[Experimental study on treatment of retinitis pigmentosa by inducing Müller cell reprogramming with Lycii Fructus and Salviae Miltiorrhizae Radix et Rhizoma].

This study aims to explore the effect of Lycii Fructus and Salviae Miltiorrhizae Radix et Rhizoma(LFSMR), a drug pair possesses the function of nourishing Yin, promoting blood circulation, and brightening the eyes, in treating retinitis pigmentosa(RP)by inhibiting the gliosis of Müller cells(MCs) and inducing their reprogramming and differentiation into various types of retinal nerve cells. Twelve C57 mice were used as the normal control group, and 48 transgenic RP(rd10) mice were randomly divided into the model group, positive control group, and low and high dose LFSMR groups, with 12 mice in each group. HE staining was used to detect pathological changes in the retina, and an electroretinogram was used to detect retinal function. Retinal optical coherence tomography was used to detect retinal thickness and perform fundus photography, and laser speckle perfusion imaging was used to detect local retinal blood flow. Digital PCR was used to detect gene expression related to retinal nerve cells, and immunofluorescence was used to detect protein expression related to retinal nerve cells. LFSMR could significantly improve the pathological changes, increase the amplitude of a and b waves, increase the retinal thickness, restore retinal damage, and increase retinal blood flow in mice with RP lesions. LFSMR could also significantly inhibit the m RNA expression of the glial fibrillary acidic protein( GFAP) during the pathogenesis of RP and upregulate m RNA expression of sex determining region Y box protein 2(SOX2), paired box protein 6(Pax6),rhodopsin, protein kinase C-α(PKCα), syntaxin, and thymic cell antigen 1. 1(Thy1. 1). LFSMR could significantly inhibit GFAP protein expression and enhance protein expression of SOX2, Pax6, rhodopsin, PKCα, syntaxin, and Thy1. 1. It could also reverse the pathological changes in the retina of rd10 mice, improve retinal function and fundus performance, increase retinal thickness, enhance local retinal blood flow, and exert therapeutic effects on RP. The mechanism of action of LFSMR may be related to inhibiting the gliosis of MCs and promoting their reprogramming and differentiation into various types of retinal nerve cells.

Ischemia-reperfusion injury in a salvaged penumbra: Longitudinal high-tesla perfusion magnetic resonance imaging in a rat model.

INTRODUCTION: Although ischemia-reperfusion (I/R) injury varies between cortical and subcortical regions, its effects on specific regions remain unclear. In this study, we used various magnetic resonance imaging (MRI) techniques to examine the spatiotemporal dynamics of I/R injury within the salvaged ischemic penumbra (IP) and reperfused ischemic core (IC) of a rodent model, with the aim of enhancing therapeutic strategies by elucidating these dynamics. MATERIALS AND METHODS: A total of 17 Sprague-Dawley rats were subjected to 1 h of transient middle cerebral artery occlusion with a suture model. MRI, including diffusion tensor imaging (DTI), T2-weighted imaging, perfusion-weighted imaging, and T1 mapping, was conducted at multiple time points for up to 5 days during the I/R phases. The spatiotemporal dynamics of blood-brain barrier (BBB) modifications were characterized through changes in T1 within the IP and IC regions and compared with mean diffusivity (MD), T2, and cerebral blood flow. RESULTS: During the I/R phases, the MD of the IC initially decreased, normalized after recanalization, decreased again at 24 h, and peaked on day 5. By contrast, the IP remained relatively stable. Both the IP and IC exhibited hyperperfusion, with the IP reaching its peak at 24 h, followed by resolution, whereas hyperperfusion was maintained in the IC until day 5. Despite hyperperfusion, the IP maintained an intact BBB, whereas the IC experienced persistent BBB leakage. At 24 h, the IC exhibited an increase in the T2 signal, corresponding to regions exhibiting BBB disruption at 5 days. CONCLUSIONS: Hyperperfusion and BBB impairment have distinct patterns in the IP and IC. Quantitative T1 mapping may serve as a supplementary tool for the early detection of malignant hyperemia accompanied by BBB leakage, aiding in precise interventions after recanalization. These findings underscore the value of MRI markers in monitoring ischemia-specific regions and customizing therapeutic strategies to improve patient outcomes.

Estimating the volume of penumbra in rodents using DTI and stack-based ensemble machine learning framework.

BACKGROUND: This study investigates the potential of diffusion tensor imaging (DTI) in identifying penumbral volume (PV) compared to the standard gadolinium-required perfusion-diffusion mismatch (PDM), utilizing a stack-based ensemble machine learning (ML) approach with enhanced explainability. METHODS: Sixteen male rats were subjected to middle cerebral artery occlusion. The penumbra was identified using PDM at 30 and 90 min after occlusion. We used 11 DTI-derived metrics and 14 distance-based features to train five voxel-wise ML models. The model predictions were integrated using stack-based ensemble techniques. ML-estimated and PDM-defined PVs were compared to evaluate model performance through volume similarity assessment, the Pearson correlation analysis, and Bland-Altman analysis. Feature importance was determined for explainability. RESULTS: In the test rats, the ML-estimated median PV was 106.4 mL (interquartile range 44.6-157.3 mL), whereas the PDM-defined median PV was 102.0 mL (52.1-144.9 mL). These PVs had a volume similarity of 0.88 (0.79-0.96), a Pearson correlation coefficient of 0.93 (p < 0.001), and a Bland-Altman bias of 2.5 mL (2.4% of the mean PDM-defined PV), with 95% limits of agreement ranging from -44.9 to 49.9 mL. Among the features used for PV prediction, the mean diffusivity was the most important feature. CONCLUSIONS: Our study confirmed that PV can be estimated using DTI metrics with a stack-based ensemble ML approach, yielding results comparable to the volume defined by the standard PDM. The model explainability enhanced its clinical relevance. Human studies are warranted to validate our findings. RELEVANCE STATEMENT: The proposed DTI-based ML model can estimate PV without the need for contrast agent administration, offering a valuable option for patients with kidney dysfunction. It also can serve as an alternative if perfusion map interpretation fails in the clinical setting. KEY POINTS: • Penumbral volume can be estimated by DTI combined with stack-based ensemble ML. • Mean diffusivity was the most important feature used for predicting penumbral volume. • The proposed approach can be beneficial for patients with kidney dysfunction.

Qi-Shen-Tang alleviates retinitis pigmentosa by inhibiting ferroptotic features via the NRF2/GPX4 signaling pathway.

Ferroptosis has been observed during retinal photoreceptor cell death, suggesting that it plays a role in retinitis pigmentosa (RP) pathogenesis. Qi-Shen-Tang (QST) is a combination of two traditional Chinese medicines used for the treatment of ophthalmic diseases; however, its mechanism of action in RP and ferroptosis remains unclear. Therefore, this study aimed to explore the effect and potential molecular mechanisms of QST on RP. QST significantly improved tissue morphology and function of the retina in the RP model mice. A significant increase in retinal blood flow and normalization of the fundus structure were observed in mice in the treatment group. After QST treatment, the level of iron and the production of malondialdehyde decreased significantly; the levels of superoxide dismutase and glutathione increased significantly; and the protein expression of glutathione peroxidase 4 (GPX4), glutathione synthetase, solute carrier family 7 member 11, and nuclear factor erythroid 2-related factor 2 (NRF2) increased significantly. The molecular docking results demonstrated potential interactions between the small molecules of QST and the key proteins of NRF2/GPX4 signaling pathway. Our results indicate that QST may inhibit ferroptosis by inhibiting the NRF2/GPX4 signaling pathway, thereby reducing RP-induced damage to retinal tissue.

Optogenetic stimulation in the medial prefrontal cortex modulates stimulus valence from rewarding and aversive to neutral states.

Introduction: Understanding the modulations of the medial prefrontal cortex (mPFC) in the valence of the stimulus from rewarding and aversive status to neutral status is crucial for the development of novel treatments for drug addiction. This study addressed this issue and examined whether optogenetic ChR2 photostimulation in the cingulate, prelimbic, and infralimbic cortices of the mPFC regulated the valence of saccharin solution consumption from the rewarding property, the aversive property induced by morphine's conditioning, and the neutral states via saccharin extinction processes after morphine's conditioning. Methods: All rats received virus infection, buried optical fiber, optical stimulation, water deprivation, and saccharin solution consumption phases. In Experiment 1, rats were given ChR2 virus infection into the cingulate cortex (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL) to influence the rewarding saccharin solution consumption under photostimulation. In Experiment 2, rats were given ChR2 or EYFP virus infection into the Cg1, PrL, and IL to alter the saccharin solution consumption in the morphine-induced aversively conditioned taste aversion (CTA) and the saccharin solution consumption in the neutral state following the extinction process under photostimulation. Later, the immunohistochemical staining with c-Fos protein was performed for the Cg1, IL, PrL, nucleus accumbens core, nucleus accumbens shell, central amygdala, basolateral amygdala, ventral tegmental area, and dentate gyrus. Results: The results showed that optogenetic PrL stimulation decreased the rewarding valence of saccharin solution consumption and increased the morphine-induced, aversive valence of saccharin solution consumption. PrL stimulation decreased the neutral valence of saccharin solution consumption via the extinction process. Cg1 optogenetic stimulation increased the rewarding valence of saccharin solution consumption and the aversive valence of saccharin solution consumption induced by morphine in conditioning. Optogenetic IL stimulation increased the aversive valence of saccharin solution consumption induced by morphine via conditioning. Conclusion: Altogether, optogenetic stimulation in the subareas of the mPFC modulated the reward, aversion, and neutral valences of the stimulus and altered neuronal activity in the mPFC, amygdala, nucleus accumbens, and hippocampus. Notably, the change of valence was temporary alternation during light-on related to the light-off periods. However, the findings may provide insights in the development of novel treatments for addictive symptoms.

Neuronal activity of the medial prefrontal cortex, nucleus accumbens, and basolateral amygdala in conditioned taste aversion and conditioned place preference induced by different doses of morphine administrations in rats.

To re-examine the paradoxical effect hypothesis of abused drugs, the present study concerned whether different doses of morphine disparately affect neuronal activity and associations among the subareas of the medial prefrontal cortex (mPFC: cingulate cortex 1-Cg1, prelimbic cortex-PrL, infralimbic cortex-IL), the subregions of the nucleus accumbens (NAc; both core and shell), and the basolateral amygdala (BLA) following conditioned taste aversion (CTA) and conditioned place preference (CPP). All rats were given a 0.1% saccharin solution for 15-min, and they were intraperitoneally injected with saline or 20, 30, or 40 mg/kg morphine to form the aversive CTA learning. Later, half of the rats were tested for CPP (including the CTA and then CPP tests) for 30-min. Finally, the immunohistochemical staining with c-Fos was conducted after the behavioral test. After the CTA test, c-Fos (%) in the Cg1 and PrL (but not the IL) was more in 20-40 mg/kg of the morphine groups; c-Fos (%) in the NAc core, NAc shell, and BLA was more in the 30-40 mg/kg morphine group. After the CPP test, the Cg1, PrL, IL, and BLA showed more c-Fos (%) in 20 mg/kg morphine; the NAc core showed fewer in c-Fos (%) in the 30-40 mg/kg morphine groups. The mPFC subregions (e.g., Cg1, PrL, and IL), NAc subareas (e.g., NAc core and NAc shell), and BLA were involved in the different doses of morphine injections. The correlation analysis showed that a positive correlation was observed between PrL and IL with NAc core with low doses of morphine and with NAc shell with increasing doses of morphine after the CTA test. After the CPP, an association between PrL and NAc core and NAc shell at low doses and between IL and BLA and NAc shell with increasing doses of morphine. Therefore, different neural substrates and the neural connectivity are observed following different doses of morphine and after the CTA and CPP tests. The present data extend the paradoxical effect hypothesis of abused drugs.

Trends in Helicobacter pylori-related gastric ulcer research from 2012 to 2022: A bibliometric and visual analysis.

Background: Helicobacter pylori-related gastric ulcer (H. pylori-related GU) is one of the most common digestive system diseases that have received widespread attention from researchers. The purpose of this article was to analyze the research status and hotspots of H. pylori-related GU and to predict its future research directions. Methods: The article and review papers associated with H. pylori-related GU published from 2012 to 2022 were retrieved from the Web of Science Core Collection (WoSCC). The analysis of knowledge maps and bibliometrics was done with CiteSpace 6.1.R2 Basic and VOSviewer 1.6.18. Results: A total of 2,971 articles were included in the study. Between 2012 and 2022, the number of papers published showed an increasing trend. China was the most prolific country, and the United States was the most influential country. Baylor College of Medicine had the largest number of publications and citations among publishing agencies. World Journal of Gastroenterology published the most articles on the H. pylori-related GU field, and GUT was the journal with the most cited articles. Yamaoka Y from Japan was the most productive author, and Graham DY from the USA was the most influential author. A keyword and reference analysis showed that the hot topics of research were the mechanism of H. pylori and the treatment of H. pylori-related GU. The keywords that emerged in the recent 5 years were oxidative stress, probiotics, competitive acid blocker, vonoprazan, gut microbiota, and neutrophil-activating protein. Conclusion: Over the recent 10 years, research on H. pylori-related GU has generally shown an increasing trend. The treatment and pathogenesis of H. pylori-related GU remain a hot topic of research. The treatment of H. pylori by oxidative stress and competitive acid inhibitor mechanisms, the influence of gastrointestinal flora on H. pylori, probiotic adjuvant therapy of H. pylori-related GU, and the immunoprotective effect of neutrophil activator protein could be popular research directions and trends in the future.

Oncogenic Roles of Polycomb Repressive Complex 2 in Bladder Cancer and Upper Tract Urothelial Carcinoma.

Cancers of the urinary tract are one of the most common malignancies worldwide, causing high morbidity and mortality, and representing a social burden. Upper tract urothelial carcinoma (UTUC) accounts for 5−10% of urinary tract cancers, and its oncogenic mechanisms remain elusive. We postulated that cancers of the lower and the upper urinary tract may share some important oncogenic mechanisms. Therefore, the oncogenic mechanisms discovered in the lower urinary tract may guide the investigation of molecular mechanisms in the upper urinary tract. Based on this strategy, we revisited a high-quality transcriptome dataset of 510 patients with non-muscle invasive bladder cancer (NMIBC), and performed an innovative gene set enrichment analysis of the transcriptome. We discovered that the epigenetic regulation of polycomb repressive complex 2 (PRC2) is responsible for the recurrence and progression of lower-track urinary cancers. Additionally, a PRC2-related gene signature model was discovered to be effective in classifying bladder cancer patients with distinct susceptibility of subsequent recurrence and progression (log-rank p < 0.001 and = 0.001, respectively). We continued to discover that the same model can differentiate stage T3 UTUC patients from stage Ta/T1 patients (p = 0.026). Immunohistochemical staining revealed the presence of PRC2 components (EZH2, EED, and SUZ12) and methylated PRC2 substrates (H3K27me3) in the archived UTUC tissues. The H3K27me3 exhibited higher intensity and area intensity product in stage T3 UTUC tissues than in stage Ta/T1 tissues (p = 0.006 and 0.015, respectively), implicating stronger PRC2 activity in advanced UTUC. The relationship between H3K27 methylation and gene expression is examined using correlations. The H3K27me3 abundance is positively correlated with the expression levels of CDC26, RP11-2B6, MAPK1IP1L, SFR1, RP11-196B3, CDK5RAP2, ANXA5, STX11, PSMD5, and FGFRL1. It is also negatively correlated with CNPY2, KB-1208A12, RP11-175B9, ZNF692, RANP8, RP11-245C17, TMEM266, FBXW9, SUGT1P2, and PRH1. In conclusion, PRC2 and its epigenetic effects are major oncogenic mechanisms underlying both bladder cancer and UTUC. The epigenetically regulated genes of PRC2 in urothelial carcinoma were also elucidated using correlation statistics.

Traditional Chinese Medicine prescription Huang-Qi-Jian-Zhong-Tang ameliorates indomethacin-induced duodenal ulcers in rats by affecting NF-κB and STAT signaling pathways.

Huang-Qi-Jian-Zhong-Tang (HQJZT) is a well-known traditional Chinese herbal formulation. This study aimed to investigate the duodenoprotective properties of HQJZT against Indomethacin (IND)-induced duodenal ulceration in rats, and the mechanisms involved, particularly through NF-κB and STAT signaling pathways. Our results showed that HQJZT completely protected the duodenal mucosa from ulceration caused by IND, as indicated by improved macroscopic and histological appearances. There was a significant decrease in ulcer index and microscopic score, an increase in villus height and crypt depth, and a normalization of the tissue architecture of the duodenum in rats following HQJZT treatment. Blood flow into the duodenal mucosa was significantly increased after HQJZT administration. HQJZT significantly increased PGE2 and NO levels in the duodenal mucosa. A significant reduction in the production of pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α was observed in the duodenal mucosa under treatment with HQJZT. Mechanistically, the administration of HQJZT significantly lowered the duodenal protein expression of inflammation-related genes, including p-NF-κB and p-IκBß, compared with the ulcer control group. Furthermore, the STAT signaling pathway-related protein markers p-JAK and p-STAT were significantly reduced in the HQJZT (1.30 and 2.60 g/kg) groups. As a result of these findings, HQJZT alleviates duodenal mucosal ulcers caused by IND. A protective effect of HQJZT on duodenal ulcers is attributed to its ability to improve mucosal blood flow, stimulate the production of cytoprotective mediators, minimize proinflammatory cytokines, and block the activation of NF-κB and STAT signaling pathways.

Lycium barbarum L. and Salvia miltiorrhiza Bunge protect retinal pigment epithelial cells through endoplasmic reticulum stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Lycium barbarum L. and Salvia miltiorrhiza Bunge (Gouqi and Danshen, LS) are traditional herbs for the treatment of retinal degeneration in China. LS have been integrated into pharmacopoeia and health care system of many countries around the world. However, the mechanisms by which LS protect retina are not fully clarified. AIM OF THE STUDY: We aimed at exploration of the effect of LS on retinal pigment epithelium (RPE) cells apoptosis as well as the endoplasmic reticulum (ER) stress mechanisms. MATERIAL AND METHODS: ARPE-19 cells were exposed to tunicamycin to induce ER stress, followed by LS treatment for 24 h. The cell morphology was photographed using the Incucyte S3 instrument, and the potential cytotoxic effect and viability were evaluated by CCK-8 assays. The Annexin V-FITC/PI staining and TUNEL assay were conducted to detect cells apoptotic. Western blot and digital PCR were used to detected related protein and gene expression. RESULTS: The ARPE-19 cells are increased in number and aligned after treating with LS. 1 mg/ml is the LS high dose group dose and treatment with LS increased cell vitality. LS significantly inhibit ARPE-19 cells apoptosis. Moreover, LS were markedly decreased the expression levels of ER stress-related factors in the ARPE-19 cells. CONCLUSIONS: This study reveals that LS relieve ARPE-19 cells apoptosis by inhibiting ER stress, and here we can speculate that LS have a certain protective effect on retina.

Anti-inflammatory mechanism of rhein in treating asthma based on network pharmacology.

OBJECTIVE: To predict the anti-inflammatory targets and related pathways of rhein in the treatment of asthma by using network pharmacology, and to further explore its potential mechanism in asthma. METHODS: The corresponding targets of rhein were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and the rhein-target network was constructed with Cytoscape 3.7.1 software. The Genbank and Drugbank databases were used to collect and screen asthma targets, and the rhein-target-disease interaction network was constructed. A target protein-protein interaction (PPI) network was constructed using the STRING database to screen key targets. Finally, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to identify biological processes and signaling pathways. The anti-asthmatic effects of rhein were tested in vitro, and the expression levels of proteins in the mitogen-activated protein kinase/nuclear factor kappa-B (MAPK/ NF-κB) signaling pathway were assessed by western blot analysis. RESULTS: Altogether, 83 targets of rhein were screened in the relevant databases, 989 targets of asthma were obtained in the National Center for Biotechnology Information (NCBI) GENE Database. PPI network analysis and KEGG pathway enrichment analysis predicted that rhein could regulate the epidermal active growth factor receptor (EGFR), mitogen-activated protein kinase 14 (MAPK14), tumour necrosis factor receptor superfamily member 1A (TNFRSF1A), receptor tyrosine-protein kinase erbB-2 (ERBB2), and other signaling pathways. Furthermore, we selected the MAPK signaling pathway to determine the anti-inflammatory effects of rhein. Consistently, further experiments demonstrated that rhein was shown to inhibit HBE cells inflammation. CONCLUSION: The anti-inflammatory mechanism of rhein in the treatment of asthma may be related to EGFR, MAPK14, TNFRSF1A and ERBB2 as well as their signaling pathways. To prevent the exacerbation of asthma, instead of targeting a single pathway or a single target, all these targets and their signaling pathways should be controlled holistically. Rhein may alleviate the inflammation of asthma by inhibiting the MAPK/NF-κB pathway.

Quality-Driven Regularization for Deep Learning Networks and Its Application to Industrial Soft Sensors.

The growth of data collection in industrial processes has led to a renewed emphasis on the development of data-driven soft sensors. A key step in building an accurate, reliable soft sensor is feature representation. Deep networks have shown great ability to learn hierarchical data features using unsupervised pretraining and supervised fine-tuning. For typical deep networks like stacked auto-encoder (SAE), the pretraining stage is unsupervised, in which some important information related to quality variables may be discarded. In this article, a new quality-driven regularization (QR) is proposed for deep networks to learn quality-related features from industrial process data. Specifically, a QR-based SAE (QR-SAE) is developed, which changes the loss function to control the weights of the different input variables. By choosing an appropriate inductive bias for the weight matrix, the model provides quality-relevant information for predictive modeling. Finally, the proposed QR-SAE is used to predict the quality of a real industrial hydrocracking process. Comparative experiments show that QR-SAE can extract quality-related features and achieve accurate prediction performance.

The Medial Prefrontal Cortex, Nucleus Accumbens, Basolateral Amygdala, and Hippocampus Regulate the Amelioration of Environmental Enrichment and Cue in Fear Behavior in the Animal Model of PTSD.

A growing body of evidence showed that environmental enrichment (EE) ameliorated footshock-induced fear behavior of posttraumatic stress disorder (PTSD). However, no research comprehensively tested the effect of EE, cue, and the combination of EE and cue in footshock-induced fear behavior of PTSD symptoms. The present study addressed this issue and examined whether the medial prefrontal cortex (mPFC, including the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL)), the nucleus accumbens (NAc), the basolateral amygdala (BLA), and the hippocampus (e.g., CA1, CA3, and dentate gyrus (DG)) regulated the amelioration of the EE, cue, or the combination of EE and cue. The results showed that EE or cue could reduce fear behavior. The combination of EE and cue revealed a stronger decrease in fear behavior. The cue stimulus may play an occasion setting or a conditioned stimulus to modulate the reduction in fear behavior induced by footshock. Regarding the reduction of the EE in fear behavior, the Cg1 and IL of the mPFC and the NAc upregulated the c-Fos expression; however, the BLA downregulated the c-Fos expression. The mPFC (i.e., the Cg1, PrL, and IL) and the hippocampus (i.e., the CA1, CA3, and DG) downregulated the c-Fos expression in the suppression of the cue in fear behavior. The interaction of EE and cue in reduction of fear behavior occurred in the Cg1 and NAc for the c-Fos expression. The data of c-Fos mRNA were similar to the findings of the c-Fos protein expression. These findings related to the EE and cue modulations in fear behavior may develop a novel nonpharmacological treatment in PTSD.

Involvement of the ventral tegmental area but not periaqueductal gray matter in the paradoxical rewarding and aversive effects of morphine.

The paradoxical effects of reward and aversion with abused drugs may interact to produce drug addiction, which is the so-called paradoxical effect hypothesis of abused drugs. However, there is no research examining how the ventral tegmental area (VTA) or periaqueductal gray matter (PAG) regulates morphine's paradoxical effect of reward and aversion. The present study addresses this issue, utilizing a high concentration of N-methyl-D-aspartic acid (NMDA) via injections to destroy the VTA or the PAG. Moreover, the study employed the new "pre- and postassociation" experimental paradigm (2010) to test whether the simultaneous rewarding and aversive effects of morphine can be affected by an NMDA lesion in the VTA or the PAG. The results indicated that the NMDA lesion of the VTA simultaneously reduced morphine-induced conditioned suppression of saccharin solution intake in conditioned taste aversion (CTA) and morphine-induced spent time in the preference compartment in conditioned place preference (CPP), whereas the PAG lesion did not change either measure. Thus, the VTA, but not the PAG, appears to contribute to the paradoxical effect reward in CPP and aversion in CTA induced by morphine. The VTA's involvement in morphine-induced CTA aversion and CPP reward supports the paradoxical effect hypothesis of abused drugs. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

BDNF Protein and BDNF mRNA Expression of the Medial Prefrontal Cortex, Amygdala, and Hippocampus during Situational Reminder in the PTSD Animal Model.

Whether BDNF protein and BDNF mRNA expression of the medial prefrontal cortex (mPFC; cingulated cortex area 1 (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL)), amygdala, and hippocampus (CA1, CA2, CA3, and dentate gyrus (DG)) was involved in fear of posttraumatic stress disorder (PTSD) during the situational reminder of traumatic memory remains uncertain. Footshock rats experienced an inescapable footshock (3 mA, 10 s), and later we have measured fear behavior for 2 min in the footshock environment on the situational reminder phase. In the final retrieval of situational reminder, BDNF protein and mRNA levels were measured. The results showed that higher BDNF expression occurred in the Cg1, PrL, and amygdala. Lower BDNF expression occurred in the IL, CA1, CA2, CA3, and DG. BDNF mRNA levels were higher in the mPFC and amygdala but lower in the hippocampus. The neural connection analysis showed that BDNF protein and BDNF mRNA exhibited weak connections among the mPFC, amygdala, and hippocampus during situational reminders. The present data did not support the previous viewpoint in neuroimaging research that the mPFC and hippocampus revealed hypoactivity and the amygdala exhibited hyperactivity for PTSD symptoms. These findings should be discussed with the previous evidence and provide clinical implications for PTSD.

Fructus Lycii and Salvia miltiorrhiza Bunge extract alleviate retinitis pigmentosa through Nrf2/HO-1 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Lycii and Salvia miltiorrhiza Bunge (FS) are popular Chinese herbs for the treatment of retinitis pigmentosa (RP). AIM OF THE STUDY: This study was to evaluate protective effects of FS extract on RP and to explore whether FS extract exerts its protective effects via oxidative stress by regulating Nrf2/HO-1 signaling pathway. MATERIAL AND METHODS: FS extract were identified by UPLC chromatographic analysis. Rd10 mice as the model of RP, followed by a 4-week FS extract treatment by intragastric administration. After the animal sacrifice, histopathological examination and Scotopic electroretinography (ERG) analysis were assessed. The oxidative stress markers were determined and the expression levels of Nrf2 and HO-1 mRNA were evaluated by qRT-PCR. The expression and distribution of Nrf2 and HO-1 protein were determined by Western blot and immunohistochemistry. RESULTS: The morphological changes of Outer nuclear layer (ONL) thickness and number of the ONL were observed with a significant increased, and the functional changes of a-amplitude and b-wave amplitude were measured with a markedly increased. Treatment with FS extract remarkably increased levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and decreased level of malondialdehyde (MDA). Moreover, FS extract up-regulated mRNA and protein expression of Nrf2 and HO-1. CONCLUSIONS: This study indicated that FS extract can improve retinal morphology and function, which may have occurred through the regulation of the Nrf2/HO-1 pathway to inhibit the oxidative reaction.

A Layer-Wise Data Augmentation Strategy for Deep Learning Networks and Its Soft Sensor Application in an Industrial Hydrocracking Process.

In industrial processes, inferential sensors have been extensively applied for prediction of quality variables that are difficult to measure online directly by hard sensors. Deep learning is a recently developed technique for feature representation of complex data, which has great potentials in soft sensor modeling. However, it often needs a large number of representative data to train and obtain a good deep network. Moreover, layer-wise pretraining often causes information loss and generalization degradation of high hidden layers. This greatly limits the implementation and application of deep learning networks in industrial processes. In this article, a layer-wise data augmentation (LWDA) strategy is proposed for the pretraining of deep learning networks and soft sensor modeling. In particular, the LWDA-based stacked autoencoder (LWDA-SAE) is developed in detail. Finally, the proposed LWDA-SAE model is applied to predict the 10% and 50% boiling points of the aviation kerosene in an industrial hydrocracking process. The results show that the LWDA-SAE-based soft sensor is superior to multilayer perceptron, traditional SAE, and the SAE with data augmentation only for its input layer (IDA-SAE). Moreover, LWDA-SAE can converge at a faster speed with a lower learning error than the other methods.

Exploring the Molecular Mechanism of Qing Guang An Granule in Treating Glaucoma Using Network Pharmacology and Molecular Docking.

BACKGROUND: Qing Guang An Granule (QGAG), a Chinese patent medicine, has been used clinically to treat glaucoma for more than 20 years. OBJECTIVE: To explore the possible mechanism of treatment of QGAG in glaucoma by using network pharmacology and molecular docking in this study. METHODS: Active compounds and targets of each herb in QGAG were retrieved via the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Glaucoma-related targets were acquired from OMIM and DisGeNET database. Key targets of QGAG against glaucoma were acquired by overlapping the above targets via the Venn diagram. Using the DAVID, Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the key targets were performed. The docking process was performed using the AutoDock 4.2.6 and AutoDock Vina 1.1.2. RESULTS: The 55 active compounds and 173 targets were obtained and constructed a compound-target network. The 20 key targets of QGAG in treating glaucoma were acquired, and these targets are involved in the apoptotic process, cellular response to hypoxia, negative regulation of cell growth, and ovarian follicle development. The main pathways are p53, HIF-1, PI3K-Akt, and neurotrophin signaling pathway. CONCLUSION: QGAG may exert a protective effect by acting on the optic nerve at a molecular and systemic level. This study can provide a certain basis for future researches on exploring the QGAG in treating glaucoma and provide new ideas for developing new drugs.

Basolateral Amygdala but Not Medial Prefrontal Cortex Contributes to Chronic Fluoxetine Treatments for PTSD Symptoms in Mice.

Do chronic fluoxetine treatments reduced footshock-induced posttraumatic stress disorder (PTSD) symptoms, including fear and comorbid depression, in the situational reminder phase? Moreover, are the subareas of the medial prefrontal cortex (mPFC), including the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), infralimbic cortex (IL), and basolateral amygdala (BLA), involved in the fluoxetine amelioration of PTSD symptoms? These two crucial issues were addressed in the present study. All mice were injected with chronic fluoxetine or normal saline treatments for the adaptation (14 days), footshock fear conditioning (1 day), and situational reminder (3 days) phases. After adaptation, the mice were subjected to footshock (2 mA, 10 seconds) or nonfootshock and stayed 2 min in a footshock box for 2 min for fear conditioning. Later, they were placed in the footshock box for 2 min in the situational reminder phase. In the final session of the situational reminder phase, a forced swimming test (FST) and immunohistochemical staining were conducted. The results indicated that footshock induced fear and comorbid depression. Meanwhile, chronic fluoxetine treatments reduced fear and depression behaviors. The Cg1, PrL, IL, and BLA were seemingly to increase c-Fos expression after footshock-induced PTSD symptoms in the situational reminder phase. The fluoxetine treatments reduced only the BLA's c-Fos expression. The findings suggest that BLA contributes to the fluoxetine amelioration of PTSD symptoms; however, the mPFC, including the Cg1, PrL, and IL, did not mediate PTSD symptoms' amelioration stemming from fluoxetine. The present data might help us to further understand the neural mechanism of fluoxetine treatments in PTSD symptoms.

MFAP2 is a Potential Diagnostic and Prognostic Biomarker That Correlates with the Progression of Papillary Thyroid Cancer.

BACKGROUND: Microfibril-associated protein 2 (MFAP2) is a protein coding gene that exerts important phenotypic effects on cell motility, and increasing research has indicated that MFAP2 was correlated with many cancers. However, the functional and potential clinical role of MFAP2 in papillary thyroid cancer (PTC) has not yet been verified. MATERIALS AND METHODS: We performed whole transcriptome sequencing on 78 paired PTC tissues and corresponding adjacent normal tissues and found that MFAP2 was highly expressed in PTC tissues. Then, we analyzed the expression of MFAP2 and its relation with the clinicopathological features of PTC in The Cancer Genome Atlas (TCGA) PTC genomic dataset. We detected MFAP2 expression in 40 paired PTC tissues and corresponding adjacent normal tissues through RT-qPCR (real time-quantitative polymerase chain reaction) to validate the sequencing data and TCGA cohort. Cell functional assays were performed to elucidate the function of MFAP2 in PTC cells, Western blot assay was performed to explore the correlation between MFAP2 and EMT (epithelial-mesenchymal transition)-related proteins. RESULTS: Statistical analysis showed that MFAP2 was obviously upregulated in PTC tissues compared to matched normal tissues, and the expression levels of MFAP2 in PTC tissues were strongly related with lymph node metastasis (p=0.016). The results of RT-qPCR of our own tissue specimens showed the same conclusions as that in TCGA dataset. The results of functional assays in PTC cell lines showed that MFAP2 could promote proliferation, colony formation, migration and invasion abilities and decrease the apoptotic rate in PTC cells. Western Blot assay showed that MFAP2 could regulate the expression of EMT-related proteins. CONCLUSION: MFAP2 increases the proliferation, motility and decreases the apoptosis of PTC cells, and might be a potential therapeutic target for papillary thyroid cancer.