoperative elbow function assessment based on the Steele and Graham classification, 80% of patients in group A had a score of excellent or good, compared to 78.6% of patients in group B. Two cases of nail shifting and joint protrusion were observed in group B, one of which also presented with nonunion during follow-up. Conclusions: Both KW and ESIN may achieve good clinical outcomes, but KW is associated with lower costs, easier implant removal (without the need for a secondary surgery), and lower iatrogenic complications.

Cholesterol homeostasis and cancer: a new perspective on the low-density lipoprotein receptor.

BACKGROUND: Disturbance of cholesterol homeostasis is considered as one of the manifestations of cancer. Cholesterol plays an essential role in the pleiotropic functions of cancer cells, including mediating membrane trafficking, intracellular signal transduction, and production of hormones and steroids. As a single transmembrane receptor, the low-density lipoprotein receptor (LDLR) can participate in intracellular cholesterol uptake and regulate cholesterol homeostasis. It has recently been found that LDLR is aberrantly expressed in a broad range of cancers, including colon cancer, prostate cancer, lung cancer, breast cancer and liver cancer. LDLR has also been found to be involved in various signaling pathways, such as the MAPK, NF-κB and PI3K/Akt signaling pathways, which affect cancer cells and their surrounding microenvironment. Moreover, LDLR may serve as an independent prognostic factor for lung cancer, breast cancer and pancreatic cancer, and is closely related to the survival of cancer patients. However, the role of LDLR in some cancers, such as prostate cancer, remains controversial. This may be due to the lack of normal feedback regulation of LDLR expression in cancer cells and the severe imbalance between LDLR-mediated cholesterol uptake and de novo biosynthesis of cholesterol. CONCLUSIONS: The imbalance of cholesterol homeostasis caused by abnormal LDLR expression provides new therapeutic opportunities for cancer. LDLR interferes with the occurrence and development of cancer by modulating cholesterol homeostasis and may become a novel target for the development of anti-cancer drugs. Herein, we systematically review the contribution of LDLR to cancer progression, especially its dysregulation and underlying mechanism in various malignancies. Besides, potential targeting and immunotherapeutic options are proposed.

Involvement of LDL and ox-LDL in Cancer Development and Its Therapeutical Potential.

Lipid metabolism disorder is related to an increased risk of tumorigenesis and is involved in the rapid growth of cancer cells as well as the formation of metastatic lesions. Epidemiological studies have demonstrated that low-density lipoprotein (LDL) and oxidized low-density lipoprotein (ox-LDL) are closely associated with breast cancer, colorectal cancer, pancreatic cancer, and other malignancies, suggesting that LDL and ox-LDL play important roles during the occurrence and development of cancers. LDL can deliver cholesterol into cancer cells after binding to LDL receptor (LDLR). Activation of PI3K/Akt/mTOR signaling pathway induces transcription of the sterol regulatory element-binding proteins (SREBPs), which subsequently promotes cholesterol uptake and synthesis to meet the demand of cancer cells. Ox-LDL binds to the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and cluster of differentiation 36 (CD36) to induce mutations, resulting in inflammation, cell proliferation, and metastasis of cancer. Classic lipid-lowering drugs, statins, have been shown to reduce LDL levels in certain types of cancer. As LDL and ox-LDL play complicated roles in cancers, the potential therapeutic effect of targeting lipid metabolism in cancer therapy warrants more investigation.

Celastrol Attenuates Lipid Accumulation and Stemness of Clear Cell Renal Cell Carcinoma via CAV-1/LOX-1 Pathway.

Clear cell renal cell carcinoma (ccRCC) is characterized by abnormal lipid accumulation. Celastrol is a pentacyclic triterpene extracted from Tripterygium wilfordii Hook F with anti-cancer activity. In the present study, the anticancer effects of celastrol on ccRCC and the underlying mechanisms were studied. Patients with reduced high density lipoprotein (HDL) and elevated levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL) was found to have higher risk of ccRCC. In ccRCC clinical samples and cell lines, caveolin-1 (CAV-1) was highly expressed. CAV-1 was identified as a potential prognostic biomarker for ccRCC. Celastrol inhibited tumor growth and decreased lipid deposition promoted by high-fat diet in vivo. Celastrol reduced lipid accumulation and caveolae abundance, inhibited the binding of CAV-1 and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in ccRCC cells. Furthermore, celastrol attenuated stemness through blocking Wnt/ß-catenin pathway after knockdown of CAV-1 and LOX-1. Therefore, the findings suggest that celastrol may be a promising active ingredient from traditional Chinese medicine for anti-cancer therapy.

A multidrug-resistant P-glycoprotein assembly revealed by tariquidar-probe's super-resolution imaging.

As an efflux pump, P-glycoproteins (P-gps) are over-expressed in many cancer cell types to confer them with multi-drug resistance. Many studies have focused on elucidating their molecular structure or protein expression; however, the relationship between the molecular assembly and dysfunction remains unclear. Super-resolution microscope is an excellent imaging tool to reveal the molecular biological details, but its high-quality imaging often suffers from the labeling method currently available. In this work, by exploiting its specificity and small size, tariquidar (specific inhibitor of P-gp) was modified by TAMRA to form a small chemical probe of P-gp. By direct stochastic optical reconstruction microscopic (dSTORM) imaging, tariquidar-TAMRA was first revealed to possess a higher labeling superiority and high binding specificity. Then, with the application of tariquidar-TAMRA labeling, we found that P-gps accumulate into larger and denser clusters on cancer cells and drug-resistant cells than on normal cells and drug-sensitive cells, indicating that P-gps can facilitate the pumping efficiency by aggregating together to form functional platforms. Moreover, these specific distribution patterns might serve as potential biomarkers for tumor and drug therapy screening.

PVAT targets VSMCs to regulate vascular remodelling: angel or demon.

Vascular remodelling refers to abnormal changes in the structure and function of blood vessel walls caused by injury, and is the main pathological basis of cardiovascular diseases such as atherosclerosis, hypertension, and pulmonary hypertension. Among them, the neointimal hyperplasia caused by abnormal proliferation of vascular smooth muscle cells (VSMCs) plays a key role in the pathogenesis of vascular remodelling. Perivascular adipose tissue (PVAT) can release vasoactive substances to target VSMCs and regulate the pathological process of vascular remodelling. Specifically, PVAT can promote the conversion of VSMCs phenotype from contraction to synthesis by secreting visfatin, leptin, and resistin, and participate in the development of vascular remodelling-related diseases. Conversely, it can also inhibit the growth of VSMCs by secreting adiponectin and omentin to prevent neointimal hyperplasia and alleviate vascular remodelling. Therefore, exploring and developing new drugs or other treatments that facilitate the beneficial effects of PVAT on VSMCs is a potential strategy for prevention or treatment of vascular remodelling-related cardiovascular diseases.

Celastrol ameliorates vascular neointimal hyperplasia through Wnt5a-involved autophagy.

Neointimal hyperplasia caused by the excessive proliferation of vascular smooth muscle cells (VSMCs) is the pathological basis of restenosis. However, there are few effective strategies to prevent restenosis. Celastrol, a pentacyclic triterpene, has been recently documented to be beneficial to certain cardiovascular diseases. Based on its significant effect on autophagy, we proposed that celastrol could attenuate restenosis through enhancing autophagy of VSMCs. In the present study, we found that celastrol effectively inhibited the intimal hyperplasia and hyperproliferation of VSMCs by inducing autophagy. It was revealed that autophagy promoted by celastrol could induce the lysosomal degradation of c-MYC, which might be a possible mechanism contributing to the reduction of VSMCs proliferation. The Wnt5a/PKC/mTOR signaling pathway was found to be an underlying mechanism for celastrol to induce autophagy and inhibit the VSMCs proliferation. These observations indicate that celastrol may be a novel drug with a great potential to prevent restenosis.

Functional Connectivity of Default Mode Network Subsystems in the Presymptomatic Stage of Autosomal Dominant Alzheimer's Disease.

BACKGROUND: The default mode network (DMN) could be divided into subsystems, the functional connectivity of which are different across the Alzheimer's disease (AD) spectrum. However, the functional connectivity patterns within the subsystems are unknown in presymptomatic autosomal dominant AD (ADAD). OBJECTIVE: To investigate functional connectivity patterns within the subsystems of the DMN in presymptomatic subjects carrying PSEN1, PSEN2, or APP gene mutations. METHODS: Twenty-six presymptomatic mutation carriers (PMC) and twenty-nine cognitively normal non-carriers as normal controls (NC) from the same families underwent resting state functional MRI and structural MRI. Seed-based analyses were done to obtain functional connectivity of posterior and anterior DMN. For the regions that showed significant connectivity difference between PMC and NC, volumes were extracted and compared between the two groups. Connectivity measures were then correlated with cognitive tests scores. RESULTS: The posterior DMN showed connectivity decrease in the PMC group as compared with the NC group, which was primarily the connectivity of left precuneus with right precuneus and superior frontal gyrus; the anterior DMN showed significant connectivity decrease in the PMC group, which was the connectivity of medial frontal gyrus with middle frontal gyrus. In the brain regions showing connectivity changes in the PMC group, there was no group difference in volume. A positive correlation was observed between the precuneus connectivity value and Mini-Mental State Examination total score. CONCLUSION: Functional connectivity within both posterior and anterior DMN were disrupted in the presymptomatic stage of ADAD. Connectivity disruption within the posterior DMN may be useful for early identification of general cognitive decline and a potential imaging biomarker for early diagnosis.

Total saponins from Lilium lancifolium: a promising alternative to inhibit the growth of gastric carcinoma cells.

Bulbus Lilii, as a medicinal and edible plant, has anti-inflammatory, anti-oxidative and immunopotentiating pharmacological activities, which seems to be therapeutic on cancer prevention. The purpose of this study was to investigate the effects of total saponins from Lilium lancifolium (TSLL) on proliferation, apoptosis and migration of human gastric carcinoma cells lines SGC-7901 and HGC-27 and its underlying mechanism. The results showed that TSLL inhibited the proliferation of gastric carcinoma cells by suppressing the level of proliferating cell nuclear antigen (PCNA) and increased p21 level. TSLL induced cells apoptosis by up-regulating expression of pro-apoptotic protein Bax and down-regulating anti-apoptotic protein Bcl-2 expression. Meanwhile, TSLL remarkably inhibited cell migration and invasion, decreased matrix metalloproteinase-2 (MMP-2) expression and increased tissue inhibitor of metalloproteinases-1 (TIMP-1) expression. Notably, TSLL had stronger anti-cancer effect on undifferentiated HGC-27 cells than differentiated SGC-7901 cells. Accordingly, TSLL might be a promising candidate to prevent and suppress the growth of gastric carcinoma cells.

Effects of gene mutation and disease progression on representative neural circuits in familial Alzheimer's disease.

BACKGROUND: Although structural and functional changes of the striatum and hippocampus are present in familial Alzheimer's disease, little is known about the effects of specific gene mutation or disease progression on their related neural circuits. This study was to evaluate the effects of known pathogenic gene mutation and disease progression on the striatum- and hippocampus-related neural circuits, including frontostriatal and hippocampus-posterior cingulate cortex (PCC) pathways. METHODS: A total of 102 healthy mutation non-carriers, 40 presymptomatic mutation carriers (PMC), and 30 symptomatic mutation carriers (SMC) of amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 gene, with T1 structural MRI, diffusion tensor imaging, and resting-state functional MRI were included. Representative neural circuits and their key nodes were obtained, including bilateral caudate-rostral middle frontal gyrus (rMFG), putamen-rMFG, and hippocampus-PCC. Volumes, diffusion indices, and functional connectivity of circuits were compared between groups and correlated with neuropsychological and clinical measures. RESULTS: In PMC, APP gene mutation carriers showed impaired diffusion indices of caudate-rMFG and putamen-rMFG circuits; PS1 gene mutation carriers showed increased fiber numbers of putamen-rMFG circuit. SMC showed increased diffusivity of the left hippocampus-PCC circuit and volume reduction of all regions as compared with PMC. Imaging measures especially axial diffusivity of the representative circuits were correlated with neuropsychological measures. CONCLUSIONS: APP and PS1 gene mutations affect frontostriatal circuits in a different manner in familial Alzheimer's disease; disease progression primarily affects the structure of hippocampus-PCC circuit. The structural connectivity of both frontostriatal and hippocampus-PCC circuits is associated with general cognitive function. Such findings may provide further information about the imaging biomarkers for early identification and prognosis of familial Alzheimer's disease, and pave the way for early diagnosis, gene- or circuit-targeted treatment, and even prevention.