Plakophilin 1 in carcinogenesis.

Plakophilin 1 (PKP1) belongs to the desmosome family as an anchoring junction protein in cellular junctions. It localizes at the interface of the cell membrane and cytoplasm. Although PKP1 is a non-transmembrane protein, it may become associated with the cell membrane via transmembrane proteins such as desmocollins and desmogleins. Homozygous deletion of PKP1 results in ectodermal dysplasia-skin fragility syndrome (EDSF) and complete knockout of PKP1 in mice produces comparable symptoms to EDSF in humans, although mice do not survive more than 24 h. PKP1 is not limited to expression in desmosomal structures, but is rather widely expressed in cytoplasm and nucleus, where it assumes important cellular functions. This review will summarize distinct roles of PKP1 in the cell membrane, cytoplasm, and nucleus with an overview of relevant studies on its function in diverse types of cancer.

Crystal structures of a new class of pyrimidine/purine nucleoside phosphorylase revealed a Cupin fold.

Nucleotides metabolism is a fundamental process in all organisms. Two families of nucleoside phosphorylases (NP) that catalyze the phosphorolytic cleavage of the glycosidic bond in nucleosides have been found, including the trimeric or hexameric NP-I and dimeric NP-II family enzymes. Recent studies revealed another class of NP protein in Escherichia coli named Pyrimidine/purine nucleoside phosphorylase (ppnP), which can catalyze the phosphorolysis of diverse nucleosides and yield d-ribose 1-phosphate and the respective free bases. Here, we solved the crystal structures of ppnP from E. coli and the other three species. Our studies revealed that the structure of ppnP belongs to the RlmC-like Cupin fold and showed as a rigid dimeric conformation. Detail analysis revealed a potential nucleoside binding pocket full of hydrophobic residues, and the residues involved in the dimer and pocket formation are all well conserved in bacteria. Since the Cupin fold is a large superfamily in the biosynthesis of natural products, our studies provide the structural basis for understanding, and the directed evolution of NP proteins.

Lysophosphatidylglucoside is a GPR55 -mediated chemotactic molecule for human monocytes and macrophages.

Neutrophils undergo spontaneous apoptosis within 24-48 h after leaving bone marrow. Apoptotic neutrophils are subsequently phagocytosed and cleared by macrophages, thereby maintaining neutrophil homeostasis. Previous studies have demonstrated involvement of lysophosphatidylglucoside (lysoPtdGlc), a degradation product of PtdGlc, in modality-specific repulsive guidance of spinal sensory axons, via its specific receptor GPR55. In the present study, using human monocytic cell line THP-1 as a model, we demonstrated that lysoPtdGlc induces monocyte/macrophage migration with typical bell-haped curve and a peak at concentration 10-9 M. Lysophosphatidylinositol (lysoPtdIns), a known GPR55 ligand, induced migration at higher concentration (10-7 M). LysoPtdGlc-treated cells had a polarized shape, whereas lysoPtdIns-treated cells had a spherical shape. In EZ-TAXIScan (chemotaxis) assay, lysoPtdGlc induced chemotactic migration activity of THP-1 cells, while lysoPtdIns induced random migration activity. GPR55 antagonist ML193 inhibited lysoPtdGlc-induced THP-1 cell migration, whereas lysoPtdIns-induced migration was inhibited by CB2-receptor inverse agonist. SiRNA experiments showed that GPR55 mediated lysoPtdGlc-induced migration, while lysoPtdIns-induced migration was mediated by CB2 receptor. Our findings, taken together, suggest that lysoPtdGlc functions as a chemotactic molecule for human monocytes/macrophages via GPR55 receptor, while lysoPtdIns induces random migration activity via CB2 receptor.

Immunity and coagulation and fibrinolytic processes may reduce the risk of severe illness in pregnant women with coronavirus disease 2019.

BACKGROUND: There are specific physiological features regarding the immunity and coagulation among pregnant women, which may play important roles in the development of coronavirus disease 2019. OBJECTIVE: This study aimed to determine the key factors associated with the deterioration of patients with coronavirus disease 2019 and the differentiating clinical characteristics of pregnant women with coronavirus disease 2019 to interfere with the progression of coronavirus disease 2019. STUDY DESIGN: A retrospective study of 539 Chinese Han adult patients with coronavirus disease 2019 was conducted, of which 36 cases were pregnant women. In addition, 36 pregnant women without coronavirus disease 2019 were recruited as the control. The characteristics of severe and critical illnesses, which were differentiated from mild and moderate illnesses in patients with coronavirus disease 2019, were analyzed using a machine learning algorithm. In addition, major differences between pregnant women with coronavirus disease 2019 and age-matched nonpregnant women with severe or critical coronavirus disease 2019, paired with pregnant women without coronavirus disease 2019, were explored to identify specific physiological features of pregnant women with coronavirus disease 2019. RESULTS: For the total patient population, the lymphocyte, CD3+, CD4+, CD8+, CD19+, and CD16+CD56+ cell counts were significantly lower, and white blood cell count, neutrophil count, and neutrophil-to-lymphocyte ratio were higher in those with severe or critical illness than those with mild or moderate illness (P<.001). The plasma levels of interleukin-6, interleukin-10, and interleukin-6-to-interleukin-10 ratio were significantly increased in patients with critical illness compared with patients with mild, moderate, and severe illnesses (P<.001). The above immunologic coclusters achieved an area under the receiver operating characteristic curve of 0.801 (95% confidence interval, 0.764-0.838), and its combined model with the coagulation and fibrinolysis indices (prothrombin time, D-dimer) achieved an area under the receiver operating characteristic curve of 0.815 (95% confidence interval, 0.779-0.851) using the random forest regression model to predict severe or critical illness. For pregnant women with coronavirus disease 2019, none had preexisting diseases. Compared with nonpregnant women with mild or moderate coronavirus disease 2019, pregnant women with coronavirus disease 2019 displayed increased white blood cell count, neutrophil count, neutrophil-to-lymphocyte ratio, and levels of D-dimer and fibrinogen, along with decreased lymphocyte and interleukin-4 levels (P<.05). Although they presented similar changes of immunologic markers of lymphocyte; white blood cell count; neutrophil-to-lymphocyte ratio; CD3+, CD4+, CD8+, and CD16+CD56+ cell counts; and interleukin-6-to-interleukin-10 ratio, compared with nonpregnant women with severe or critical coronavirus disease 2019, none of the pregnant women with coronavirus disease 2019 deteriorated into severe or critical illness. There was no significant difference in white blood cell count, lymphocyte count, neutrophil count, neutrophil-to-lymphocyte ratio, immunologic markers, or coagulation and fibrinolysis markers between pregnant women with coronavirus disease 2019 and pregnant women without coronavirus disease 2019. As for the discrepancy of pathophysiological features between pregnant women with coronavirus disease 2019 and nonpregnant women with severe or critical coronavirus disease 2019, the immunologic markers achieved an area under the receiver operating characteristic curve of 0.875 (95% confidence interval, 0.773-0.977), and its combined model with coagulation and fibrinolysis indices achieved an area under the receiver operating characteristic curve of 0.931 (95% confidence interval, 0.850-1.000). CONCLUSION: Immune dysregulation was identified as a crucial feature of patients with coronavirus disease 2019, which developed severe or critical illness, and pregnant women with coronavirus disease 2019 presented with similar immune responses but rarer incidences of severe or critical illness. Immune dysregulation is related to the risks of deterioration into severe or critical illness. The specific coagulation and fibrinolysis systems of pregnancy may reduce the risk of pregnant women with coronavirus disease 2019 without preexisting disease from developing severe illness.

Downregulation of miR-33 Has Protective Effect Against Aß25₋35-Induced Injury in SH-SH-SY5Y Cells.

BACKGROUND Alzheimer disease (AD) is a significant health issue for the elderly, and there are at present no clinically effective anti-AD agents. Prevention of Aß-induced neurotoxicity is proposed as a possible modality for treatment of AD. miR-33 has been proven to promote Aß secretion and impair Aß clearance in neural cells. The present study assessed whether miR-33 is involved in AD pathology. MATERIAL AND METHODS miR-33 level was detected by qRT-PCR. The Akt/mTOR pathway was analyzed by Western blot analysis. Neuron inflammation and oxidative stress were measured using commercial detection kits. Flow cytometry and Western blot assay were conducted to assess cell apoptosis, and Western blot assay was used to assess synaptic protein levels. RESULTS miR-33 expression level was markedly upregulated in SH-SY5Y cells treated with Aß25₋35. miR-33 knockdown suppressed inflammation, oxidative stress, and cell apoptosis. In addition, miR-33 knockdown improved synaptic plasticity, and the protective effect of miR-33 knockdown was discovered through suppressing activation of the Akt/mTOR signaling pathway. CONCLUSIONS Taken together, these findings suggest that miR-33 knockdown protects against Aß25₋35-induced inflammation, oxidative stress, apoptosis, and synaptic damage by suppressing activation of the Akt/mTOR pathway.

A Validation Study of the Chinese Version of the Mini-Addenbrooke's Cognitive Examination for Screening Mild Cognitive Impairment and Mild Dementia.

BACKGROUND/AIMS: There are limited cognitive screening tests for the Chinese-speaking population. This study aimed to validate the Chinese version of the Mini-Addenbrooke's Cognitive Examination (M-ACE) for detecting mild cognitive impairment (MCI) and mild dementia. Its diagnostic accuracy was compared with that of Mini-Mental State Examination (MMSE). The study also evaluated the influential factors of M-ACE scores and its convergent validity against Clinical Dementia Rating Scale (CDR) and MMSE. METHOD: One hundred sixty-nine participants were classified into 3 groups: mild dementia, MCI, and healthy control. Mini-Mental State Examination and M-ACE were administered by researchers who were blinded to the clinical grouping. Receiver operating characteristic curves were graphed to test the diagnostic accuracy. RESULTS: Mini-Addenbrooke's Cognitive Examination scores had good convergent validity against CDR and MMSE. Years of education ( r = 0.4, P < .001) yielded significant impacts on M-ACE scores. The optimal cutoff score of M-ACE to detect MCI was 25/26 (sensitivity = 0.88; specificity = 0.72) with an area under curve (AUC) significantly higher than MMSE (0.86 vs 0.72). The optimal cutoff score of M-ACE to screen mild dementia (21/22) yielded satisfactory sensitivity (0.96) and specificity (0.87) with a comparable AUC to MMSE (0.96 vs 0.94). CONCLUSIONS: Mini-Addenbrooke's Cognitive Examination was a brief and reliable tool to detect MCI and mild dementia in the Chinese-speaking population significantly superior to MMSE when detecting MCI.

Effect of Propofol on the Production of Inflammatory Cytokines by Human Polarized Macrophages.

Macrophages are key immune system cells involved in inflammatory processes. Classically activated (M1) macrophages are characterized by strong antimicrobicidal properties, whereas alternatively activated (M2) macrophages are involved in wound healing. Severe inflammation can induce postoperative complications during the perioperative period. Invasive surgical procedures induce polarization to M1 macrophages and associated complications. As perioperative management, it is an important strategy to regulate polarization and functions of macrophages during inflammatory processes. Although propofol has been found to exhibit anti-inflammatory activities in monocytes and macrophages, it is unclear whether propofol regulates the functions of M1 and M2 macrophages during inflammatory processes. This study therefore investigated the effects of propofol on human macrophage polarization. During M1 polarization, propofol suppressed the production of IL-6 and IL-1ß but did not affect TNF-α production. In contrast, propofol did not affect the gene expression of M2 markers, such as IL-10, TGF-ß, and CD206, during M2 polarization. Propofol was similar to the GABAA agonist muscimol in inducing nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) and inhibiting IL-6 and IL-1ß, but not TNF-α, production. Knockdown of Nrf2 using siRNA significantly reduced the effect of propofol on IL-6 and IL-1ß production. These results suggest that propofol prevents inflammatory responses during polarization of human M1 macrophages by suppressing the expression of IL-6 and IL-1ß through the GABAA receptor and the Nrf2-mediated signal transduction pathway.

Determining High-Intensity Sweeteners in White Spirits Using an Ultrahigh Performance Liquid Chromatograph with a Photo-Diode Array Detector and Charged Aerosol Detector.

In China, white spirit is not only an alcoholic drink but also a cultural symbol. A novel and accurate method for simultaneously determining nine sweeteners (most authorized for use in China) in white spirits by ultrahigh performance liquid chromatography (UHPLC) with a photo-diode array detector (PDA) and charged aerosol detector (CAD) was developed. The sweeteners were acesulfame, alitame, aspartame, dulcin, neotame, neohesperidine dihydrochalcone, saccharin, sodium cyclamate, and sucralose. The sweeteners were separated within 16 min using a BEH C18 column and linear gradient-elution program. The optimized method allowed low concentrations (micrograms per gram) of sweeteners to be simultaneously detected. The CAD gave good linearities (correlation coefficients > 0.9936) for all analytes at concentrations of 0.5 to 50.0 µg/g. The limits of detection were 0.16 to 0.77 µg/g. Acesulfame, dulcin, neohesperidine dihydrochalcone, and saccharin were determined using the PDA detector, which gave correlation coefficients > 0.9994 and limits of detection of 0.16 to 0.22 µg/g. The recoveries were 95.1% to 104.9% and the relative standard deviations were 1.6% to 3.8%. The UHPLC-PDA-CAD method is more convenient and cheaper than LC-MS/MS methods. The method was successfully used in a major project called "Special Action against Counterfeit and Shoddy white spirits" and to monitor risks posed by white spirits in China.

Inhibitory effects of pine nodule extract and its component, SJ-2, on acetylcholine-induced catecholamine secretion and synthesis in bovine adrenal medullary cells.

Extract of pine nodules (matsufushi) formed by bark proliferation on the surface of trees of Pinus tabulaeformis or Pinus massoniana has been used as an analgesic for joint pain, rheumatism, neuralgia, dysmenorrhea and other complaints in Chinese traditional medicine. Here we report the effects of matsufushi extract and its components on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. We found that matsufushi extract (0.0003-0.005%) and its component, SJ-2 (5-hydroxy-3-methoxy-trans-stilbene) (0.3-100 µM), but not the other three, concentration-dependently inhibited catecholamine secretion induced by acetylcholine, a physiological secretagogue. Matsufushi extract (0.0003-0.005%) and SJ-2 (0.3-100 µM) also inhibited 45Ca2+ influx induced by acetylcholine in a concentration-dependent manner, similar to its effect on catecholamine secretion. They also suppressed 14C-catecholamine synthesis and tyrosine hydroxylase activity induced by acetylcholine. In Xenopus oocytes expressing α3ß4 nicotinic acetylcholine receptors, matsufushi extract (0.00003-0.001%) and SJ-2 (1-100 µM) directly inhibited the current evoked by acetylcholine. The present findings suggest that SJ-2, as well as matsufushi extract, inhibits acetylcholine-induced catecholamine secretion and synthesis by suppression of nicotinic acetylcholine receptor-ion channels in bovine adrenal medullary cells.

Soft-Template Synthesis of Mesoporous Anatase TiO2 Nanospheres and Its Enhanced Photoactivity.

Highly crystalline mesoporous anatase TiO2 nanospheres with high surface area (higher than P25 and anatase TiO2) are prepared by a soft-template method. Despite the high specific surface area, these samples have three times lower equilibrium adsorption (<2%) than Degussa P25. The rate constant of the mesoporous anatase TiO2 (0.024 min-1) reported here is 364% higher than that of P25 (0.0066 min-1), for the same catalytic loading. The results of oxidation-extraction photometry using several reactive oxygen species (ROS) scavengers indicated that mesoporous anatase TiO2 generates more ROS than P25 under UV-light irradiation. This significant improvement in the photocatalytic performance of mesoporous spherical TiO2 arises from the following synergistic effects in the reported sample: (i) high surface area; (ii) improved crystallinity; (iii) narrow pore wall thicknesses (ensuring the rapid migration of photogenerated carriers to the surface of the material); and (iv) greater ROS generation under UV-light.

Environmental regulation effect on health poverty in China.

How does government spending on environmental protection benefit people's health? The current paper analyzed 2010 and 2018 data from the China Family Panel Studies (CFPS) database to measure the impact of province-level environmental regulations on the health of local population. The study also applied the Alkire Foster method to develop the multidimensional health poverty (MHP) score, a new index intended to measure the health status of individuals in a holistic manner. Our results indicated that more fiscal spending on environmental regulation could improve health of the local population, especially among low-income population living in the rural areas. Further, the size of health benefit differs by the type of environmental regulation. More specifically, regulations focusing on preventing environmental pollution can achieve more sizable health benefits than remedial ones. Finally, fine inhalable particle (PM2.5) has the largest mediating effect on the relationship between environmental regulation and public health. These results provide several policy implications, which highlight the importance of: scaling up fiscal environmental expenditure and optimizing the structure of environmental expenditure with more emphasis on rural areas where more low-income population are located; shifting from ex-post accountability to ex-ante prevention; and strengthening regional cooperation in environmental protection among local governments, and establishing a cross-regional coordination mechanism.

Brucine D restrains colorectal cancer tumorigenesis and autophagy by downregulating circ_0068464.

Bruceine D (BD) from Brucea javanica (L) exerts an antitumor effect in several human cancers. At present, it has not been reported whether BD inhibits the malignancy of colorectal cancer (CRC) cells. Therefore, investigating the role and regulatory mechanisms of BD in CRC is the main thrust of this study. Effect of BD on CRC cell viability, proliferation, apoptosis, invasion, and autophagy was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide, 5-ethynyl-2'-deoxyuridine, flow cytometry, transwell invasion, and western blotting assays. Expression changes of has_circ_0068464 (circ_0068464) were detected using real time quantitative polymerase chain reaction. The molecular mechanisms related to circ_0068464 were predicted through online prediction websites Starbase 2.0, circinteractome, and CircBank and validated using dual-luciferase reporter and RNA pull-down assays. The tumorigenic ability of BD and circ_0068464 on CRC was confirmed by xenograft experiments. The results showed that BD lessened CRC cell proliferation, invasion, autophagy, and prompted cell apoptosis. Circ_0068464 was overexpressed in CRC samples and cells. BD led to a significant reduction in circ_0068464 levels in cells of this carcinoma, but circ_0068464 overexpression partially rescued these effects urged by BD. Also, the combination of BD and circ_0068464 silencing decreased xenograft tumor growth compared to BD alone. Importantly, circ_0068464 could regulate ATG5 expression by functioning as a miR-520h molecular sponge. In conclusion, BD might suppress CRC growth by inhibiting the circ_0068464/miR-520h/ATG5 axis, providing a new perspective for the molecular pathogenesis of CRC and preliminarily indicating that BD may be a promising drug for CRC treatment.

Down-regulation of microRNA-23a promotes pancreatic ductal adenocarcinoma initiation and progression by up-regulation of FOXM1 expression.

Transcriptional factor Forkhead box M1 (FOXM1) plays an important role in pancreatic ductal adenocarcinoma (PDAC) development and progression. The molecular mechanisms underlying its dysregulation remain unclear. We identified and functionally validated the microRNAs (miRNAs) that critically regulate FOXM1 expression in PDAC. The expression levels of miRNA-23a (miR-23a-3p and -5p) were altered in PDAC cell lines and their effects on FOXM1 signaling and cell proliferation and migration and tumorigenesis were examined in vitro and in vivo using mouse PDAC models. Compared with non-tumor pancreatic tissues, PDAC tissues and cell lines exhibited significantly reduced levels of miR-23a expression. Reduced miR-23a expression and concomitant increase in FOXM1 expression were also observed in acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia, the major premalignant lesions of PDAC. Transgenic expression of miR-23a reduced the expression of FOXM1 and suppressed cell proliferation and migration in PDAC cells, whereas the inhibitors of miR-23a did the opposite. Loss or reduced levels of miR-23a increased the levels of FOXM1 expression, while increased expression of FOXM1 down-regulated miR-23a expression, suggesting that miR-23a and FOXM1 were mutual negative regulators of their expression in PDAC cells. Therefore, the miR-23a/FOXM1 signaling axis is important in PDAC initiation and progression and could serve as an interventional or therapeutic target for patients with early or late stages of PDAC.

Lanthanum hydroxide protects kidney through gut microbiota in a rat model of chronic kidney disease.

The progression of chronic kidney diseases (CKD) is complex, influenced by a myriad of factors including gut microbiota. While emerging evidence suggests that gut microbiota can have beneficial effects in managing CKD, it is also recognized that dysbiosis may contribute to the progression of CKD and associated uremic complications. Our previous research has demonstrated the efficacy of lanthanum hydroxide in delaying kidney failure and preserving renal function. However, the role of lanthanum hydroxide in modulating gut microbiota in this context remains unclear. In our study, we induced CKD in rats using adenine, leading to gut microbial dysbiosis, kidney pathology, and disturbances in amino acid metabolism. In this adenine-induced CKD model with hyperphosphatemia, treatment with lanthanum hydroxide improved renal function. This improvement was associated with the restoration of gut microbial balance and an increase in urine ammonium metabolism. These results suggest that the therapeutic potential of lanthanum hydroxide in CKD may be partly due to its ability to reshape gut microbiota composition. This study underscores the significance of lanthanum hydroxide in kidney protection, attributing its benefits to the modulation of gut microbiota in a rat model of CKD.

Senescence program and its reprogramming in pancreatic premalignancy.

Tumor is a representative of cell immortalization, while senescence irreversibly arrests cell proliferation. Although tumorigenesis and senescence seem contrary to each other, they have similar mechanisms in many aspects. Pancreatic ductal adenocarcinoma (PDA) is highly lethal disease, which occurs and progresses through a multi-step process. Senescence is prevalent in pancreatic premalignancy, as manifested by decreased cell proliferation and increased clearance of pre-malignant cells by immune system. However, the senescent microenvironment cooperates with multiple factors and significantly contributes to tumorigenesis. Evidently, PDA progression requires to evade the effects of cellular senescence. This review will focus on dual roles that senescence plays in PDA development and progression, the signaling effectors that critically regulate senescence in PDA, the identification and reactivation of molecular targets that control senescence program for the treatment of PDA.

Tibial nerve electrical stimulation for fecal incontinence: a systematic review and meta-analysis.

Tibial nerve stimulation (TNS) therapy is widely used to treat fecal incontinence (FI), but still, some controversy exists. This study aimed to determine whether TNS could improve FI from different evaluation angles. A systematic review and meta-analysis were conducted to provide indirect evidence of TNS treatment for FI. We searched for the original studies in PubMed, Embase, Web of Science, Ebsco Medline, Ovid Medline, and Cochrane Central Register of Controlled Trials published before November 31, 2021. The standardized mean difference was the efficacy analysis statistic, and the effect was expressed by the 95% confidence interval (CI). For the case series, we calculated the mean difference of the number of patients evaluated at baseline and last follow-up. Four randomized controlled trials (RCTs, four hundred and sixty participants) and eighteen case series (eight hundred and thirty-eight participants) were included in the study. The results of the RCTs showed that the number of weekly episodes of FI significantly reduced in the TNS group compared with the sham stimulation group. The results of the case series showed that TNS reduced the number of patients with FI per week. The Cleveland Clinic Florida FI Score significantly reduced. The post-treatment results of maximum squeeze pressure and maximum resting pressure were significantly different from baseline. This study showed that TNS to some extent reduced the number of patients with FI, reduced clinical symptoms, and improved anal physiological function. Despite the low quality of overall evidence, TNS still shows some potential as a safe treatment for FI.

Sennoside A restrains TRAF6 level to modulate ferroptosis, inflammation and cognitive impairment in aging mice with Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disease and a momentous cause of dementia in the elderly. Sennoside A (SA) is an anthraquinone compound and possesses decisive protective functions in various human diseases. The purpose of this research was to elucidate the protective effect of SA against AD and investigate its mechanism. METHODS: Male APPswe/PS1dE9 (APP/PS1) transgenic mice with a C57BL/6J background were chosen as AD model. Age-matched nontransgenic littermates (C57BL/6 mice) were negative controls. SA's functions in AD in vivo were estimated by cognitive function analysis, Western blot, hematoxylin-eosin staining, TUNEL staining, Nissl staining, detection of Fe2+ levels, glutathione and malondialdehyde contents, and quantitative real-time PCR. Also, SA's functions in AD in LPS-induced BV2 cells were examined using Cell Counting Kit-8 assay, flow cytometry, quantitative real-time PCR, Western blot, enzyme-linked immunosorbent assay, and analysis of reactive oxygen species levels. Meanwhile, SA's mechanisms in AD were assessed by several molecular experiments. RESULTS: Functionally, SA mitigated cognitive function, hippocampal neuronal apoptosis, ferroptosis, oxidative stress, and inflammation in AD mice. Furthermore, SA reduced BV2 cell apoptosis, ferroptosis, oxidative stress, and inflammation induced by LPS. Rescue assay revealed that SA abolished the high expressions of TRAF6 and p-P65 (NF-κB pathway-related proteins) induced by AD, and this impact was reversed after TRAF6 overexpression. Conversely, this impact was further enhanced after TRAF6 knockdown. CONCLUSIONS: SA relieved ferroptosis, inflammation and cognitive impairment in aging mice with AD through decreasing TRAF6.

S1PR2 Regulates Autophagy Through the AKT/mTOR Pathway to Promote Pathological Damage in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a fatal and debilitating neurodegenerative disease. Sphingosine-1-phosphate receptor 2 (S1PR2), one of the receptors of S1P, is a key regulatory factor for various diseases. OBJECTIVE: This study aimed to explore the role and possible mechanism of S1PR2 in AD. METHODS: S1PR2 expression in the AD mice was detected, and after intervening S1PR2 expression with sh-S1PR2 in AD mice, the behavioral changes, pathological lesions of the hippocampus, autophagy level, and AKT/mTOR pathway activation were analyzed. Furthermore, SH-SY5Y cells were induced by Aß25-35 to construct an AD cell model, and the effects of sh-S1PR2 on proliferation, apoptosis, autophagy, and AKT/mTOR pathway of AD cells were investigated. In addition, the effects of pathway inhibitor rapamycin on model cells were further analyzed. RESULTS: The expression of S1PR2 was significantly increased in AD mice, the sh-S1PR2 significantly improved behavioral dysfunction, alleviated pathological injury of the hippocampus, increased the number of neurons, and inhibited Aß production and p-tau expression, showing a positive effect on the AD pathology. In addition, silencing of S1PR2 expression significantly promoted the autophagy level and inhibited the activation of the AKT/mTOR pathway in AD model mice. In vitro experiments further confirmed that sh-S1PR2 promoted cell proliferation, inhibited apoptosis, relieved cytopathology, promoted autophagy, and inhibited the activation of the AKT/mTOR pathway in the cell model. The use of rapamycin further confirmed the role of AKT/mTOR pathway-mediated autophagy in the regulation of AD by S1PR2. CONCLUSION: S1PR2 promoted AD pathogenesis by inhibiting autophagy through the activation of AKT/mTOR pathway.

Analysis of gene expression profiles in Alzheimer's disease patients with different lifespan: A bioinformatics study focusing on the disease heterogeneity.

Objective: Alzheimer's disease (AD) as the most frequent neurodegenerative disease is featured by gradual decline of cognition and social function in the elderly. However, there have been few studies focusing on AD heterogeneity which exists both genetically and clinically, leading to the difficulties of AD researches. As one major kind of clinical heterogeneity, the lifespan of AD patients varies significantly. Aiming to investigate the potential driving factors, the current research identified the differentially expressed genes (DEGs) between longer-lived AD patients and shorter-lived ones via bioinformatics analyses. Methods: Qualified datasets of gene expression profiles were identified in National Center of Biotechnology Information Gene Expression Omnibus (NCBI-GEO). The data of the temporal lobes of patients above 60 years old were used. Two groups were divided according to the lifespan: the group ≥85 years old and the group <85 years old. Then GEO2R online software and R package of Robust Rank Aggregation (RRA) were used to screen DEGs. Bioinformatic tools were adopted to identify possible pathways and construct protein-protein interaction network. Result: Sixty-seven AD cases from four qualified datasets (GSE28146, GSE5281, GSE48350, and GSE36980) were included in this study. 740 DEGs were identified with 361 upregulated and 379 downregulated when compared longer-lived AD patients with shorter-lived ones. These DEGs were primarily involved in the pathways directly or indirectly associated with the regulation of neuroinflammation and cancer pathogenesis, as shown by pathway enrichment analysis. Among the DEGs, the top 15 hub genes were identified from the PPI network. Notably, the same bioinformatic procedures were conducted in 62 non-AD individuals (serving as controls of AD patients in the four included studies) with distinctly different findings from AD patients, indicating different regulatory mechanisms of lifespan between non-AD controls and AD, reconfirming the necessity of the present study. Conclusion: These results shed some lights on lifespan-related regulatory mechanisms in AD patients, which also indicated that AD heterogeneity should be more taken into account in future investigations.

Using proteomics and metabolomics to identify therapeutic targets for senescence mediated cancer: genetic complementarity method.

Background: Senescence have emerged as potential factors of lung cancer risk based on findings from many studies. However, the underlying pathogenesis of lung cancer caused by senescence is not clear. In this study, we try to explain the potential pathogenesis between senescence and lung cancer through proteomics and metabonomics. And try to find new potential therapeutic targets in lung cancer patients through network mendelian randomization (MR). Methods: The genome-wide association data of this study was mainly obtained from a meta-analysis and the Transdisciplinary Research in Cancer of the Lung Consortium (TRICL), respectively.And in this study, we mainly used genetic complementarity methods to explore the susceptibility of aging to lung cancer. Additionally, a mediation analysis was performed to explore the potential mediating role of proteomics and metabonomics, using a network MR design. Results: GNOVA analysis revealed a shared genetic structure between HannumAge and lung cancer with a significant genetic correlation estimated at 0.141 and 0.135, respectively. MR analysis showed a relationship between HannumAge and lung cancer, regardless of smoking status. Furthermore, genetically predicted HannumAge was consistently associated with the proteins C-type lectin domain family 4 member D (CLEC4D) and Retinoic acid receptor responder protein 1 (RARR-1), indicating their potential role as mediators in the causal pathway. Conclusion: HannumAge acceleration may increase the risk of lung cancer, some of which may be mediated by CLEC4D and RARR-1, suggestion that CLEC4D and RARR-1 may serve as potential drug targets for the treatment of lung cancer.