Attached indigenous microalgal-bacterial consortium with greater stress-resistance facilitated recovery of integrated fixed-film system after experiencing short-term stagnation inhibition.

Stability of integrated fixed-film indigenous microalgal-bacterial consortium (IF-IMBC) requires further investigation. This study focused on the influence of short-term stagnation (STS), caused by influent variations or equipment maintenance, on IF-IMBC. Results showed that the IF-IMBC system experienced initial inhibition followed by subsequent recovery during STS treatment. Enhanced organics utilization was believed to contribute to system recovery. It is proposed that the attached IMBC possessed greater stress resistance. On the one hand, a higher increase in bacteria potentially participating in organic degradation was observed. Moreover, the dominant eukaryotic species significantly decreased in suspended IMBC while its abundance remained stable in the attached state. On the other hand, increased abundance for most functional enzymes was primarily observed in the attached bacteria. This fundamental research aims to bridge the knowledge gap regarding the response of IMBC to variations in operational conditions.

Ginsenoside Rg1 mitigates cerebral ischaemia/reperfusion injury in mice by inhibiting autophagy through activation of mTOR signalling.

Reperfusion injury, which is distinct from ischaemic injury, occurs when blood flow is restored in previously ischaemic brain tissue, further compromising neurons and other cells and worsening the injury. There is currently a lack of pharmaceutical agents and therapeutic interventions that specifically mitigate cerebral ischaemia/reperfusion (I/R) injury. Ginsenoside Rg1 (Rg1), a protopanaxatriol-type saponin isolated from Panax ginseng C. A. Meyer, has been found to protect against cerebral I/R injury, but its intricate protective mechanisms remain to be elucidated. Numerous studies have shown that autophagy plays a crucial role in protecting brain tissue during the I/R process and is emerging as a promising therapeutic strategy for effective treatment. In this study, we investigated whether Rg1 protected against I/R damage in vitro and in vivo by regulating autophagy. Both MCAO and OGD/R models were established. SK-N-AS and SH-SY5Y cells were subjected to OGD followed by reperfusion with Rg1 (4-32 µM). MCAO mice were injected with Rg1 (30 mg·kg-1·d-1. i.p.) for 3 days before and on the day of surgery. Rg1 treatment significantly mitigated ischaemia/reperfusion injury both in vitro and in vivo. Furthermore, we demonstrated that the induction of autophagy contributed to I/R injury, which was effectively inhibited by Rg1 in both in vitro and in vivo models of cerebral I/R injury. Rg1 inhibited autophagy through multiple steps, including impeding autophagy initiation, inducing lysosomal dysfunction and inhibiting cathepsin enzyme activities. We revealed that mTOR activation was pivotal in mediating the inhibitory effect of Rg1 on autophagy. Treatment with Torin-1, an autophagy inducer and mTOR-specific inhibitor, significantly reversed the impact of Rg1 on autophagy, decreasing its protective efficacy against I/R injury both in vitro and in vivo. In conclusion, our results suggest that Rg1 may serve as a promising drug candidate against cerebral I/R injury by inhibiting autophagy through activation of mTOR signalling.

Exploration of radiotherapy strategy for brain metastasis patients with driver gene positivity in lung cancer.

Objective: To assess the disparities in effectiveness and identify outcome predictors in the treatment of a targeted-first and radiotherapy-first regimen with driver gene-positive lung cancer brain metastases. Materials and Methods: This retrospective study analyzed patients with driver gene-positive lung cancer brain metastases who received first-targeted and first-radiotherapy regimens, respectively, with SIB-WBRT (whole brain tissue 40 Gy/20 fractions, tumor tissue boosted to 56-60 Gy/20 fractions) and local irradiation (prescription dose range of 20-60 Gy/2-25 fractions, most commonly delivered as 30 Gy/5 fractions, with a BED range of 28-100.8 Gy) at Peking Union Medical College Hospital from September 2015 to December 2021. The primary endpoint was intracranial progression free survival (iPFS). Secondary endpoints included overall survival (OS), intracranial new lesions, and tumor control. The Kaplan-Meier method was utilized to depict and estimate iPFS, OS, intracranial new lesions and tumor control. The Cox regression analysis was conducted to assess the association between relevant factors and outcomes. Results: 88 patients were enrolled in targeted-first and radiotherapy-first regimen, totally. And no difference was found in the comparison of iPFS between the two groups (HR=1.180, 95%CI: 0.622-2.237, P=0.613). No difference was found in the comparison of OS between the two groups (HR=1.208, 95%CI: 0.679-2.150, P=0.520). No difference was found in the comparison of intracranial new lesions between the two groups (HR=1.184, 95%CI: 0.569-2.463, P=0.652). There was a difference in the local control time between the two groups, with radiotherapy-first regimen being superior (HR=2.397, 95% CI:1.453-3.954, P<0.001). Patient age (HR=1.054, 95%CI: 1.026- 1.082, P<0.001), radiotherapy modality (HR=0.128, 95%CI: 0.041-0.401, P<0.001), metastasis volume (HR=1.426, 95%CI: 1.209-1.682, P<0.001), number of metastases(HR=14.960, 95%CI: 1.990-112.444, P=0.009), extracranial disease status (HR=0.387, 95%CI: 0.170-0.880, P=0.023) and therapy sequence (HR=13.800, 95%CI: 4.455-42.751, P<0.001) were associated with local control. Conclusion: Targeted-first regimen was not found to improve patients' iPFS relative to radiotherapy-first regimen in patients with brain metastases. Radiotherapy-first regimen for brain metastases demonstrated superior local control compared to targeted-first regimen. Patient's age, radiotherapy modality, metastasis volume, number of metastases, extracranial disease status and therapy sequence may be related to local control of metastases.

[Mechanism of n-butanol fraction of Wenxia Formula combining with gefitinib in treating non-small cell lung cancer based on network pharmacology and in vitro experiment].

This study combined network pharmacology, molecular docking, and in vitro experiments to explore the potential mechanism of the active components of the n-butanol fraction of Wenxia Formula(NWXF) combined with gefitinib(GEF) in treating non-small cell lung cancer(NSCLC). Ultra-performance liquid chromatography-quadrupole Orbitrap mass spectrometry(UPLC-Q-Orbitrap MS) was employed to detect the main chemical components of NWXF. The active components of NWXF were retrieved from SwissADME, and the candidate targets of these active components were retrieved from SwissTargetPrediction. Online Mendelian Inheritance in Man(OMIM) and GeneCards were searched for the targets of NSCLC. Cytoscape 3.9.0 and STRING were employed to build the protein-protein interaction(PPI) network with the common targets shared by NWXF and NSCLC. Gene Ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment were performed in DAVID to predict the potential mechanisms. Finally, molecular docking between the main active ingredients and key targets was conducted in SYBYL-X 2.0. The methyl thiazolyl tetrazolium(MTT) assay was employed to evaluate the inhibitory effects of NWXF and/or GEF on the proliferation of human non-small cell lung cancer cells(A549 and PC-9). Additionally, the impact of NWXF on human embryonic lung fibroblast cells(MRC-5) was assessed. The effectiveness of the drug combination was evaluated based on the Q value. The terminal-deoxynucleoitidyl transferase mediated nick-end labeling(TUNEL) assay was employed to examine the apoptosis of A549 and PC-9 cells treated with NWXF and/or GEF. Quantitative real-time PCR(qRT-PCR) was employed to measure the mRNA levels of epidermal growth factor receptor(EGFR), c-Jun N-terminal kinase(JNK), and Bcl2-associated X protein(Bax) in the A549 and PC-9 cells treated with NWXF and/or GEF. Western blot was employed to determine the protein levels of EGFR, p-EGFR, JNK, p-JNK, and Bax in the A549 and PC-9 cells treated with NWXF and/or GEF. A total of 77 active components, 488 potential targets, and 49 key targets involved in the treatment of NSCLC with NWXF were predicted. The results of GO annotation showed that NWXF may treat NSCLC by regulating the biological processes such as cell proliferation, apoptosis, and protein phosphorylation. KEGG enrichment revealed that the key targets of NWXF in treating NSCLC were enriched in the mitogen-activated protein kinase(MAPK), phosphatidylinositol 3-kinase(PI3K)-protein kinase B(AKT), hypoxia-inducible factor-1(HIF-1), and microRNA-related signaling pathways. Molecular docking results showed that 91.9% of the docking scores were greater than 5, indicating the strong binding capability between main active components and key targets. The cell experiments demonstrated that NWXF combined with GEF synergistically inhibited the proliferation, promoted the apoptosis, decreased p-EGFR/EGFR and p-JNK/JNK values, down-regulated the mRNA levels of EGFR and JNK, and up-regulated the mRNA and protein levels of Bax in A549 and PC-9 cells. In conclusion, NWXF combined with GEF can regulate the EGFR/JNK pathway to promote the apoptosis of NSCLC cells, thus treating NSCLC.

Continuous suture technique increases the complete closure rate of colorectal mucosal defects after endoscopic resection: a single-blind, randomized controlled trial.

BACKGROUND: Complete closure of mucosal defects after colorectal endoscopic submucosal dissection (ESD)/piecemeal endoscopic mucosal resection (p-EMR) procedures reduces postoperative adverse events, but the complete closure rate of the traditional method using only hemostatic clips is not satisfactory. Therefore, we invented a continuous suture technique using a barbed suture and clips to increase the complete closure rate of colorectal mucosal defects. METHODS: Patients with a single large (≥ 2 cm) colorectal lesion were recruited. After completion of the ESD/p-EMR procedures, they were randomly allocated to the treatment group or control group. The mucosal defects of the treatment group were closed using barbed suture and clips, while the control group was closed using only clips. RESULTS: From January 18, 2022 to April 13, 2022, a total of 62 patients with colorectal lesions were enrolled, with 31 patients in each group. Complete closure was achieved in 29 patients (93.5%) in the treatment group and 18 patients (58.1%) in the control group (P = 0.001). The median closure time was 13 min in the treatment group and 19 min in the control group (P < 0.001). The median closure speed was 6.4 cm2/10 min in the treatment group and 3.5 cm2/10 min in the control group (P = 0.008). CONCLUSIONS: This study provided a clinically feasible continuous suture technique that was safe and effective for the complete closure of colorectal mucosal defects after endoscopic resection.

Balloon-occluded retrograde transvenous obliteration and simultaneous endoscopic cyanoacrylate injection for treating gastric varices draining through gastrorenal shunts.

BACKGROUND AND STUDY AIMS: Balloon-occluded retrograde transvenous obliteration-assisted endoscopic cyanoacrylate injection (E-BRTO) temporarily treats gastric fundic varices draining through gastrorenal shunts (GRS) occluding the GRS with a balloon, then endoscopically injecting cyanoacrylate. We retrospectively examined the safety, feasibility, and efficacy of E-BRTO. PATIENTS AND METHODS: We enrolled 85 patients with hepatic cirrhosis plus gastric fundic varices with GRS; 34 underwent E-BRTO. The 51 patients who refused all secondary prophylactic treatments served as controls. RESULTS: Finally, 33 of the 34 patients underwent successful E-BRTO without major adverse events. Gastric varices were eradicated from all 33 patients in the E-BRTO group; the average follow-up time was 161.0 (74.0) weeks (mean [SD]). Four end-point events (12%) were recorded during the follow-up period. In the control group, 33 patients (65%) suffered repeat variceal bleeding, resulting in seven deaths. The cumulative rebleeding rates of the E-BRTO group on the 6th, 24th, 48th, 96th, 144th, 192nd, 240th, and 288th week were 0%, 3%, 9%, 9%, 13%, 13%, 13%, and 13%, while the cumulative rebleeding rates of the control group in the same period were 10%, 20%, 35%, 46%, 55%, 65%, 76%, and 76%. CONCLUSIONS: E-BRTO was safe, feasible, and well tolerated by patients with hepatic cirrhosis plus gastric fundic varices with GRS. Over the long-term follow-up period, the E-BRTO group demonstrated a lower rate of repeat bleeding than the control group.

Start-up and maintenance of indigenous microalgae-bacteria consortium treating toilet wastewater through partial nitrification and nitrite-type denitrification.

Microalgae-bacteria consortium (MBC) provides an alternative to sustainable treatment of human toilet wastewater (TWW) and resource recovery. This study compared the conventional activated sludge system and wastewater indigenous MBC system (IMBC) for nitrogen removal in TWW through the coupled partial nitrification (PN) and nitrite-type denitrification process. PN was firstly established by alternating FA and FNA. Subsequently, the successful PN maintenance with the nitrite accumulation rate ranging between 90.1-95.3% was achieved using two strategies: light irradiation with the appropriate specific light energy density at 0.0188-0.0598 kJ/mg VSS and the timely nitrite-type denitrification with the algae-secreted organics as the carbon source, eventually resulting in the nitrite accumulation rate ranging between 90.1-95.3%. In the IMBC-PN system, bacterial metabolism contributed to 91.5% of nitrogen removal and the rest was through microalgal assimilation. This study offers a sustainable hybrid IMBC-PN process for high NH4+-N strength wastewater treatment (e.g., TWW), which theoretically saves 23.5% aeration and 34.2% carbon source as well as reduces 17.0% sludge production.

Glycemic dispersion: a new index for screening high glycemic variability.

OBJECTIVE: For patients with diabetes, high-frequency and -amplitude glycemic variability may be more harmful than continuous hyperglycemia; however, there is still a lack of screening indicators that can quickly and easily assess the level of glycemic variability. The aim of this study was to investigate whether the glycemic dispersion index is effective for screening high glycemic variability. METHODS: A total of 170 diabetes patients hospitalized in the Sixth Affiliated Hospital of Kunming Medical University were included in this study. After admission, the fasting plasma glucose, 2-hour postprandial plasma glucose, and glycosylated hemoglobin A1c were measured. The peripheral capillary blood glucose was measured seven times in 24 h, before and after each of three meals and before bedtime. The standard deviation of the seven peripheral blood glucose values was calculated, and a standard deviation of > 2.0 was used as the threshold of high glycemic variability. The glycemic dispersion index was calculated and its diagnostic efficacy for high glycemic variability was determined by the Mann-Whitney U test, receiver operating characteristic (ROC) curve and, Pearson correlation analysis. RESULTS: The glycemic dispersion index of patients with high glycemic variability was significantly higher than that of those with low glycemic variability (p < 0.01). The best cutoff value of the glycemic dispersion index for screening high glycemic variability was 4.21. The area under the curve (AUC) was 0.901 (95% CI: 0.856-0.945) and had a sensitivity of 0.781 and specificity of 0.905. It was correlated with the standard deviation of blood glucose values (r = 0.813, p < 0.01). CONCLUSIONS: The glycemic dispersion index had good sensitivity and specificity for screening high glycemic variability. It was significantly associated with the standard deviation of blood glucose concentration and is simple and easy to calculate. It was an effective screening indicator of high glycemic variability.

Qingyihuaji Formula promotes apoptosis and autophagy through inhibition of MAPK/ERK and PI3K/Akt/mTOR signaling pathway on pancreatic cancer in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Qingyihuaji Formula (QYHJ), a widely used traditional Chinese medicine (TCM), has been used to treat patients with cancer in China. However, the effect and mechanism of QYHJ on pancreatic ductal adenocarcinoma (PDAC) remains unclear. AIM OF THE STUDY: This study aimed to explore the roles and evaluate the possible underlying molecular mechanisms of QYHJ and its core component in PDAC using label-free quantitative proteomics in conjunction with network pharmacology-based analysis. MATERIALS AND METHODS: By screening differentially expressed proteins (DEPs) in proteomics and QYHJ-predicted gene sets, we identified QYHJ-related PDAC targets annotated with bioinformatic analysis. A subcutaneous tumor model was established to assess the role of QYHJ in vivo. The effects of quercetin (Que), a core component of QYHJ, on cell proliferation, migration, invasion, apoptosis, and autophagy in SW1990 and PANC-1 cells were investigated in vitro. Immunohistochemistry, western blotting, mRFP-GFP-LC3 adenovirus, and kinase analysis were used to determine the underlying mechanisms. RESULTS: Bioinformatics analysis revealed that 41 QYHJ-related PDAC targets were closely related to the cellular response to nitrogen compounds, positive regulation of cell death, regulation of epithelial cell apoptotic processes, and chemokine signaling pathways. CASP3, SRC, STAT1, PTPN11, PKM, and PAK1 with high expression were identified as hub DEPs in the PPI network, and these DEPs were associated with poor overall survival and STAT 1, MAPK/ERK, and PI3K/Akt/mTOR signaling pathways in PDAC patients. QYHJ significantly promoted tumor death in nude mice. Moreover, quercetin inhibited the proliferation, migration, and invasion of PDAC cells. Additionally, Que induced apoptosis and autophagy in PDAC cells. Mechanistically, QYHJ and Que significantly activated STAT 1 and remarkably inhibited the MAPK/ERK and PI3K/Akt/mTOR signaling pathways in vivo and in vitro, respectively. Importantly, ERK1/2 inactivation contributes to que-induced apoptosis in SW1990 and PANC-1 cells. CONCLUSIONS: These results suggest that QYHJ and Que are promising anti-PDAC avenues that benefit from their multiform mechanisms.

Research progress of microfluidic chips in age-related macular degeneration / 国际眼科杂志(Guoji Yanke Zazhi)

Age-related macular degeneration(ARMD)is the primary cause of severe visual impairment and blindness in people over 60 years old. With the aging of the global population, the incidence of the disease is also rising year by year. However, the pathogenesis and treatment strategy of ARMD need to be further explored. As a cutting-edge science and technology, microfluidic chips can build a comprehensive microsystem that simulates the condition and function of human tissues and organs, which has the advantages of less sample consumption and short analysis time. In recent years, many studies have confirmed that microfluidic chips can bring brand new technology solutions to the basic and clinical research of ARMD. This article will discuss and review the application progress of microfluidic chips in the areas of ARMD mechanism research, drug evaluation and clinical translation, providing a theoretical reference for further research on the diagnosis and treatment of ARMD.

MTBP enhances the activation of transcription factor ETS-1 and promotes the proliferation of hepatocellular carcinoma cells.

Increasing evidence indicates that the oncoprotein murine double minute (MDM2) binding protein (MTBP) can be considered a pro-oncogene of human malignancies; however, its function and mechanisms in hepatocellular carcinoma (HCC) are still not clear. In the present work, our results demonstrate that MTBP could function as a co-activator of transcription factor E26 transformation-specific sequence (ETS-1), which plays an important role in HCC cell proliferation and/or metastasis and promotes proliferation of HCC cells. Using luciferase and real-time polymerase chain reaction (qPCR) assays, MTBP was found to enhance the transcription factor activation of ETS-1. The results from chromatin co-immunoprecipitation showed that MTBP enhanced the recruitment of ETS-1 to its downstream gene's (mmp1's) promoter region with ETS-1 binding sites. In cellular and nude mice models, overexpression of MTBP was shown to promote the proliferation of MHCC97-L cells with low endogenous MTBP levels, whereas the knockdown of MTBP led to inhibition of the proliferation of MHCC97-H cells that possessed high endogenous levels of MTBP. The effect of MTBP on ETS-1 was confirmed in the clinical specimens; the expression of MTBP was positively correlated with the downstream genes of ETS-1, mmp3, mmp9, and uPA. Therefore, by establishing the role of MTBP as a novel co-activator of ETS-1, this work expands our knowledge of MTBP or ETS-1 and helps to provide new ideas concerning HCC-related research.

Potential Mechanisms of Biejiajian Pill in the Treatment of Diabetic Atherosclerosis Based on Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation.

Background: Biejiajian pill (BJJP), a classical traditional Chinese formula, has been reported that it has an effective treatment for diabetic atherosclerosis in recent years, but its underlying mechanisms remain elusive. The study aimed to explore the potential mechanisms of BJJP on diabetic atherosclerosis by integrating network pharmacology, molecular docking, and molecular dynamics simulation. Methods: The active components of BJJP were collected by TCMSP and TCMID, and then the potential targets were obtained from the SwissTargetPrediction database. The targets related to diabetic atherosclerosis were identified from the GeneCards and OMIM databases. The intersection of the potential targets regulated by active components of BJJP and the targets of diabetic atherosclerosis were common targets, which were visualized by the Venn diagram. The common targets were imported into the STRING database to construct a protein-protein interaction (PPI) network. The network of "Medicine-Compound-Target" was constructed with Cytoscape 3.7.1 software. GO functional enrichment analysis and KEGG pathway enrichment analysis were performed using the DAVID database and visualized through bioinformatics. The intersecting targets were input into Cytoscape 3.7.1 software, and the Network Analyzer tool was employed to screen out the key targets. Then molecular docking was used to verify the binding affinity between the active compounds and the key targets, and molecular dynamics simulation was used to investigate the stability of the binding models. Results: A total of 81 active components, 186 targets of BJJP, and 4041 targets of diabetic atherosclerosis were obtained. Furthermore, 121 overlapping targets were identified. GO functional enrichment analysis revealed that these targets were correlated with the oxidation-reduction process, negative regulation of apoptotic process, inflammatory response, and other biological processes. The results of the KEGG pathway enrichment analysis showed that the common targets mainly participated in proteoglycans in cancer, PPAR signaling pathway, adherens junction, insulin resistance, HIF-1 signaling pathway, PI3K-Akt signaling pathway, etc. The results of molecular docking confirmed that the core active components in BJJP could bind well to the key targets. Results from molecular dynamics simulation showed that the binding energies of AKT1-Luteolin, MMP9-quercetin, and MMP9-luteolin complexes were -28.93 kJ·mol-1, -37.12 kJ·mol-1, and -62.91 kJ·mol-1, respectively. Conclusion: The study revealed that BJJP is characterized as multicomponent, multitarget, and multipathway to treat diabetic atherosclerosis, which is helpful to provide ideas and a basis for pharmacological research and clinical application in the future.

Detecting the Research Trends and Hot Spots in External Irradiation Therapy for Rectal Cancer.

Purpose: The aim of this study is to visualize and analyze the research hot pots in radiation therapy for rectal cancer and provide researchers with a clear and visual reference for subsequent studies. Methods: The literature scientometric analysis about "external beam radiation therapy (EBRT) for rectal cancer" was made through the WoSCC (2010 to 2019). And the data was visualized and analyzed by the Microsoft Office Excel (2019) and CiteSpace (V. 5.7.R1). Results: 4,263 relevant articles were downloaded. The number of published articles per year has been increasing (2010-2020). The United States published the highest number of articles. The UK has the strongest partnerships with other countries/regions. Leiden University has the highest number of published articles and University Texas MD Anderson Cancer Center has extensive collaborations with other academic institutions. The number of articles published in the Diseases of the Colon Rectum is the most, and the Journal of Clinical Oncology is the most cited. 27 articles became the strongest burst citations lasting until 2020. In recent years, a lot of research has been done on "watch and wait", "short-course radiotherapy", "MRI", "neoadjuvant radiotherapy, "MRI in rectal cancer", "chemotherapy regimen improvement", "adding adjuvant chemotherapy", and so on. Conclusion: The current research hot pots may be the "watch and wait", "short-course radiotherapy", "MRI", "neoadjuvant chemoradiotherapy", "MRI in rectal cancer", "chemotherapy regimen improvement", and "adding adjuvant chemotherapy".

[Narrative evidence-based medicine:a strategy for evaluation of clinical efficacy of Chinese medicine].

Rich experience of clinical diagnosis and treatment has been accumulated in the developmental history of Chinese medicine, and the efficacy has been increasingly accepted by the public. However, the evaluation of clinical efficacy is currently based more on scientific evidence instead of merely the changes of patient symptoms. In Chinese medicine, the changes of major disease indicators, patient symptoms, and pathogenesis are the major criteria for the evaluation of clinical efficacy. The lack of well-accepted and uniform criteria and the uncertainty of subjective evaluation limit the development of clinical Chinese medicine. Evidence-based medicine combines clinical skills with the current best evidence. Narrative medicine, utilizing people's narratives in clinical practice, emphasizes patient feelings, willingness, and value orientation. The introduction of both evidence-based medicine and narrative medicine into the evaluation of clinical efficacy refers to the construction of the clinical efficacy evaluation system in a paradigm of participatory diagnosis and treatment. It can fully reflect the characteristics of Chinese medicine, respect the values of patients, and achieve universal clinical evidence. Therefore, it helps to improve the diagnosis and treatment, the relationship between doctors and patients, patients' life quality and decision-making awareness, and finally the new evaluation model of clinical efficacy of Chinese medicine.

PACAP-derived mutant peptide MPAPO protects trigeminal ganglion cell and the retina from hypoxic injury through anti-oxidative stress, anti-apoptosis, and promoting axon regeneration.

The purpose of this study was to determine whether the MPAPO, derived peptide of pituitary adenylate cyclase-activating polypeptide (PACAP), would protect trigeminal ganglion cells (TGCs) and the mice retinas from a hypoxic insult. The nerve endings of the ophthalmic nerve of the trigeminal nerve are widely distributed in eye tissues. In TGCs after hypoxia exposure, we discovered that reactive oxygen species level, the contents of cytosolic cytochrome c and cleaved-caspase-3 were significantly increased, in the meanwhile, m-Calpain was activated and cytoskeleton proteins (αII-spectrin and Synapsin) were degraded, neurites of TGCs disappeared, but these effects were reversed in TGCs treated with MPAPO. The structure of the mice retinas after hypoxic exposure was disordered. Increased lipid peroxidation (LPO), decreased glutathione (GSH) levels, and decreased superoxide dismutase (SOD) activity, positive cells of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), the disintegration of nerve fibers was examined in the retinas following a hypoxic insult. Disordered retina was attenuated with MPAPO eye drops, as well as hypoxia-induced apoptosis in the developing retina, increase in LPO, and decrease in GSH levels and SOD activity of the retina. Moreover, the disintegrated retinal nerve fibers were reassembled after MPAPO treatment. These results suggest that hypoxia induces oxidative stress, apoptosis, and neurites disruption, while MPAPO is remarkably protective against these adverse effects of hypoxia in TGCs and the developing retinas by specifically activating PAC1 receptor.

MDM2 Binding Protein Induces the Resistance of Hepatocellular Carcinoma Cells to Molecular Targeting Agents via Enhancing the Transcription Factor Activity of the Pregnane X Receptor.

The MDM2 binding protein (MTBP) has been considered an important regulator of human malignancies. In this study, we demonstrate that the high level of MTBP's endogenous expression is correlated with poor prognosis of advanced hepatocellular carcinoma (HCC) patients who received sorafenib. MTBP interacted with the Pregnane X receptor (PXR) and enhanced the transcription factor activity of PXR. Moreover, MTBP enhanced the accumulation of PXR in HCC cells' nuclear and the recruitment of PXR to its downstream gene's (cyp3a4's) promoter region. Mechanically, the knockdown of MTBP in MHCC97-H cells with high levels of MTBP decelerated the clearance or metabolism of sorafenib in HCC cells and led to the resistance of HCC cells to sorafenib. Whereas overexpression of MTBP in in MHCC97-L cells with low levels of MTBP showed the opposite trend. By establishing the interaction between MTBP and PXR, our results indicate that MTBP could function as a co-activator of PXR and could be a promising therapeutic target to enhance the sensitivity of HCC cells to molecular targeting agents.

Circadian misalignment leads to changes in cortisol rhythms, blood biochemical variables and serum miRNA profiles.

The circadian clock plays a critical role in synchronizing the inner molecular, metabolic and physiological processes to environmental cues that cycle with a period of 24 h. Non-24 h and shift schedules are commonly used in maritime operations, and both of which can disturb circadian rhythms. In this study, we first conducted an experiment in which the volunteers followed a 3-d rotary schedule with consecutive shift in sleep time (rotatory schedule), and analyzed the changes in salivary cortisol rhythms and blood variables. Next we conducted another experiment in which the volunteers followed an 8 h-on and 4-h off schedule (non-24-h schedule) to compare the changes in blood/serum variables. The rotatory schedule led to elevated levels of serum cortisol during the early stage, and the phase became delayed during the early and late stages. Interestingly, both of the schedules caused comprehensive changes in blood/serum biochemical variables and increased phosphate levels. Furthermore, transcriptomic analysis of the plasma miRNAs from the volunteers following the rotatory schedule identified a subset of serum miRNAs targeting genes involved in circadian rhythms, sleep homeostasis, phosphate transport and multiple important physiological processes. Overexpression of miRNAs targeting the phosphate transport associated genes, SLC20A1 and SLC20A2, showed altered expression due to rotary schedule resulted in attenuated cellular levels of phosphate, which might account for the changed levels in serum phosphate. These findings would further our understanding of the deleterious effects of shift schedules and help to optimize and enhance the performances and welfare of personnel working on similar schedules.

Reversible Splenial Lesion Syndrome (RESLES) After Chemotherapy of Oral Tegafur-uracil in a Female With Locally Rectal Adenocarcinoma.

A 42-year-old woman with reversible splenial lesion syndrome (RESLES) and rectal adenocarcinoma presented with sudden-onset delirium after the sixth cycle of her chemotherapy drug, oral tegafur-uracil (300 mg/m/day, days 1-14, with treatment cycle repeated every 21 days). Accompanied by the anti-CV2 antibody, paraphasia, and a loss of bimanual coordination, the patient's etiology and clinical manifestations of RESLES are unlike those of other reported cases of RESLES. Tegafur-uracil is an oral fluoropyrimidine that has a similar effect to 5-fluorouracil as an adjuvant treatment for colorectal cancer. The possibility that the toxicity of chemotherapeutic drugs may play a role in the pathogenesis of cytotoxic edema in the splenium of the corpus callosum and extracallosal white matter should be investigated further.

Effect of Wenxia Changfu Formula Combined With Cisplatin Reversing Non-Small Cell Lung Cancer Cell Adhesion-Mediated Drug Resistance.

Non-small cell lung cancer (NSCLC), the major form of primary lung cancer, is a common cause of cancer-related death worldwide. Cell adhesion-mediated drug resistance (CAM-DR), a form of chemotherapy resistance, has been reported to confer resistance to various chemotherapeutic agents. Integrin ß1 signaling plays an important role in CAM-DR and has been proposed as a potential target for NSCLC. Wenxia Changfu Formula (WCF) is a Traditional Chinese Compound Prescription for the intervention treatment of NSCLC combined with cisplatin (DDP). This study aims to investigate the effect and mechanism of WCF combined with DDP in reversing CAM-DR. Firstly, the chemical profile of WCF was characterized by UPLC/Q-TOF-MS analysis. A total of 237 compounds with mzCloud Best Match of greater than 70 were identified by using the online database mzCloud. Secondly, we established A549 three-dimensional(3D) cells cultured in vitro and nude mice xenografts models of the A549 cell line with Integrin ß1 overexpression. In vitro, the cell viability, migration and adhesion were measured though MTT Assay, Wound Healing Assay and Cell Adhesion Assay, the Integrin ß1 expression of the A549 cells was assessed through immunocytochemistry; in vitro, the transplanted tumor morphology and the colocalization of Integrin ß1 and its ligands were tested by HE staining and immunofluorescence. As a result, we found that the combination effectively reduced cell viability, suppressed migration and adhesion, and downregulated the protein level of Integrin ß1 in three-dimensional cultured A549 cells. And the combination of WCF with DDP significantly inhibited tumor growth, increased organelle vacuolations and decreased colocalization of Integrin ß1 and its ligands including fibulin-2 and laminin. Taken together, our results confirm that the combination of WCF with DDP could reverse the lung cancer CAM-DR through the Integrin ß1 signaling pathway.

Pharmacological and metagenomics evidence of polysaccharide from Polygonum multiflorum in the alleviation of insulin resistance.

Total polysaccharide from Polygonum multiflorum (PS) and 2,3,5,4'-tetrahydroxy-stilbene-2-O-ß-D-glucoside (TSG) could relieve high-fat and high-sugar diet (HF-HSD) induced rats' insulin resistance (IR) by gut microbiota and host regulation. We found that PS and TSG significantly reversed the increase of fasting blood glucose and the decrease of glucose tolerance in HF-HSD induced IR rats. PS and TSG effectively reversed the imbalance of Firmicutes/Bacteroides caused by an HF-HSD, and significantly reduced the relative abundance of Proteobacteria. It also affected the functional genes of gut microbiota and regulated short-chain fatty acids (SCFAs) and its downstream signal protein molecules. Together, these results indicated that PS and TSG alleviated HF-HSD induced IR by promoting gut microbiota and host function. Thus, PS and TSG may be promising lead substances for developing IR inhibitors that could regulate gut microbiota and its molecular messenger SCFAs to remedy IR.