Search

Acetylcholine regulates various cognitive functions through broad cholinergic innervation. However, specific cholinergic subpopulations, circuits and molecular mechanisms underlying recognition memory remain largely unknown. Here we show that Ngfr + cholinergic neurons in the substantia innominate (SI)/nucleus basalis of Meynert (nBM)-medial prefrontal cortex (mPFC) circuit selectively underlies recency judgements. Loss of nerve growth factor receptor (Ngfr -/- mice) reduced the excitability of cholinergic neurons in the SI/nBM-mPFC circuit but not in the medial septum (MS)-hippocampus pathway, and impaired temporal order memory but not novel object and object location recognition. Expression of Ngfr in Ngfr -/- SI/nBM restored defected temporal order memory. Fiber photometry revealed that acetylcholine release in mPFC not only predicted object encounters but also mediated recency judgments of objects, and such acetylcholine release was absent in Ngfr -/- mPFC. Chemogenetic and optogenetic inhibition of SI/nBM projection to mPFC in ChAT-Cre mice diminished mPFC acetylcholine release and deteriorated temporal order recognition. Impaired cholinergic activity led to a depolarizing shift of GABAergic inputs to mPFC pyramidal neurons, due to disturbed KCC2-mediated chloride gradients. Finally, potentiation of acetylcholine signaling upregulated KCC2 levels, restored GABAergic driving force and rescued temporal order recognition deficits in Ngfr -/- mice. Thus, NGFR-dependent SI/nBM-mPFC cholinergic circuit underlies temporal order recognition memory., (© 2024. The Author(s).)

Abstract: Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-β in neurons, which is a key step in senile plaque formation. Therefore, restoring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease. Microtubule acetylation/deacetylation plays a central role in lysosomal acidification. Here, we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease. Furthermore, we found that treatment with valproic acid markedly enhanced autophagy, promoted clearance of amyloid-β aggregates, and ameliorated cognitive deficits in a mouse model of Alzheimer's disease. Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease, in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification., (Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.)

Background: A gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with type 2 diabetes mellitus (T2DM). Few previous prospective studies have addressed associations between the changes in TMAO and T2DM incidence., Methods: Data were derived from a longitudinal cohort conducted from 2019 to 2021 in rural areas of Fuxin County, Liaoning Province, China, and 1515 diabetes-free participants aged above 35 years were included. The concentrations of serum TMAO and its precursors were measured at two time points, namely in 2019 and 2021. TMAO and TMAO changes (ΔTMAO) were separately tested in a logistic regression model. For further examination, the odds ratios (ORs) for T2DM were calculated according to a combination of TMAO levels and ΔTMAO levels., Results: During a median follow-up of 1.85 years, 81 incident cases of T2DM (5.35%) were identified. Baseline TMAO levels exhibited a nonlinear relationship, first decreasing and then increasing, and only at the highest quartile was it associated with the risk of T2DM. The OR for T2DM in the highest quartile of serum TMAO was 3.35 (95%CI: 1.55-7.26, p  = 0.002), compared with the lowest quartile. As for its precursors, only choline level was associated with T2DM risk and the OR for T2DM in the Q3 and Q4 of serum choline was 3.37 (95%CI: 1.41-8.05, p = 0.006) and 4.72 (95%CI: 1.47-15.13, p  = 0.009), respectively. When considering both baseline TMAO levels and ΔTMAO over time, participants with sustained high TMAO levels demonstrated a significantly increased risk of T2DM, with a multivariable-adjusted OR of 8.68 (95%CI: 1.97, 38.34)., Conclusion: Both initial serum TMAO levels and long-term serum TMAO changes were collectively and significantly associated with the occurrence of subsequent T2DM events. Interventions aimed at normalizing TMAO levels, such as adopting a healthy dietary pattern, may be particularly beneficial in T2DM prevention.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid‑β (Aβ) in the brain. The gut/brain axis may serve a role in AD pathogenesis. The present study investigated deposition of Aβ in the intestinal epithelium and its potential effects on intestinal barrier function in a transgenic mouse model of AD. To investigate alterations in the structure and functionality of the intestinal mucosal barrier in AD model mice, hematoxylin and eosin staining for Paneth cell count, Alcian blue‑periodic acid Schiff staining for goblet cells, immunohistochemistry and immunofluorescence for mucin (MUC)2 and wheat germ agglutin expression, transmission electron microscopy for mucosal ultrastructure, FITC‑labeled dextran assay for intestinal permeability, quantitative PCR for goblet cell precursor expression and western blot analysis for tight junction proteins, MUC2 and inflammatory cytokine detection were performed. The results showed that AD model mice exhibited excessive Aβ deposition in the intestinal epithelium, which was accompanied by increased intestinal permeability, inflammatory changes and decreased expression of tight junction proteins. These alterations in the intestinal barrier led to an increased proliferation of goblet and Paneth cells and increased mucus synthesis. Dysfunction of gut barrier occurs in AD and may contribute to its etiology. Future therapeutic strategies to reverse AD pathology may involve early manipulation of gut physiology and its microbiota.

Background: Circular RNAs (circRNAs) are known to play a crucial role in a variety of malignancies. However, the precise role of circRNAs in cervical squamous cell carcinoma (CSCC) remains largely unknown., Methods: The expression of circ0001955 was determined by real-time quantitative PCR and fluorescence in situ hybridization. To examine the effects of circ0001955 on CSCC metastasis and growth, functional experiments were conducted in vitro and in vivo. Mechanistically, nucleocytoplasmic separation, dual luciferase reporter assay, RNA antisense purification experiments, and rescue experiments were performed to confirm the interaction between circ0001955, miR-188-3p, and NCAPG2 in CSCC., Results: Here, we demonstrated that a circRNA derived from the CSNK1G1 gene (circ0001955) is significantly upregulated in CSCC. The overexpression of circ0001955 promotes tumor proliferation and metastasis, whereas the knockdown of circ0001955 exerts the opposite effects. Mechanistically, circ0001955 competitively binds miR-188-3p and prevents miR-188-3p from reducing the levels of NCAPG2, activating the AKT/mTOR signaling pathway to induce epithelial mesenchymal transformation. Notably, the application of an inhibitor of mTOR significantly antagonized circ0001955-mediated CSCC tumorigenesis., Conclusion: circ0001955 promotes CSCC tumorigenesis and metastasis via the miR-188-3p/NCAPG2 axis which would provide an opportunity to search new therapeutic targets for CSCC., (© 2023. The Author(s).)

Background: Periodontitis is one of the most common oral diseases and has been shown to be a risk factor for systemic diseases. Our aim was to investigate the relationship between periodontitis and cognitive impairment and to explore the role of the P38 MAPK signaling pathway in this process., Methods: We established a periodontitis model by ligating the first molars of SD rats with silk thread and injecting Porphyromonas gingivalis ( P. gingivalis ) or P. gingivalis plus the P38 MAPK inhibitor SB203580 at the same time for ten weeks. We assessed alveolar bone resorption and spatial learning and memory using microcomputed tomography and the Morris water maze test, respectively. We used transcriptome sequencing to explore the genetic differences between the groups. The gingival tissue, peripheral blood and hippocampal tissue were assessed for the cytokines TNF-α, IL-1β, IL-6, IL-8 and C reactive protein (CRP) with enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR). We observed the presence of P. gingivalis in the hippocampus of rats by paraffin-fluorescence in situ hybridization (FISH). We determined the activation of microglia by immunofluorescence. Finally, Western blot analysis was employed to determine the expression of amyloid precursor protein (APP), β-site APP-cleaving enzyme 1 (BACE1) and P38MAPK pathway activation., Results: We demonstrated that silk ligature-induced periodontitis plus injection of P. gingivalis into subgingival tissue could lead to memory and cognitive impairment. Transcriptome sequencing results suggested that there were neurodegenerative diseases in the P. gingivalis group, and the MWM test showed that periodontitis reduced the spatial learning and memory ability of mild cognitive impairment (MCI) model rats. We found high levels of inflammatory factors (TNF-α, IL-1β, IL-6, and IL-8) and CRP in the gingiva, peripheral blood and hippocampus, and the expression of APP and BACE1 was upregulated, as was the P38 MAPK pathway activation. Activated microglia and the presence of P. gingivalis were also found in the hippocampus. P38 MAPK inhibitors mitigated all of these changes., Conclusion: Our findings strongly suggest that topical application of P. gingivalis increases the inflammatory burden in the peripheral and central nervous systems (CNS) and that neuroinflammation induced by activation of P38 MAPK leads to impaired learning and memory in SD rats. It can also modulate APP processing. Therefore, P38 MAPK may serve as a linking pathway between periodontitis and cognitive impairment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jin, Ning, Liu, Zhao and Ye.)

The cellulose nanocrystals (CNC) has attracted widespread attention in reinforced materials. However, the application of CNC in electrospinning has been limited due to its self-polymerization. Herein, a cobweb-like nanofibrous membrane was fabricated by electrospinning the polyacrylonitrile (PAN) and sulfydryl-functionalized CNC (SC). The SC content could reach to 48 wt% after the thiolation modification. The membrane with ultrafine fibers and interlaced nets possessed outstanding porosity (91.7%) and underwater superoleophobicity. An ultrahigh permeation flux of 1244 L·m -2 ·h -1 with a separation efficiency of >99.9% was achieved driven by gravity. The mechanical properties also enhanced significantly with the increase of SC. When the addition amount of SC was 48 wt%, the maximum tensile stress was 2.9 MPa, which was 3.4 times than that of the PAN membrane. The antifouling performance and chemical stability endowed the SC(48)/PAN membrane with intriguing reusability, thus making it exhibit enormous potential in oil/water separation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Data on kidney cancer burden are valuable for health-related policy making., Objective: To report the results of the Global Burden of Disease 2017 study on global kidney cancer burden estimates grouped by gender, age, region, country or territory, and sociodemographic index (SDI) from 1990 to 2017., Design, Setting, and Participants: This study is based on the Global Burden of Disease database., Outcome Measurements and Statistical Analysis: We report here detailed estimates and temporal trends of the burden estimates of kidney cancer from 1990 to 2017, stratified by gender and age, in 195 countries and territories. We further evaluated the relationship between these estimates and the SDI, a composite indicator of income per person, years of education, and fertility as a measurement of the socioeconomic level of a country/region. The percentage change and estimated annual percentage change of incidence, mortality, and disability-adjusted life years (DALYs) were calculated to quantify temporal trends., Results and Limitations: Globally, age-standardized incidence rates, age-standardized death rates, and DALYs of kidney cancer in males exhibited an increase of 0.387%/yr, 0.345%/yr, and 0.046%/yr, respectively, from 1990 to 2017. This trend was mainly due to the increase in middle and low-middle SDI quintile countries. However, in females, decreasing trends of -0.324%/yr, -0.330%/yr, and -0.669%/yr, respectively, were observed. These trends were mainly due to the decrease in high, high-middle, and middle SDI quintile countries. Study limitations included differences in data collection practices, coding systems, and quality of data sources., Conclusions: The burden estimate pattern of kidney cancer trends varies widely between genders and throughout the world. Low-middle and middle SDI quintile countries face the highest burden estimates, especially for males. Efforts to increase health care investment are needed in these countries., Patient Summary: The global burden estimate of kidney cancer trends increased in males; however, it decreased in females., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Circular RNAs (circRNAs) are regulatory molecules that participate in the occurrence, development and progression of tumors. To obtain a complete blueprint of cervical carcinogenesis, we analyzed the temporal transcriptomic landscapes of mRNAs and circRNAs. Microarrays were performed to identify the circRNA and mRNA expression profiles of cervical squamous cell carcinoma (CSCC) and high-grade squamous intraepithelial lesion (HSIL) patients compared with normal controls (NC). Short time-series expression miner (STEM) was utilized to characterize the time-course expression patterns of circRNAs and mRNAs from NC to HSIL and CSCC. A total of 3 circRNA profiles and 3 mRNA profiles with continuous upregulated patterns were identified and selected for further analysis. Furthermore, functional annotation showed that the mRNAs were associated with DNA repair and cell division. The protein-protein interaction (PPI) network analysis revealed that the ten highest-degree genes were considered to be hub genes. Subsequently, a competing endogenous RNA (ceRNA) network analysis and real-time PCR validation indicated that hsa_circ_0001955/hsa-miR-6719-3p/CDK1, hsa_circ_0001955/hsa-miR-1277-5p/NEDD4L and hsa_circ_0003954/hsa-miR-15a-3p/SYCP2 were highly correlated with cervical carcinogenesis. Silencing of hsa_circ_0003954 inhibited SiHa cell proliferation and perturb the cell cycle in vitro . This study provides insight into the molecular events regulating cervical carcinogenesis, identifies functional circRNAs in CSCC, and improves the understanding of the pathogenesis and molecular biomarkers of CSCC and HSIL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Luo, Li, Zhao, Chang, Zhang, Zou, Gao and Wang.)

Osteoporosis (OP) is a debilitating skeletal abnormality involving bone remodeling and bone cell homeostasis characterized by decreased bone strength and high fracture risk. A novel therapeutic intervention for OP by manipulating cellular autophagy-apoptosis processes to promote skeletal homeostasis is presented. Protective effects of the naturally occurring plant extract Liquiritigenin (LG) were demonstrated in an ovariectomy (OVX)-OP mouse model and preosteoblast MC3T3-E1 cells. Micro-CT and histological staining assessments of skeletal phenotype were applied alongside detection of autophagy activity in osteocytes and MC3T3-E1 cells by transmission electron microscopy (TEM). The effects of LG on chloroquine (CQ)- and the apoptosis-inducing TS-treated osteogenic differentiations and status of lysosomes within MC3T3-E1 cells were analyzed by Neutral red, Alizarin red S and alkaline phosphatase (ALP) staining and Western blot assays. Treatment with LG prevented bone loss, increased osteogenic differentiation in vivo and in vitro , and inhibited osteoclast formation to some extent. TEM analyses revealed that LG can improve auto-lysosomal degradation within osteocytes from OVX mice and MC3T3-E1 cells. The abnormal status of lysosomes associated with CQ and TS treatments was notably alleviated by LG which also reduced levels of apoptosis-induced inhibition of osteogenic differentiation and averted abnormal osteogenic differentiation as a consequence of a blockage in autolysosome degradation. Overall, LG stimulates bone growth in OVX mice through increased osteogenic differentiation and regulation of autophagy-apoptosis mechanisms, presenting an auspicious natural therapy for OP., (© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Background: In the absence of practical and reliable predictors for whether the endocervical curettage (ECC) procedure should be performed, decisions regarding patient selection are usually based on the colposcopists' clinical judgment instead of evidence. We aimed to develop and validate a practical prediction model that uses available information to reliably estimate the need to perform ECC in patients suspected of having cervical lesions., Methods: In this retrospective study, 2088 patients who underwent colposcopy, colposcopically directed biopsy (CDB) and ECC procedures between September 2019 and September 2020 at the Second Hospital of Shanxi Medical University were included. The data were analyzed with univariate and multivariable logistic regression. Least absolute shrinkage and selection operator (LASSO) was used to select predictors for ECC positivity. The ECC prediction model was presented as a nomogram and evaluated in terms of discrimination and calibration. Furthermore, this model was validated internally with cross-validation and bootstrapping., Results: Significant trends were found for ECC positivity with increasing age (P = 0.001), menopause (P = 0.003), Human papillomavirus (HPV) status (P < 0.001), severity of ThinPrep Cytological Test (TCT) (P < 0.001), original squamous epithelium ectopia (P = 0.037) and colposcopy impression (P < 0.001) by multivariable logistic regression analysis. The ECC prediction model was developed based on the following predictors: age, menopause, symptom of contact bleeding, severity of TCT, HPV status, cervix visibility, original squamous epithelium ectopia, acetowhite changes and colposcopic impression. This model had satisfactory calibration and good discrimination, with an area under the receiver operator characteristic curve (AUC) of 0.869 (95% confidence interval 0.849 to 0.889)., Conclusions: A readily applicable clinical prediction model was constructed to reliably estimate the probability of ECC positivity in patients suspicious of having cervical lesions, which may help clinicians make decisions regarding the ECC procedure and possibly prevent adverse effects., (© 2021. The Author(s).)

The pathogenesis of Alzheimer's disease (AD) involves activation of many NLRP3 inflammatory bodies, which may be related to amyloid β peptide and aggregation of misfolded proteins. Autophagy is an important regulator of inflammatory bodies. However, autophagy shows dynamic changes in the development of AD, and its role in inflammation remains controversial. In this study, the key link between autophagic disorders and the NLRP3 inflammasome in AD was investigated. APP/PS1 double transgenic mice and C57 mice with Aβ 25-35 injected into the lateral ventricle were used as two animal models of AD. Immunofluorescence staining and Western blot analysis showed that NLRP3 inflammasome-related proteins and inflammatory cytokines, such as IL-1α, IL-1β, IL-6, IL-12, and TNF-α, were increased and microglia were activated in the brains of both AD animal models. Endogenous overexpression of the APPswe gene and exogenous addition of Aβ 25-35 increased the expression of NLRP3 inflammasome-related proteins, while exogenous Aβ 25-35 intervention more significantly activated inflammation. Furthermore, LC3 was increased in the AD animal and cell models, and the level of Lamp1 decreased. After overexpression of the primary regulator of lysosomal biogenesis, TFEB, the lysosome protein Lamp1 was increased, and LC3 and inflammatory protein expression were decreased. These results suggest that the NLRP3 inflammasome-mediated inflammatory response is activated in AD animal and cell models, which may be related to the decline in autolysosome function. Overexpression of the TFEB protein can reduce the inflammatory response by improving autolysosome function in AD model cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhou, Xiao, Zhao, Tan, Long, Yu and He.)

Alterations in glucose metabolism occur in the brain in the early stage of Alzheimer's disease (AD), and menopausal women have more severe metabolic dysfunction and are more prone to dementia than men. Although estrogen deficiency-induced changes in glucose metabolism have been previously studied in animal models, their molecular mechanisms in AD remain elusive. To investigate this issue, double transgenic (APP/PS1) female mice were subjected to bilateral ovariectomy at 3 months of age and were sacrificed 1 week, 1 month and 3 months after surgery to simulate early, middle and late postmenopause, respectively. Our analysis demonstrated that estrogen deficiency exacerbates learning and memory deficits in this mouse model of postmenopause. Estrogen deficiency impairs the function of mitochondria in glucose metabolism. It is possible that the occurrence of AD is associated with the aberrant mitochondrial ERβ-mediated IGF-1/IGF-1R/GSK-3β signaling pathway. In this study, we established a potential mechanism for the increased risk of AD in postmenopausal women and proposed a therapeutic target for AD due to postmenopause., (© 2022 Chongqing Medical University. Production and hosting by Elsevier B.V.)

Background: Currently, no study has focused on the postoperative erectile function in patients with benign prostatic hyperplasia (BPH) by comparing Hiraoka's transurethral detachment of prostate (TUDP) and transurethral resection of prostate (TURP)., Aim: To compare the effects of Hiraoka's TUDP and TURP on postoperative erectile function in patients with BPH after long-term follow-up., Methods: A total of 104 consecutive patients with BPH treated in our hospital between September 2018 and February 2019 were included in the study. All patients who met the inclusion criteria were randomly divided into the Hiraoka's TUDP (n = 52) and TURP (n = 52) groups. Patient baseline data were collected. The international index of erectile function (IIEF-5), minimal clinically important difference (MCID), and quality of life scale (QOLS) were used to evaluate erectile function and quality of life 3, 6, and 12 months after surgery. Primary study endpoints were IIEF-5 and MCID. Secondary study endpoints were QOLS and independent prognostic factors for MCID., Outcomes: Hiraoka's TUDP experienced greater improvement in postoperative IIEF5 scores than patients who underwent TURP., Results: Patients in the Hiraoka's TUDP group had significantly higher mean IIEF-5 scores than those in the TURP group 6 and 12 months after surgery (6 months: 18.9 vs 14.8, P < .001; 12 months: 18.1 vs 15.7, P < .001). The percentages of patients in the TUDP group who achieved an MCID were 88.5% and 80.8%, compared to 30.8% and 46.2% in the TURP group (P < .001 for both), 6 and 12 months after the operation, respectively. Patients in the TUDP group had lower QOLS scores than those in the TURP group after the surgery. The surgical method was an independent prognostic factor for MCID (odds ratio = 0.218)., Clinical Implications: Until now, no study has focused on the postoperative erectile function in patients with BPH by comparing Hiraoka's TUDP and TURP. Our study addressed this issue, which can add a new paradigm in the management to BPH., Strength & Limitations: The comparison between Hiraoka's TUDP and TURP using a statistically appropriate, adequately powered methodology is the strength of the study. The single center and less participants are the limitations of the study. We believe that multicenter and large-sample studies are needed to further verify these study conclusions., Conclusions: Among similar cohorts of patients with BPH who underwent TUDP and TURP, patients who underwent Hiraoka's TUDP experienced greater improvement in postoperative IIEF5 scores than patients who underwent TURP, while improvement in IPSS was similar among both groups. Pan C, Zhan Y, Zhao Y, et al. Comparison of Hiraoka's Transurethral Detachment Prostatectomy and Transurethral Resection of the Prostate Effects on Postoperative Erectile Function in Patients With Benign Prostatic Hyperplasia: A Prospective Randomized Controlled Study. J Sex Med 2020;17:2181-2190., (Copyright © 2020 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the effectiveness and safety of traditional Chinese medical therapy for cancer-related fatigue., Methods: We systematically searched eight electronic databases up to June 2017 for randomized clinical trials of traditional Chinese medical therapy for cancer-related fatigue. Two authors independently extracted data and assessed the risk bias of the included trials using the Cochrane Handbook. Data were analyzed by RevMan 5.2 software., Results: A total of 23 trials involving 1832 participants identified with cancer-related fatigue were included. Twenty trials reported a beneficial effect of traditional Chinese medical therapy on cancer-related fatigue. On pooling the data from Chinese herbal medicine therapy and acupuncture or moxibustion therapy, respectively, significant differences were found between experimental groups and control groups. Fatigue improvement rates showed significant differences between traditional Chinese medical therapy and control groups [odds ratio (OR), 7.62; 95% confidence interval (CI), 3.75-15.49; P < 0.000 01; and OR, 3.78; 95% CI, 2.29-6.23; P < 0.000 01). Fatigue change scores also showed significant differences between the two groups (mean difference, -0.91; 95% CI, -0.16 to -0.65; P < 0.000 01). Eleven trials demonstrated that traditional Chinese medical therapy improved the quality of life of cancer patients. No severe adverse effects occurred in traditional Chinese medical therapy groups., Conclusion: Meta-analysis showed that Chinese medical therapy seems to be effective and safe in the treatment of cancer-related fatigue.

Purpose: Radical cystectomy (RC) is the primary treatment strategy for patients with muscular invasive bladder cancer (MIBC). However, the prognosis is poor and tumor recurrence is not rare, in particular, urethral recurrence (UR) in male patients who underwent RC combined with urinary diversion. Here, we have developed and validated a model for predicting UR in these patients., Patients and Methods: The development cohort comprised 310 patients who underwent RC combined with urinary diversion at our center between 1 January 2007 and 31 December 2015. Clinicopathologic data of patients were comprehensively recorded. Multivariate Cox proportional hazard regression was used for building a predictive model with regression coefficients and backward stepwise selection applied by utilizing the likelihood ratio test with Akaike's information criterion as the stopping rule. An independent cohort consisting of 131 consecutive patients treated from 1 January 2016 to 31 December 2017 was used for validation. The performance of this predictive model was assessed with respect to discrimination, calibration, and clinical usefulness., Results: The predictors of this model included body mass index, history of transurethral resection of bladder tumor, tumor grade, tumor stage, and concomitant carcinoma in situ. In the validation cohort, the model showed good discrimination with a concordance index of 0.777 (95% CI, 0.618 to 0.937) and calibration. Decision curve analysis also demonstrated the clinical utility of the model., Conclusion: The predictive model facilitated postoperative individualized prediction of UR in male patients with MIBC after RC combined with urinary diversion and it may therefore serve to improve follow-up strategies., Competing Interests: The authors (Zeqi Liu, Xuanyu Zhang, Bin Wu, Yueyang Zhao, Song Bai) declare that they have no competing interests for this work. Song Bai certifies that all conflicts of interest, including specific financial interests, relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending) are none. There was no role in this study of funding source., (© 2020 Liu et al.)

Background: Surgical resection of pheochromocytoma may lead to high risk factors for intraoperative hemodynamic instability (IHD), which can be life-threatening. This study aimed to investigate the risk factors that could predict IHD during pheochromocytoma surgery by data mining., Method: Relief-F was used to select the most important features. The accuracies of seven data mining models (CART, C4.5, C5.0, and C5.0 boosted), random forest algorithm, Naive Bayes and logistic regression were compared, the cross-validation, hold-out, and bootstrap methods were used in the validation phase. The accuracy of these models was calculated independently by dividing the training and the test sets. Receiver-Operating Characteristic curves were used to obtain the area under curve (AUC)., Result: Random forest had the highest AUC and accuracy values of 0.8636 and 0.8509, respectively. Then, we improved the random forest algorithm according to the classification of imbalanced data. Improved random forest model had the highest specificity and precision among all algorithms, including relatively higher sensitivity (recall) and the highest f1-score integrating recall and precision. The important attributes were body mass index, mean age, 24 h urine vanillylmandelic acid/upper normal limit value, tumor size and enhanced computed tomography difference., Conclusions: The improved random forest algorithm may be useful in predicting IHD risk factors in pheochromocytoma surgery. Data mining technologies are being increasingly applied in clinical and medical decision-making, and provide continually expanding support for the diagnosis, treatment, and prevention of various diseases.

Autophagy has been reported to play a dual "double-edged sword" role in the occurrence and development of Alzheimer's disease (AD). To assess the relationship between AD and autophagy, the dynamic changes of autophagic flux in the brain of postmortem AD patients, animal models and cell models were studied. The results showed that autophagosomes (APs) accumulation and expression of lysosomal markers were decreased in the brains of AD patients. In the brain of APP/PS1 double transgenic mice, APs did not accumulate before the formation of SPs but accumulated along with the deposition of SPs, as well as the level of lysosomal markers cathepsin B and Lamp1 protein decreased significantly. In the brains of APP/PS1/LC3 triple - transgenic mice, the number of APs increased with age, but the number of ALs did not increase accordingly. The activation of autophagy is mainly due to the increase in Aβ rather than the overexpression of mutated APP gene. However, both the treatment with exogenous Aβ 25-35 and the mutation of the endogenous APP gene blocked the fusion of APs with lysosomes and decreased lysosomal functioning in AD model cells, which may be the main mechanism of autophagy dysregulation in AD.

Dihydroartemisinin (DHA) is an active metabolite of sesquiterpene trioxane lactone extracted from Artemisia annua, which is used to treat malaria worldwide. DHA can activate autophagy, which is the main mechanism to remove the damaged cell components and recover the harmful or useless substances from eukaryotic cells and maintain cell viability through the autophagy lysosomal degradation system. Autophagy activation and autophagy flux correction are playing an important neuroprotective role in the central nervous system, as they accelerate the removal of toxic protein aggregates intracellularly and extracellularly to prevent neurodegenerative processes, such as Alzheimer's disease (AD). In this study, we explored whether this mechanism can mediate the neuroprotective effect of DHA on the AD model in vitro and in vivo . Three months of DHA treatment improved the memory and cognitive impairment, reduced the deposition of amyloid β plaque, reduced the levels of Aβ40 and Aβ42, and ameliorated excessive neuron apoptosis in APP/PS1 mice brain. In addition, DHA treatment increased the level of LC3 II/I and decreased the expression of p62. After Bafilomycin A1 and Chloroquine (CQ) blocked the fusion of autophagy and lysosome, as well as the degradation of autolysosomes (ALs), DHA treatment increased the level of LC3 II/I and decreased the expression of p62. These results suggest that DHA treatment can correct autophagic flux, improve autophagy dysfunction, inhibit abnormal death of neurons, promote the clearance of amyloid-β peptide (Aβ) fibrils, and have a multi-target effect on the neuropathological process, memory and cognitive deficits of AD., (Copyright © 2020 Zhao, Long, Ding, Jiang, Liu, Li, Liu, Peng, Wang, Feng and He.)

In order to ensure the safety of spacecrafts in orbit, impact location is an important part of structural health monitoring systems. In this paper, an impact location algorithm based on posterior probability correlation is proposed to solve the problem, that is, the impact point in the stiffened structure of a spacecraft is difficult to locate. The algorithm combines the Gaussian cross-correlation possibility weight method and the Bayesian posterior probability method. The cross-correlation possibility weight superposition based on grids was used to reduce the dependence of the accuracy of time difference extraction. Gaussian and normalized fitting were used to compensate the reflection, modal transformation, and amplitude attenuation of a stiffened plate. The location result was further optimized by the posterior probability. The proposed algorithm can be applied to the impact source localization of complex stiffened plate structures. The experiment results showed that the average location error can be 2.57 cm with proper sensor network schemes.

Background: Alzheimer's disease (AD) is one of the worst neurodegenerative disorders worldwide, with extracellular senile plaques (SP), subsequent intracellular neurofibrillary tangles (NFTs) and final neuron loss and synaptic dysfunction as the main pathological characteristics. Excessive apoptosis is the main cause of irreversible neuron loss. Thus, therapeutic intervention for these pathological features has been considered a promising strategy to treat or prevent AD. Dihydroartemisin (DHA) is a widely used first-line drug for malaria. Our previous study showed that DHA treatment significantly accelerated Aβ clearance, improved memory and cognitive deficits in vivo and restored autophagic flux both in vivo and in vitro., Methods: The present study intended to explore the neuroprotective effect of DHA on neuron loss in APP/PS1 double-transgenic mice and the underlying mechanisms involved. Transmission electron microscope (TEM) analysis showed that DHA significantly reduced the swollen endoplasmic reticulum (ER) in APP/PS1 mice. Western blot analysis indicated that DHA upregulated the level of NeuN, NeuroD, MAP2, and synaptophysin and promoted neurite outgrowth. Meanwhile, DHA greatly corrected the abnormal levels of Brain-derived neurotrophic factor (BDNF) and rescued the neuronal loss in the hippocampal CA1 area. Western blot analysis revealed that DHA notably down-regulated the protein expression of full length caspase-3, cleaved caspase-3 and Bax. In parallel, the expression of the anti-apoptotic protein Bcl-2 increased after oral DHA treatment., Results: Altogether, these results indicate that DHA protected AD mice from neuron loss via promoting the expression of BDNF and other neuroplasticity-associated proteins and suppressing the inhibition of neuronal apoptosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Lung cancer is a leading cause of cancer-related death worldwide. Previously we demonstrated that polyphyllin I (PPI), a bioactive component extracted from Paris polyphylla, inhibited the growth of non-small cell lung cancer (NSCLC) cells through the SAPK/JNK-mediated suppressing p65, DNMT1 and EZH2 expressions. However, the molecular mechanism underlying anti-lung cancer effect by PPI still remain elusive., Purpose: In this current study, we further explored the molecular mechanism underlying the anti-lung cancer effect of PPI., Methods: MTT, Cell-Light TM  EdU DNA cell proliferation and colony formation assays were used to measure cell growth. Western blot were used to examine protein levels of c-Jun and p21. The expression level of long non-codingth RNA HOX transcript antisense RNA (HOTAIR) was measured by qRT-PCR. The p21 promoter activity was measured by Dual-Luciferase Reporter Assay System. The transient transfection experiments were used to silence and overexpression of c-Jun, p21 and HOTAIR. Tumor xenograft and bioluminescent imaging experiments were carried out to confirm the   in vitro findings., Results:  We showed that PPI suppressed growth of NSCLC cells. Mechanistically, we observed that PPI reduced expression of HOTAIR, while increased transcription factor c-Jun protein levels. Additionally, PPI also induced protein expression and promoter activity of p21, a cyclin-dependent kinase inhibitor. While exogenously expressed HOTAIR showed no effect on c-Jun levels, silencing of c-Jun significantly reversed the PPI-inhibited HOTAIR expression. Moreover, excessive expressed c-Jun further enhanced PPI-inhibited HOTAIR expression and PPI-induced p21 protein levels. Intriguingly, overexpression of HOTAIR and silencing of c-Jun overcame the PPI-induced p21 protein and promoter activity. Finally, silencing of p21 neutralized the PPI-inhibited cell proliferation. Similar results were also found in one xenograft mouse model., Conclusion:  Our results demonstrate that PPI inhibits growth of NSCLC cells through regulation of HOTAIR and c-Jun expressions, which lead to induction of p21 gene. The interactions among HOTAIR, c-Jun and p21 regulatory axis converge in the overall anti-lung cancer effect of PPI. This study unveils an additional new mechanism for the anti-lung cancer role of PPI., Competing Interests: The authors declare that they have no competing interests in this work., (© 2019 Zhao et al.)

Ethnopharmacological Relevance: The Chinese herbal medicine Fuzheng Kang-Ai (FZKA) decoction obtained from Guangdong Kangmei Pharmaceutical Company, which contains 12 components with different types of constituents, has been used as part of the adjuvant treatment of lung cancer for decades. We previously showed that FZKA decoction enhances the growth inhibition of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant non-small cell lung cancer (NSCLC) cells by suppressing glycoprotein mucin 1 (MUC1) expression. However, the molecular mechanism underlying the therapeutic potential, particularly in sensitizing or/and enhancing the anti-lung cancer effect of EGFR-TKIs, remains unclear., Materials and Methods: Cell viability was measured using 3-(4, 5-diMEThylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and 5-ethynyl -2'-deoxyuridine (EdU) assays. Western blot analysis was performed to examine the protein expressions of DNA methyltransferase 1 (DNMT1), specificity protein 1 (SP1), and MET, an oncogene encoding for a trans-membrane tyrosine kinase receptor activated by the hepatocyte growth factor (HGF). The expression of MET mRNA was measured by quantitative real-time PCR (qRT-PCR). Exogenous expression of DNMT1 and SP1, and MET were carried out by transient transfection assays. The promoter activity of MET was tested using Dual-luciferase reporter assays. A nude mouse xenografted tumor model further evaluated the effect of the combination of FZKA decoction and erlotinib in vivo., Results: The combination of FZKA and erlotinib produced an even greater inhibition of NSCLC cell growth. FZKA decreased the expressions of DNMT1, SP1, and MET (c-MET) proteins, and the combination of FZKA and erlotinib demonstrated enhanced responses. Interestingly, there was a mutual regulation of DNMT1 and SP1. In addition, exogenously expressed DNMT1 and SP1 blocked the FZKA-inhibited c-MET expression. Moreover, excessive expressed MET neutralized FZKA-inhibited growth of NSCLC cells. FZKA decreased the mRNA and promoter activity of c-MET, which was not observed in cells with ectopic expressed DNMT1 gene. Similar findings were observed in vivo., Conclusion: FZKA decreases MET gene expression through the repression and mutual regulation of DNMT1 and SP1 in vitro and in vivo. This leads to inhibit the growth of human lung cancer cells. The combination of FZKA and EGFR-TKI erlotinib exhibits synergy in this process. The regulatory loops among the DNMT1, SP1 and MET converge in the overall effects of FZKA and EGFR-TKI erlotinib. This in vitro and in vivo study clarifies an additional novel molecular mechanism underlying the anti-lung cancer effects in response to the combination of FZKA and erlotinib in gefitinib-resistant NSCLC cells., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFTs) and massive loss of neuronal cells in the brain. Adult hippocampus continuously generates new neurons throughout life to shape brain function and impaired neurogenesis may contribute to a series of cognitive deterioration associated with AD. Enhancing endogenous neurogenesis represents a promising strategy that may ameliorate AD-associated cognitive defects. However, neurogenesis-enhancing approaches and underlying mechanisms are still not well studied. Here, using a mouse model of AD amyloid precursor protein (APP/PS1/Nestin-GFP triple transgenic mice, 3xTgAD), we examined the effects of 4 weeks of valproic acid (VPA) treatment on hippocampal neurogenesis in 2- and 6-month-old mice. VPA treatment promoted cell proliferation and increased the density of immature neurons in the dentate gyrus (DG) of the hippocampus of 3xTgAD mice. Consistent with enhanced neurogenesis, behavioral and morphological analysis showed that VPA treatment improved the learning and memory ability of 3xTgAD mice. Mechanistically, VPA treatment increased β-catenin levels, accumulated the inactive form of glycogen synthase kinase-3β (GSK-3β), and induced the expression of NeuroD1, a Wnt target gene involved in neurogenesis, suggesting the activation of the Wnt signaling pathway in the hippocampus of 3xTgAD mice. This study indicates that VPA stimulates neurogenesis in the adult hippocampus of AD mice model through the Wnt pathway, highlighting VPA as a potential therapeutic for treating AD and related diseases.

Aims: The optimal time for mesenchymal stem cell (MSCs) transplantation remains an unresolved issue. We compared the effects of MSCs on a rat remnant kidney model., Methods: Male Sprague-Dawley rats were randomly divided and treated with a corresponding reagent at 4, 8, 12 and 16 weeks, respectively. A remnant kidney model was established and MSCs were injected into rats. The migration of MSCs was then assessed by using cell-tracking experiments. Renal function and histological analyses were performed 4 weeks after MSC transplantation. Immunohistochemistry, Western blotting and real-time polymerase chain reaction were used to detect the TGF-β1 and α-SMA levels., Results: Four weeks after MSC injection, MSCs were found to migrate to the injured kidney. Significant histological damage improvement was observed after the treatment of MSCs at 4 and 8 weeks. The functional benefits of MSC treatment were observed in the 5/6 nephrectomy (Nx) + MSC group and the benefits were significantly higher at 4 and 8 weeks than at other time points (p < 0.05). Meanwhile, serum creatinine and urea levels as well as glomerular sclerosis and tubulointerstitial injury indexes were decreased at 4 and 8 weeks. Compared with the 5/6 Nx + PBS group, TGF-β1 and α-SMA levels were decreased in the 5/6 Nx + MSC group., Conclusion: These data can be used to optimize the MSC transplantation time point as a therapeutic modality.