Sorting nexin 5 mediates virus-induced autophagy and immunity.

Autophagy, a process of degradation that occurs via the lysosomal pathway, has an essential role in multiple aspects of immunity, including immune system development, regulation of innate and adaptive immune and inflammatory responses, selective degradation of intracellular microorganisms, and host protection against infectious diseases1,2. Autophagy is known to be induced by stimuli such as nutrient deprivation and suppression of mTOR, but little is known about how autophagosomal biogenesis is initiated in mammalian cells in response to viral infection. Here, using genome-wide short interfering RNA screens, we find that the endosomal protein sorting nexin 5 (SNX5)3,4 is essential for virus-induced, but not for basal, stress- or endosome-induced, autophagy. We show that SNX5 deletion increases cellular susceptibility to viral infection in vitro, and that Snx5 knockout in mice enhances lethality after infection with several human viruses. Mechanistically, SNX5 interacts with beclin 1 and ATG14-containing class III phosphatidylinositol-3-kinase (PI3KC3) complex 1 (PI3KC3-C1), increases the lipid kinase activity of purified PI3KC3-C1, and is required for endosomal generation of phosphatidylinositol-3-phosphate (PtdIns(3)P) and recruitment of the PtdIns(3)P-binding protein WIPI2 to virion-containing endosomes. These findings identify a context- and organelle-specific mechanism-SNX5-dependent PI3KC3-C1 activation at endosomes-for initiation of autophagy during viral infection.

TLR9 and beclin 1 crosstalk regulates muscle AMPK activation in exercise.

The activation of adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle coordinates systemic metabolic responses to exercise1. Autophagy-a lysosomal degradation pathway that maintains cellular homeostasis2-is upregulated during exercise, and a core autophagy protein, beclin 1, is required for AMPK activation in skeletal muscle3. Here we describe a role for the innate immune-sensing molecule Toll-like receptor 9 (TLR9)4, and its interaction with beclin 1, in exercise-induced activation of AMPK in skeletal muscle. Mice that lack TLR9 are deficient in both exercise-induced activation of AMPK and plasma membrane localization of the GLUT4 glucose transporter in skeletal muscle, but are not deficient in autophagy. TLR9 binds beclin 1, and this interaction is increased by energy stress (glucose starvation and endurance exercise) and decreased by a BCL2 mutation3,5 that blocks the disruption of BCL2-beclin 1 binding. TLR9 regulates the assembly of the endolysosomal phosphatidylinositol 3-kinase complex (PI3KC3-C2)-which contains beclin 1 and UVRAG-in skeletal muscle during exercise, and knockout of beclin 1 or UVRAG inhibits the cellular AMPK activation induced by glucose starvation. Moreover, TLR9 functions in a muscle-autonomous fashion in ex vivo contraction-induced AMPK activation, glucose uptake and beclin 1-UVRAG complex assembly. These findings reveal a heretofore undescribed role for a Toll-like receptor in skeletal-muscle AMPK activation and glucose metabolism during exercise, as well as unexpected crosstalk between this innate immune sensor and autophagy proteins.

The abscisic acid-responsive element binding factors MAPKKK18 module regulates abscisic acid-induced leaf senescence in Arabidopsis.

The mitogen-activated protein kinase kinase kinase 18 (MAPKKK18) has been reported to play a role in abiotic stress priming in long-term abscisic acid (ABA) response including drought tolerance and leaf senescence. However, the upstream transcriptional regulators of MAPKKK18 remain to be determined. Here, we report ABA-responsive element binding factors (ABFs) as upstream transcription factors of MAPKKK18 expression. Mutants of abf2, abf3, abf4, and abf2abf3abf4 dramatically reduced the transcription of MAPKKK18. Our electrophoresis mobility shift assay and dual-luciferase reporter assay demonstrated that ABF2, ABF3, and ABF4 bound to ABA-responsive element cis-elements within the promoter of MAPKKK18 to transactivate its expression. Furthermore, enrichments of the promoter region of MAPKKK18 by ABF2, ABF3, and ABF4 were confirmed by in vivo chromatin immunoprecipitation coupled with quantitative PCR. In addition, we found that mutants of mapkkk18 exhibited obvious delayed leaf senescence. Moreover, a genetic study showed that overexpression of ABF2, ABF3, and ABF4 in the background of mapkkk18 mostly phenocopied the stay-green phenotype of mapkkk18 and, expression levels of five target genes of ABFs, that is, NYE1, NYE2, NYC1, PAO, and SAG29, were attenuated as a result of MAPKKK18 mutation. These findings demonstrate that ABF2, ABF3, and ABF4 act as transcription regulators of MAPKKK18 and also suggest that, at least in part, ABA acts in priming leaf senescence via ABF-induced expression of MAPKKK18.

The microRNA miR-202 prevents precocious spermatogonial differentiation and meiotic initiation during mouse spermatogenesis.

Spermatogonial differentiation and meiotic initiation during spermatogenesis are tightly regulated by a number of genes, including those encoding enzymes for miRNA biogenesis. However, whether and how single miRNAs regulate these processes remain unclear. Here, we report that miR-202, a member of the let-7 family, prevents precocious spermatogonial differentiation and meiotic initiation in spermatogenesis by regulating the timely expression of many genes, including those for key regulators such as STRA8 and DMRT6. In miR-202 knockout (KO) mice, the undifferentiated spermatogonial pool is reduced, accompanied by age-dependent decline of fertility. In KO mice, SYCP3, STRA8 and DMRT6 are expressed earlier than in wild-type littermates, and Dmrt6 mRNA is a direct target of miR-202-5p. Moreover, the precocious spermatogonial differentiation and meiotic initiation were also observed in KO spermatogonial stem cells when cultured and induced in vitro, and could be partially rescued by the knockdown of Dmrt6. Therefore, we have not only shown that miR-202 is a regulator of meiotic initiation but also identified a previously unknown module in the underlying regulatory network.

IndGOterm: a qualitative method for the identification of individually dysregulated GO terms in cancer.

Individual pathway analysis can dissect heterogeneities among different cancer patients and provide efficient guidelines for individualized therapy. However, the existence of the batch effect brings extensive limitations for the application of many individual methods for pathway analysis. Previously, researchers proposed that methods based on within-sample relative expression ordering (REO) of the genes are notably insensitive to 'batch effects'. In this article, we focus on the Gene Ontology (GO) database and propose an individual qualitative GO term analysis method (IndGOterm) based on the REO of genes. Compared with some current widely used single-sample enrichment analysis methods, such as ssGSEA and GSVA, IndGOterm has a predominance of ignoring the batch effects caused by diverse technologies. Through the survival and drug responses analysis, we found IndGOterm could capture more terms connected to cancer than other single-sample enrichment analysis methods. Furthermore, through the application of IndGOterm, we found some terms that present different dysregulation models that manifest heterogenetic in homologous patients. Collectively, these results attested that IndGOterm could capture useful information from patients and be a useful tool to reveal the intrinsic characteristic of cancer. An open-source R statistical analysis package 'IndGOterm' is available at https://github.com/robert19960424/IndGOterm.

Modulating ß-Keto-enamine-Based Covalent Organic Frameworks for Photocatalytic Atom-Transfer Radical Addition Reaction.

The atom-transfer radical addition (ATRA) reaction simultaneously forges carbon-carbon and carbon-halogen bonds. However, frequently-used photosensitizers such as precious transition metal complexes, or organic dyes have limitations in terms of their potential toxicity and recyclability. Three ß-ketoenamine-linked covalent organic frameworks (COFs) from 1,3,5-triformylphloroglucinol and 1,4-phenylenediamines with variable transient photocurrent and photocatalytic activity have been prepared. A COF bearing electron-deficient Cl atoms displayed the highest photocatalytic activity toward the ATRA reaction of polyhalogenated alkanes to give halogenated olefins under visible light at room temperature. This heterogeneous photocatalyst exhibited good functional group tolerance and could be recycled without significant loss of activity.

A Mine Water Source Prediction Model Based on LIF Technology and BWO-ELM.

The traditional methods for identifying water sources in coal mines lack the ability to quickly detect water sources and are prone to causing secondary pollution of samples. In contrast, laser induced fluorescence (LIF) technology has been introduced for the identification of coal mine water sources due to its high sensitivity and real-time performance. However, extreme learning machine (ELM) have shortcomings in randomly selecting weights and biases. The Beluga Whale Optimization (BWO) algorithm has efficient optimization capability, global search capability, adaptability and parallelism, and can find the optimal weights and biases in a short time. The combination of LIF technology and BWO-ELM model can be applied to quickly identify the welling water source in coal mine. Select sandstone water and old goaf water from the Huainan mining area as experimental samples, and mix them in different proportions to prepare 7 mixed water samples for testing. Utilize LIF technology to obtain spectral curve images, preprocess them with polynomial smoothing algorithm (SG) and spectral multiple scattering correction (MSC), and perform dimensionality reduction using factor analysis (FA) and linear discriminant analysis (LDA) methods. Finally, construct ELM models, Long Short Term Memory (LSTM) models, BWO-ELM models, and Particle Swarm Optimization Extreme Learning Machine(PSO-ELM) models for the dimensionality reduced data. In order to improve the reliability and accuracy of the results, the experimental results were kept to 5 decimal places. From the experimental results, it can be seen that SG-LDA-BWO-ELM has the best fitting effect, with a fitting coefficient of 0.99990, a root mean square error of 0.00041, a mean square error approaching 0, and an average absolute error of 0.00021. It has the best convergence and the smallest absolute error among all models, making it the most suitable for identifying mine water inrush. It is of great significance for preventing and controlling mine water disasters and ensuring coal mine production safety.

Plant-derived virulence arresting drugs as novel antimicrobial agents: Discovery, perspective, and challenges in clinical use.

Antimicrobial resistance (AMR) emerges as a severe crisis to public health and requires global action. The occurrence of bacterial pathogens with multi-drug resistance appeals to exploring alternative therapeutic strategies. Antivirulence treatment has been a positive substitute in seeking to circumvent AMR, which aims to target virulence factors directly to combat bacterial infections. Accumulated evidence suggests that plant-derived natural products, which have been utilized to treat infectious diseases for centuries, can be abundant sources for screening potential virulence-arresting drugs (VADs) to develop advanced therapeutics for infectious diseases. This review sums up some virulence factors and their actions in various species of bacteria, as well as recent advances pertaining to plant-derived natural products as VAD candidates. Furthermore, we also discuss natural VAD-related clinical trials and patents, the perspective of VAD-based advanced therapeutics for infectious diseases and critical challenges hampering clinical use of VADs, and genomics-guided identification for VAD therapeutic. These newly discovered natural VADs will be encouraging and optimistic candidates that may sustainably combat AMR.

Exploring quality evaluation markers of Fructus Psoraleae based on chemometric analysis integrated with network pharmacology.

INTRODUCTION: Fructus Psoraleae (FP) is a well-known traditional Chinese medicine for the treatment of osteoporosis. However, major quality differences were witnessed owing to its various origins, thus influencing its safety and efficacy. OBJECTIVES: The study aimed to evaluate the quality of FP from different origins and predict its quality evaluation markers. METHODS: Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry was employed for tentative characterisation of the constituents in 10 batches of FP, followed by the utilisation of multivariate statistical analysis methods including principal component analysis and orthogonal partial least squares discriminant analysis for quality evaluation. Network pharmacology approaches were utilised to explore the underlying mechanism of the screened chemotaxonomic markers in treating osteoporosis. RESULTS: Forty-one components in FP including, chalcones, coumarins, coumestans, flavonoids, iso-flavonoids, and phenolics, were characterised based on their fragmentation pathways. Ten batches of FP were basically divided into three categories, and eight chemotaxonomic markers including isopsoralen, calamenene, bakuchiol, psoralen, bavachinin, isoneobavaisoflavone, corylifol C, and neobavaisoflavone were screened. Network pharmacology revealed that the chemotaxonomic markers can act on targets such as AKT1, HSP90AA1, and EGFR and possess effects mainly through glycolysis and wnt/ß-catenin signalling to alleviate osteoporosis. Molecular docking and molecular dynamic simulation confirmed the good binding affinity and stability between proteins and selected markers. So, eight chemotaxonomic markers were all preferentially recommended as quality evaluation markers. CONCLUSION: The study not only provides a reference for the improvement of quality control of FP but also offers a theoretical basis for its further in-depth research in osteoporosis.

The Biological Activity of Ganoderma lucidum on Neurodegenerative Diseases: The Interplay between Different Active Compounds and the Pathological Hallmarks.

Neurodegenerative diseases represent a cluster of conditions characterized by the progressive degeneration of the structure and function of the nervous system. Despite significant advancements in understanding these diseases, therapeutic options remain limited. The medicinal mushroom Ganoderma lucidum has been recognized for its comprehensive array of bioactive compounds with anti-inflammatory and antioxidative effects, which possess potential neuroprotective properties. This literature review collates and examines the existing research on the bioactivity of active compounds and extracts from Ganoderma lucidum in modulating the pathological hallmarks of neurodegenerative diseases. The structural information and preparation processes of specific components, such as individual ganoderic acids and unique fractions of polysaccharides, are presented in detail to facilitate structure-activity relationship research and scale up the investigation of in vivo pharmacology. The mechanisms of these components against neurodegenerative diseases are discussed on multiple levels and elaborately categorized in different patterns. It is clearly presented from the patterns that most polysaccharides of Ganoderma lucidum possess neurotrophic effects, while ganoderic acids preferentially target specific pathogenic proteins as well as regulating autophagy. Further clinical trials are necessary to assess the translational potential of these components in the development of novel multi-target drugs for neurodegenerative diseases.

Record High Iodate Anion Capture by a Redox-Active Cationic Polymer Network.

As a critical radioactive anionic contaminant, traditional adsorbents primarily remove iodate (IO3 -) through ion exchange or hard acid-hard base interactions, but suffer from limited affinity and capacity. Herein, employing the synergistic effect of ion exchange and redox, we successfully synthesized a redox-active cationic polymer network (SCU-CPN-6, [C9H10O2N5 ⋅ Cl]n) by merging guanidino groups with ion-exchange capability and phenolic groups with redox ability via a Schiff base reaction. SCU-CPN-6 exhibits a groundbreaking adsorption capacity of 896 mg/g for IO3 -. The inferior adsorption capacities of polymeric networks containing only redox (~0 mg/g) or ion exchange (232 mg/g) fragments underscore the synergistic "1+1>2" effect of the two mechanisms. Besides, SCU-CPN-6 shows excellent uptake selectivity for IO3 - in the presence of high concentrations of SO4 2-, Cl-, and NO3 -. Meanwhile, a high distribution coefficient indicates its exemplary deep-removal performance for low IO3 - concentration. The synergic strategy not only presents a breakthrough solution for the efficient removal of IO3 - but also establishes a promising avenue for the design of advanced adsorbents for diverse applications.

Stereoselective Synthesis of Polysubstituted Conjugated Dienes Enabled by Photo-Driven Sequential Sigmatropic Rearrangement.

We here reported a highly stereoselective method for the synthesis of polysubstituted conjugated dienes from α-aryl α-diazo alkynyl ketones and pyrazole-substituted unsymmetric aminals under mild conditions, which was promoted by photo-irridation and involved with 1,6-dipolar intermediate and quadruple sigmatropic rearrangements, was successfully developed. In this transformation, the cleavage of four bonds and the recombination of five bonds were implemented in one operational step. This protocol provided a modular tool for constructing dienes from amines, pyrazoles and α-alkynyl-α-diazoketones in one-pot manner. The results of mechanistic investigation indicated that the plausible reaction path underwent the 1,6-sigmatropic rearrangement instead of the 1,5-sigmatropic rearrangement.

Ultraviolet metalens for photoacoustic microscopy with an elongated depth of focus.

Ultraviolet photoacoustic microscopy (UV-PAM) can achieve in vivo imaging without exogenous markers and play an important role in pathological diagnosis. However, traditional UV-PAM is unable to detect enough photoacoustic signals due to the very limited depth of focus (DOF) of excited light and the sharp decrease in energy with increasing sample depth. Here, we design a millimeter-scale UV metalens based on the extended Nijboer-Zernike wavefront-shaping theory which can effectively extend the DOF of a UV-PAM system to about 220 µm while maintaining a good lateral resolution of 1.063 µm. To experimentally verify the performance of the UV metalens, a UV-PAM system is built to achieve the volume imaging of a series of tungsten filaments at different depths. This work demonstrates the great potential of the proposed metalens-based UV-PAM in the detection of accurate diagnostic information for clinicopathologic imaging.

Risk stratification and prognostic value of multi-modal MRI-based radiomics for extranodal nasal-type NK/T-cell lymphoma.

BACKGROUND: Magnetic resonance imaging (MRI) performs well in the locoregional assessment of extranodal nasal-type NK/T-cell lymphoma (ENKTCL). It's important to assess the value of multi-modal MRI-based radiomics for estimating overall survival (OS) in patients with ENKTCL. METHODS: Patients with ENKTCL in a prospectively cohort were systemically reviewed and all the pretreatment MRI were acquisitioned. An unsupervised spectral clustering method was used to identify risk groups of patients and radiomic features. A nomogram-revised risk index (NRI) plus MRI radiomics signature (NRI-M) was developed, and compared with the NRI. RESULTS: The 2 distinct type I and II groups of the MRI radiomics signatures were identified. The 5-year OS rates between the type I and type II groups were 87.2% versus 67.3% (P = 0.002) in all patients, and 88.8% versus 69.2% (P = 0.003) in early-stage patients. The discrimination and calibration of the NRI-M for OS prediction demonstrated a better performance than that of either MRI radiomics or NRI, with a mean area under curve (AUC) of 0.748 and 0.717 for predicting the 5-year OS in all-stages and early-stage patients. CONCLUSIONS: The NRI-M model has good performance for predicting the prognosis of ENKTCL and may help design clinical trials and improve clinical decision making.

Value of 2D ultrasonography in the diagnosis and evaluation of intrauterine adhesions - a prospective study.

RESEARCH QUESTION: What is the value of 2D ultrasonography in the diagnosis and assessment of intrauterine adhesions (IUA)? DESIGN: This was a prospective study conducted at a hysteroscopy centre. RESULTS: Of a total of 600 subjects recruited, 41 dropped out and 559 were finally enrolled and analysed. The observed 2D ultrasonography features, in decreasing order of frequency, were 'irregular endometrium' (37.9%), 'broken endometrial echo' (23.4%), 'thin endometrium' (13.7%), 'loss of endometrial echo' (13.1%,), 'hyperechoic focus' (12.5%) and 'fluid in the cavity' (8.8%). The sensitivity of individual ultrasound features ranged from 8.8% to 37.9%, whereas the specificity of individual ultrasound features ranged from 78.9% to 100%. When all the six ultrasound features were considered together, the sensitivity and specificity were 71.7% and 66.2% respectively. The sensitivity, specificity and accuracy of ultrasound diagnosis in the mid-proliferative phase, peri-ovulatory phase and mid-luteal phase did not appear to be significantly different statistically, although the results in the mid-proliferative phase appeared to be consistently higher than those in the mid-luteal phase. In women confirmed to have IUA, the likelihood of the adhesions being severe in nature in the presence of zero, one, two or three or more ultrasound features was 8.7%, 23.0%, 40.2% and 80.5%, respectively (P < 0.001). CONCLUSIONS: The findings in this study support the notions that ultrasonography examination in women suspected to have IUA cannot replace hysteroscopy in the diagnosis of the condition. However, it does provide useful clinical information regarding severity and could help in the planning of hysteroscopy to optimize management.

A spectral learning path for simultaneous multi-parameter detection of water quality.

Water quality parameters (WQP) are the most intuitive indicators of the environmental quality of water body. Due to the complexity and variability of the chemical environment of water body, simple and rapid detection of multiple parameters of water quality becomes a difficult task. In this paper, spectral images (named SPIs) and deep learning (DL) techniques were combined to construct an intelligent method for WQP detection. A novel spectroscopic instrument was used to obtain SPIs, which were converted into feature images of water chemistry and then combined with deep convolutional neural networks (CNNs) to train models and predict WQP. The results showed that the method of combining SPIs and DL has high accuracy and stability, and good prediction results with average relative error of each parameter (anions and cations, TOC, TP, TN, NO3--N, NH3-N) at 1.3%, coefficient of determination (R2) of 0.996, root mean square error (RMSE) of 0.1, residual prediction deviation (RPD) of 16.2, and mean absolute error (MAE) of 0.067. The method can achieve rapid and accurate detection of high-dimensional water quality multi-parameters, and has the advantages of simple pre-processing and low cost. It can be applied not only to the intelligent detection of environmental waters, but also has the potential to be applied in chemical, biological and medical fields.

Adaptation of prelimbic cortex mediated by IL-6/STAT3/Acp5 pathway contributes to the comorbidity of neuropathic pain and depression in rats.

BACKGROUND: The adaption of brain region is fundamental to the development and maintenance of nervous system disorders. The prelimbic cortex (PrL) participates in the affective components of the pain sensation. However, whether and how the adaptation of PrL contributes to the comorbidity of neuropathic pain and depression are unknown. METHODS: Using resting-state functional magnetic resonance imaging (rs-fMRI), genetic knockdown or overexpression, we systematically investigated the activity of PrL region in the pathogenesis of neuropathic pain/depression comorbid using the combined approaches of immunohistochemistry, electrophysiology, and behavior. RESULTS: The activity of PrL and the excitability of pyramidal neurons were decreased, and the osteoclastic tartrate-resistant acid phosphatase 5 (Acp5) expression in PrL neurons was upregulated following the acquisition of spared nerve injury (SNI)-induced comorbidity. Genetic knockdown of Acp5 in pyramidal neurons, but not parvalbumin (PV) neurons or somatostatin (SST) neurons, attenuated the decrease of spike number, depression-like behavior and mechanical allodynia in comorbidity rats. Overexpression of Acp5 in PrL pyramidal neurons decreased the spike number and induced the comorbid-like behavior in naïve rats. Moreover, the expression of interleukin-6 (IL-6), phosphorylated STAT3 (p-STAT3) and acetylated histone H3 (Ac-H3) were significantly increased following the acquisition of comorbidity in rats. Increased binding of STAT3 to the Acp5 gene promoter and the interaction between STAT3 and p300 enhanced acetylation of histone H3 and facilitated the transcription of Acp5 in PrL in the modeled rodents. Inhibition of IL-6/STAT3 pathway prevented the Acp5 upregulation and attenuated the comorbid-like behaviors in rats. CONCLUSIONS: These data suggest that the adaptation of PrL mediated by IL-6/STAT3/Acp5 pathway contributed to the comorbidity of neuropathic pain/depression induced by SNI.

Phase 1 trial of apatinib combined with intensity-modulated radiotherapy in unresectable hepatocellular carcinoma.

BACKGROUND: To investigate the maximum tolerated dose (MTD) of apatinib delivered during and after intensity-modulated radiotherapy (IMRT) for unresectable hepatocellular carcinoma (HCC). METHODS: Patients with unresectable HCC who were not eligible for radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), or residual/ recurrent after the prior local treatment were enrolled. Patients were scheduled to be treated with IMRT at 50-60 Gy/25-30 fractions. Oral apatinib tablets were administered concurrently with IMRT and continued thereafter. We used a 3 + 3 dose-escalation design, with three dose levels of apatinib (250, 500, and 750 mg). Grade 3 or more severe adverse events (AEs) were defined as dose-limiting toxicities (DLTs). The treatment response was calculated using the Modified Response Evaluation Criteria in Solid Tumours. RESULTS: Nine patients with Barcelona Clinic Liver Cancer Stage C were included. One patient withdrew from the apatinib 250 mg group and another patient was added. No DLTs occurred in the apatinib 250 mg group. Five patients were included in the apatinib 500 mg group, and 2 cases of DLT (grade 3 leukopenia) were found among them. Dose escalation was terminated and the MTD was determined to be 250 mg. Common grade 1-2 AEs included fatigue, hypertension, dizziness, bone marrow suppression, and hyperbilirubinemia. The median follow-up time for all patients was 16.0 months. Three patients achieved complete response and another three achieved partial response. The objective response rate was 6/9 (66.7%), and the disease control rate was 9/9 (100%). Three patients relapsed out of the radiation field. The median progression-free survival was 17.0 months, and the median overall survival was 16.7 months. CONCLUSIONS: When combined with IMRT, apatinib 250 mg daily was recommended for a phase 2 study of unresectable HCC. The antitumor activity of the combination treatment was encouraging. The safety and efficacy of apatinib combined with IMRT for unresectable HCC should be further investigated in future studies. TRIAL REGISTRATION: Registration No. ChiCTR1800018309 . Registered 11 September 2018. Retrospectively registered, https://www.chictr.org.cn/showproj.aspx?proj=30461 .

Metformin Relieves Bortezomib-Induced Neuropathic Pain by Regulating AMPKa2-Mediated Autophagy in the Spinal Dorsal Horn.

Chemotherapy-induced neuropathic pain is a major clinical problem with limited treatment options. Here, we show that metformin relieves bortezomib (BTZ)-evoked induction and maintenance of neuropathic pain by preventing the reduction in the expression of Beclin-1, an autophagy marker, in the spinal dorsal horn. Application of rapamycin or 3-methyladenine, autophagy inducer and inhibitor, respectively, affected the mechanical allodynia differently. Co-application of 3-methyladenine and metformin partially inhibited the effect of metformin in recovering Beclin-1 expression and in reducing the pain behavior in rats subjected to BTZ treatment. BTZ treatment also reduced the expression of AMPKa2 in the dorsal horn, which was recovered by metformin treatment. Overexpression of AMPKa2 attenuated the BTZ-evoked reduction in Beclin-1 expression and mechanical allodynia, whereas intrathecal injection of AMPKa2 siRNA decreased the Beclin-1 expression and induced mechanical allodynia in naive rats. Moreover, BTZ treatment increased the GATA3 expression in the dorsal horn, and GATA3 siRNA attenuated the AMPKa2 downregulation and mechanical allodynia induced by BTZ. Chromatin immunoprecipitation further showed that BTZ induced an increased recruitment of GATA3 to multiple sites in the AMPKa2 promoter region. Furthermore, decreased acetylation and increased methylation of histone H3 in the AMPKa2 promoter in the spinal dorsal horn was detected after BTZ treatment. Our findings suggest that metformin may regulate AMPKa2-mediated autophagy in the dorsal horn and alleviate the behavioral hypersensitivity induced by BTZ.

Adsorption of Congo red and tetracycline onto water treatment sludge biochar: characterisation, kinetic, equilibrium and thermodynamic study.

In this study, readily available inexpensive water treatment sludge (WTS) was used to prepare adsorbent for the removal of Congo red (CR) and tetracycline (TC) from aqueous solutions. The structural characteristics and adsorption properties of WTS biochar were characterised via scanning electron microscope, energy dispersive X-ray spectroscopy, Brunauer-Emmett-Teller and Fourier Transform infrared spectroscopy. In batch experiments, the adsorption factors, kinetics, isothermal curves and thermodynamics of the adsorption properties were investigated. The optimum preparation condition of WTS biochar was 400 °C for 4 h under O2-limited pyrolysis, which exhibited increased specific surface area and pore structures. The best adsorption was observed when the pH of the CR and TC solutions was 7 and 4, respectively. The adsorption process followed the pseudo-second-order model, indicating that the main control step was the chemical adsorption process. Isotherm data were best described by the Langmuir model, and the maximum adsorption capacities for CR and TC were 116.4 and 58.5 mg·g-1, respectively. Thermodynamic parameters revealed that the adsorption process was spontaneous and endothermic. According to the analysis, the adsorption mechanism of CR could be attributed to electrostatic attraction, π-π conjugation and hydrogen bonding, whereas that of TC was potentially associated with cation exchange, complex precipitation, π-π conjugation and hydrogen bonding.