NPCDR: natural product-based drug combination and its disease-specific molecular regulation.

Natural product (NP) has a long history in promoting modern drug discovery, which has derived or inspired a large number of currently prescribed drugs. Recently, the NPs have emerged as the ideal candidates to combine with other therapeutic strategies to deal with the persistent challenge of conventional therapy, and the molecular regulation mechanism underlying these combinations is crucial for the related communities. Thus, it is urgently demanded to comprehensively provide the disease-specific molecular regulation data for various NP-based drug combinations. However, no database has been developed yet to describe such valuable information. In this study, a newly developed database entitled 'Natural Product-based Drug Combination and Its Disease-specific Molecular Regulation (NPCDR)' was thus introduced. This database was unique in (a) providing the comprehensive information of NP-based drug combinations & describing their clinically or experimentally validated therapeutic effect, (b) giving the disease-specific molecular regulation data for a number of NP-based drug combinations, (c) fully referencing all NPs, drugs, regulated molecules/pathways by cross-linking them to the available databases describing their biological or pharmaceutical characteristics. Therefore, NPCDR is expected to have great implications for the future practice of network pharmacology, medical biochemistry, drug design, and medicinal chemistry. This database is now freely accessible without any login requirement at both official (https://idrblab.org/npcdr/) and mirror (http://npcdr.idrblab.net/) sites.

Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/Cl- efflux signaling pathway.

BACKGROUND: Osteoarthritis (OA), in which macrophage-driven synovitis is considered closely related to cartilage destruction and could occur at any stage, is an inflammatory arthritis. However, there are no effective targets to cure the progression of OA. The NOD-, LRR-,and pyrin domain-containing protein 3 (NLRP3) inflammasome in synovial macrophages participates in the pathological inflammatory process and treatment strategies targeting it are considered to be an effective approach for OA. PIM-1 kinase, as a downstream effector of many cytokine signaling pathways, plays a pro-inflammatory role in inflammatory disease. METHODS: In this study, we evaluated the expression of the PIM-1 and the infiltration of synovial macrophages in the human OA synovium. The effects and mechanism of PIM-1 were investigated in mice and human macrophages stimulated by lipopolysaccharide (LPS) and different agonists such as nigericin, ATP, Monosodium urate (MSU), and Aluminum salt (Alum). The protective effects on chondrocytes were assessed by a modified co-culture system induced by macrophage condition medium (CM). The therapeutic effect in vivo was confirmed by the medial meniscus (DMM)-induced OA in mice. RESULTS: The expression of PIM-1 was increased in the human OA synovium which was accompanied by the infiltration of synovial macrophages. In vitro experiments, suppression of PIM-1 by SMI-4a, a specific inhibitor, rapidly inhibited the NLRP3 inflammasome activation in mice and human macrophages and gasdermin-D (GSDME)-mediated pyroptosis. Furthermore, PIM-1 inhibition specifically blocked the apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization in the assembly stage. Mechanistically, PIM-1 inhibition alleviated the mitochondrial reactive oxygen species (ROS)/chloride intracellular channel proteins (CLICs)-dependent Cl- efflux signaling pathway, which eventually resulted in the blockade of the ASC oligomerization and NLRP3 inflammasome activation. Furthermore, PIM-1 suppression showed chondroprotective effects in the modified co-culture system. Finally, SMI-4a significantly suppressed the expression of PIM-1 in the synovium and reduced the synovitis scores and the Osteoarthritis Research Society International (OARSI) score in the DMM-induced OA model. CONCLUSIONS: Therefore, PIM-1 represented a new class of promising targets as a treatment of OA to target these mechanisms in macrophages and widened the road to therapeutic strategies for OA.

Design, synthesis, antiviral and fungicidal activities of novel polycarpine simplified analogues.

Fungal and viral diseases account for 70-80% of agricultural production losses caused by microbial diseases. Synthetic fungicides and antiviral agents have been used to treat plant diseases caused by plant pathogenic fungi and viruses, but their use has been criticized due to their adverse side effects. As alternative strategies, natural fungicides and antiviral agents have attracted many researchers' interest in recent years. Herein, we designed and synthesized a series of novel polycarpine simplified analogues. Antiviral activity research against tobacco mosaic virus (TMV) revealed that most of the designed compounds have good antiviral activities. The virucidal activities of 4, 6d, 6f, 6h, and 8c are higher than that of polycarpine and similar to that of ningnanmycin. The structure simplified compound 8c was selected for further antiviral mechanism research which showed that compound 8c could inhibit the formation of 20S protein discs by acting on TMV coat protein. These compounds also displayed broad-spectrum fungicidal activities against 7 kinds of plant fungi. This work lays the foundation for the application of polycarpine simplified analogues in crop protection.

Research on Simultaneous Measurement of Magnetic Field and Temperature Based on Petaloid Photonic Crystal Fiber Sensor.

In this paper, we propose and design a magnetic field and temperature sensor using a novel petaloid photonic crystal fiber filled with magnetic fluid. The PCF achieves a high birefringence of more than 1.43 × 10-2 at the wavelength of 1550 nm via the design of material parameters, air hole shape and the distribution of the photonic crystal fiber. Further, in order to significantly improve the sensitivity of the sensor, the magnetic-fluid-sensitive material is injected into the pores of the designed photonic crystal fiber. Finally, the sensor adopts a Mach-Zehnder interferometer structure combined with the ultra-high birefringence of the proposed petaloid photonic crystal fiber. Magnetic field and temperature can be simultaneously measured via observing the spectral response of the x-polarization state and y-polarization state. As indicated via simulation analysis, the sensor can realize sensitivities to magnetic fields and temperatures at -1.943 nm/mT and 0.0686 nm/°C in the x-polarization state and -1.421 nm/mT and 0.0914 nm/°C in the y-polarization state. The sensor can realize the measurement of multiple parameters including temperature and magnetic intensity and has the advantage of high sensitivity.

Discovery of Barakacin and Its Derivatives as Novel Antiviral and Fungicidal Agents.

Pesticides are essential for the development of agriculture. It is urgent to develop green, safe and efficient pesticides. Bisindole alkaloids have unique and concise structures and broad biological activities, which make them an important leading skeleton in the creation of new pesticides. In this work, we synthesized bisindole alkaloid barakacin in a simple seven-step process, and simultaneously designed and synthesized a series of its derivatives. Biological activity research indicated that most of these compounds displayed good antiviral activities against tobacco mosaic virus (TMV). Among them, compound 14b exerted a superior inhibitory effect in comparison to commercially available antiviral agent ribavirin, and could be expected to become a novel antiviral candidate. Molecular biology experiments and molecular docking research found that the potential target of compound 14b was TMV coat protein (CP). These compounds also showed broad-spectrum anti-fungal activities against seven kinds of plant fungi.

Heterologous expression of pediocin/papA in Bacillus subtilis.

Listeria monocytogenes is a food-borne pathogen. Pediocin is a group IIα bacteriocin with anti-listeria activity that is naturally produced by Pediococcus acidilactic and Lactobacillus plantarum. The pedA/papA gene encodes pediocin/plantaricin. In native hosts, the expression and secretion of active PedA/PapA protein rely on the accessory protein PedC/PapC and ABC transporter PedD/PapD on the same operon. The excretion machines were also necessary for pediocin protein expression in heterologous hosts of E. coli, Lactobacillus lactis, and Corynebacterium glutamicum. In this study, two vectors carrying the codon sequence of the mature PapA peptide were constructed, one with and one without a His tag. Both fragments were inserted into the plasmid pHT43 and transformed into Bacillus subtilis WB800N. The strains were induced with IPTG to secrete the fused proteins PA1 and PA2. Supernatants from both recombinant strains can inhibit Listeria monocytogenes ATCC54003 directly. The fused protein possesses inhibition activity as a whole dispense with removal of the leading peptide. This is the first report of active pediocin/PapA expression without the assistance of PedCD/PapCD in heterogeneous hosts. In addition, the PA1 protein can be purified by nickel-nitrilotriacetic acid (Ni-NTA) metal affinity chromatography.

Chemokine (C-C motif) receptor 2 is associated with the pathological grade and inflammatory response in IgAN children.

BACKGROUND: Chemokine (C-C motif) receptor 2 (CCR2) is involved in important physiological and pathological processes, such as inflammation and autoimmune diseases. Abnormal immune and inflammatory responses play a critical role in the development and progression of IgA nephritis (IgAN). However, the role of CCR2 in IgAN is unknown. METHODS: Fifteen IgAN children who were diagnosed by kidney biopsy provided kidney biopsy tissue, blood and urine samples, and age-matched healthy control subjects (blood donators n = 12; tissue donators n = 8) were included. Immunohistochemical analysis was used to detect the expression of CCR2, MCP-1, IL-6, IL-17, and TNF-α in the kidney tissues. Relative optical density (OD) was calculated by Image J software, and the correlation between CCR2 expression and pathological grade in IgAN children was analyzed. RESULTS: The expression of CCR2 significantly increased in mesangial cells of children with IgAN compared to that in control group (P < 0.001), especially in IgAN patients with Lee's grade III to IV (P < 0.001). Interestingly, CCR2 expression was positively correlated with Lee's grade (r = 0.9152, P = 0.0001) in IgAN children. The expression levels of inflammatory factors were markedly increased in IgAN children, and importantly CCR2 expression was positively correlated with it's expression level. CONCLUSIONS: The results suggest that CCR2 signaling might be involved in pathological process and inflammatory responses of children IgAN, and could potentially be an intervention target in children IgAN.

Insight into Lotusine and Puerarin in Repairing Alcohol-Induced Metabolic Disorder Based on UPLC-MS/MS.

Alcohol is an essential element in human culture. However, alcoholism has contributed to numerous health issues, including alcoholic fatty liver and sudden death. We found that the alkaloid lotusine possessed hepato- and neuroprotection against alcohol injuries. Lotusine showed comparable protective effects to puerarin, a widely recognized antagonist against alcohol damage. To better understand the metabolic response to alcohol injury and antagonist molecules, we applied sensitive zebrafish and LC-ESI-MS to collect metabolites related to alcohol, puerarin and lotusine exposure. LC-MS identified 119 metabolites with important physiological roles. Differential metabolomic analysis showed that alcohol caused abnormal expression of 82 metabolites (60 up-regulated and 22 down-regulated). These differential metabolites involved 18 metabolic pathways and modules, including apoptosis, necroptosis, nucleotide and fatty acid metabolism. Puerarin reversed seven metabolite variations induced by alcohol, which were related to necroptosis and sphingolipid metabolism. Lotusine was found to repair five metabolites disorders invoked by alcohol, mainly through nucleotide metabolism and glutathione metabolism. In phenotypic bioassay, lotusine showed similar activities to puerarin in alleviating behavioral abnormalities, neuroapoptosis and hepatic lipid accumulation induced by alcohol exposure. Our findings provided a new antagonist, lotusine, for alcohol-induced damage and explored the roles in repairing abnormal metabolism.

Development and validation of a five-lncRNA signature with prognostic value in colon cancer.

Dysregulation of long noncoding RNAs (lncRNAs) has been found in a large number of human cancers, including colon cancer. Therefore, the implementation of potential lncRNAs biomarkers with prognostic prediction value are very much essential. GSE39582 data set was downloaded from database of Gene Expression Omnibus. Re-annotation analysis of lncRNA expression profiles was performed by NetAffx annotation files. Univariate and multivariate Cox proportional analyses helped select prognostic lncRNAs. Algorithm of random survival forest-variable hunting (RSF-VH) together with stepwise multivariate Cox proportional analysis were performed to establish lncRNA signature. The log-rank test was carried out to analyze and compare the Kaplan-Meier survival curves of patients' overall survival (OS). Receiver operating characteristic (ROC) analysis was used for comparing the survival prediction regarding its specificity and sensitivity based on lncRNA risk score, followed by calculating the values of area under the curve (AUC). The single-sample GSEA (ssGSEA) analysis was used to describe biological functions associated with this signature. Finally, to determine the robustness of this model, we used the validation sets including GSE17536 and The Cancer Genome Atlas data set. After re-annotation analysis of lncRNAs, a total of 14 lncRNA probes were obtained by univariate and multivariate Cox proportional analysis. Then, the RSF-VH algorithm and stepwise multivariate Cox analysis helped to build a five-lncRNA prognostic signature for colon cancer. The patients in group with high risk showed an obviously shorter survival time compared with patients in group with low risk with AUC of 0.75. In addition, the five-lncRNA signature can be used to independently predict the survival of patients with colon cancer. The ssGSEA analysis revealed that pathways such as extracellular matrix-receptor interaction was activated with an increase in risk score. These findings determined the strong power of prognostic prediction value of this five-lncRNA signature for colon cancer.

Niacin fine-tunes energy homeostasis through canonical GPR109A signaling.

The incidence of overweight and obesity has become a global public health problem, constituting a major risk factor for numerous comorbidities. Despite tremendous efforts, effective pharmacological agents for the treatment of obesity are still limited. Here, we showed that in contrast to lactate receptor GPR81, niacin receptor GPR109A-deficient mice had progressive weight gain and hepatic fat accumulation. Using high-fat diet-induced mouse model of obesity, we demonstrated that niacin treatment apparently protected against obesity without affecting food intake in wild-type mice but not in GPR109A-deficient mice. Further investigation showed that niacin treatment led to a remarkable inhibition of hepatic de novo lipogenesis. Additionally, we demonstrated that niacin treatment triggered brown adipose tissue and/or white adipose tissue thermogenic activity via activation of GPR109A. Moreover, we observed that mice exposed to niacin exhibited a dramatic decrease in intestinal absorption of sterols and fatty acids. Taken together, our findings demonstrate that acting on GPR109A, niacin shows the potential to maintain energy homeostasis through multipathways, representing a potential approach to the treatment of obesity, diabetes and cardiovascular disease.-Ye, L., Cao, Z., Lai, X., Wang, W., Guo, Z., Yan, L., Wang, Y., Shi, Y., Zhou, N. Niacin fine-tunes energy homeostasis through canonical GPR109A signaling.

Nitric oxide and hydrogen peroxide increase glucose-6-phosphate dehydrogenase activities and expression upon drought stress in soybean roots.

KEY MESSAGE: Changes in glucose-6-phosphate dehydrogenase (G6PD) isoforms activities and expression were investigated in soybean roots under drought, suggesting that cytosolic G6PD plays a main role by regulating H2O2 signal and redox homeostasis. G6PD acts a vital role in plant growth, development and stress adaptation. Drought (PEG6000 treatment) could markedly increase the enzymatic activities of cytosolic G6PD (Cyt-G6PD) and compartmented G6PD (mainly plastidic P2-G6PD) in soybean roots. Application of G6PD inhibitor upon drought condition dramatically decreased the intracellular NADPH and reduced glutathione levels in soybean roots. Nitric oxide (NO) and hydrogen peroxide (H2O2) participated in the regulation of Cyt-G6PD and P2-G6PD enzymatic activities under drought stress. Diphenylene iodonium (DPI), an inhibitor of NADPH oxidase, abolished the drought-induced accumulation of H2O2. The exogenous application of H2O2 and its production inhibitor (DPI) could stimulate and inhibit the NO accumulation, respectively, but not vice versa. qRT-PCR analysis confirmed that NO, as the downstream signal of H2O2, positively regulated the transcription of genes encoding Cyt-G6PD (GPD5, G6PD6, G6PD7) under drought stress in soybean roots. Comparatively, NO and H2O2 signals negatively regulated the gene expression of compartmented G6PD (GPD1, G6PD2, G6PD4), indicating that a post-transcriptional mechanism was involved in compartmented G6PD regulation. Taken together, the high Cyt-G6PD activity is essential for maintaining redox homeostasis upon drought condition in soybean roots, and the H2O2-dependent NO cascade signal is differently involved in Cyt-G6PD and compartmented G6PD regulation.

Response Surface Optimization of an Extraction Method for the Simultaneous Detection of Sulfamethoxazole and 17ß-Estradiol in Soil.

Antibiotics and hormones widely exist in fertilizers and manures, which are excessively used in agriculture and animal husbandry. Considering their potential harm to the environment and human health, the detection of antibiotics and hormones has become a necessity. However, current methods find it difficult to simultaneously extract and detect antibiotics and hormones in soil and to maintain a high level of accuracy and a low cost. In this study, a straightforward, convenient, and simultaneous extraction and detection method of a representative antibiotic (sulfamethoxazole, SMZ) and hormone (17ß-Estradiol, E2) in soil has been established. Ultrasound-assisted extraction (UAE) was used in the pretreatment process and high-performance liquid chromatography with the ultraviolet detector (HPLC-UV) method was then chosen in the detection process. By means of single factors and response surface experiments, optimal extraction conditions were a 41-mL buffer solution (pH 4.27) mixed with 1 g of soil sample, an ultrasonication time of 36 min, an ultrasonication temperature of 25 °C, and two extraction cycles. The detection limits of 0.3-10 µg/kg and quantification limits of 1-30 µg/kg have been obtained. Finally, the optimized simultaneous extraction and detection method was validated by three different real soil samples with recoveries ranging from 79.49% to 86.47%.

Structural basis for the interaction of diapause hormone with its receptor in the silkworm, Bombyx mori.

Diapause hormone (DH) is a 24-aa amidated neuropeptide that elicits the embryonic diapause of the silkworm, Bombyx mori ( Bommo), via sensitive and selective interaction with its receptor, Bommo DH receptor ( Bommo-DHR). Previous studies of the structure-activity relationship of Bommo-DH were all based on an in vivo diapause-induction bioassay, which has provided little information on the structure of Bommo-DHR or its iteration with DH. Here, to unveil the interaction of Bommo-DH with its receptor, N-terminally truncated analogs and alanine-scanning mutants of Bommo-DH were chemically synthesized and functionally evaluated by using a Cy5.5-labeled Bommo-DH competitive binding assay and Bommo-DHR-based functional assays, including cAMP assay and Ca2+ mobilization assay. Our study demonstrates that the C-terminal residues of Arg23 and Leu24 of Bommo-DH are essential for the binding and activation of Bommo-DHR, and that Trp19 and Phe20 also contribute to the functional activity of Bommo-DH. In contrast, when Gly21 or Pro22 were replaced with alanine, both mutants exhibited binding and signaling activities that were indistinguishable from the wild-type peptide. Furthermore, our homology modeling and molecular dynamics simulations, together with experimental validations, have identified the residues of Glu89, Phe172, Phe194, and Tyr299 in Bommo-DHR that are critically involved in the interaction with Bommo-DH. These results may deepen our understanding of the interactions of class-A GPCRs with their peptidic ligands, particularly those between pheromone biosynthesis-activating neuropeptide/DH family neuropeptides and their cognate receptors.-Shen, Z., Jiang, X., Yan, L., Chen, Y., Wang, W., Shi, Y., Shi, L., Liu, D., Zhou, N. Structural basis for the interaction of diapause hormone with its receptor in the silkworm, Bombyx mori.

IgA1 isolated from Henoch-Schönlein purpura children promotes proliferation of human mesangial cells in vitro.

Previous studies show that the proliferation of human mesangial cells (HMCs) played a significant part in the pathogenesis of Henoch-Schönlein purpura nephritis (HSPN). The aim of this study was to explore the proliferation of HMCs induced by IgA1 isolated from the sera of HSP patients. HMCs were cultured in three different types of media, including IgA1 from patients with HSP (HSP IgA1 group), healthy children (healthy IgA1 group) and medium (control group). The proliferation of HMCs incubated with IgA1 was determined by cell counting kit-8 assay and bromodeoxyuridine incorporation. The expression of ERK1/2 and phosphatidylinositol 3 kinase/protein kinase B/mammalian targets of the rapamycin (PI3K/AKt/mTOR) signals and transferrin receptor (TfR/CD71) was detected with the methods of immunoblotting. The results indicated that the proliferation of HMCs significantly increased in the HSP IgA1 group compared with that in the control group or the healthy IgA1 group (P < 0.001). Moreover, we found that IgA1 isolated from HSP patients activated ERK and PI3K/AKt/mTOR signals, and markedly increased TfR/CD71 expression in HMCs. These effects induced by IgA1 isolated from patients with HSP were inhibited by human TfR polyclonal antibody (hTfR pAb) and soluble human transferrin receptor (sTfR), indicating that IgA1-induced HMC proliferation and ERK1/2 and PI3K/AKt/mTOR activation were dependent on TfR/CD71 engagement. Altogether, these data suggested that TfR/CD71 overexpression and ERK1/2 and PI3K/AKt/mTOR activation were engaged in HMC proliferation induced by IgA1 from HSP patients, which might be related to the mesangial injury of HSPN.

[Preparation of angiopep-2-modified FITC-labeled neurotoxin nanoparticles and in vitro release characteristics].

In order to prepare angiopep-2 modified fluorescein isothiocyanate-labeled neurotoxin nanoparticles( ANG-NPs/FITCNT),emulsion/solvent evaporation method was used with m PEG-PLA and ANG-PEG-PLA( in proper proportions) as carriers and with FITC-NT as drug. With particle size and encapsulation efficiency as comprehensive indexes,the effects of different ultrasound power and ultrasound time combinations on the process were investigated. The in vitro release characteristics of nanoparticles in PBS buffer at p H 7. 4 and p H 6. 5 were investigated by dialysis method. The results indicated that the optimum process for preparing ANG-NPs/FITC-NT was as follows: ultrasonic power 90 W,ultrasonic time 30 s. In such optimal process,ANG-NPs/FITC-NT were well-shaped under the transmission electron microscope,with an average particle size of( 123. 9±0. 5) nm,Zeta potential of(-10. 5±0. 5) m V,encapsulation efficiency of( 68. 1±0. 4) %,and the drug loading of( 0. 82±0. 01) %. The in vitro drug release profiles of the nanoparticles in PBS buffer at p H 7. 4 and p H 6. 5 were both consistent with Ritger-Peppas equation,ln Q = 0. 508 8 lnt-2. 285 0,r = 0. 961 5( p H 7. 4) and ln Q= 0. 449 9 lnt-1. 855 3,r = 0. 970 3( p H 6. 5),respectively. The experiment results proved that the nanoparticles prepared by emulsion/solvent evaporation method had uniform particle size,high encapsulation efficiency and in vitro sustained release characteristic,which might be a potential carrier for NT intracerebral drug delivery.

Bombyx neuropeptide G protein-coupled receptor A7 is the third cognate receptor for short neuropeptide F from silkworm.

The short neuropeptide F (sNPF) neuropeptides, closely related to vertebrate neuropeptide Y (NPY), have been suggested to exert pleiotropic effects on many physiological processes in insects. In the silkworm (Bombyx mori) two orphan G protein-coupled receptors, Bombyx neuropeptide G protein-coupled receptor (BNGR) A10 and A11, have been identified as cognate receptors for sNPFs, but other sNPF receptors and their signaling mechanisms in B. mori remain unknown. Here, we cloned the full-length cDNA of the orphan receptor BNGR-A7 from the brain of B. mori larvae and identified it as a receptor for Bombyx sNPFs. Further characterization of signaling and internalization indicated that BNGR-A7, -A10, and -A11 are activated by direct interaction with synthetic Bombyx sNPF-1 and -3 peptides. This activation inhibited forskolin or adipokinetic hormone-induced adenylyl cyclase activity and intracellular Ca2+ mobilization via a Gi/o-dependent pathway. Upon activation by sNPFs, BNGR-A7, -A10, and -A11 evoked ERK1/2 phosphorylation and underwent internalization. On the basis of these findings, we designated the receptors BNGR-A7, -A10, and -A11 as Bommo-sNPFR-1, -2, and -3, respectively. Moreover, the results obtained with quantitative RT-PCR analysis revealed that the three Bombyx sNPF receptor subtypes exhibit differential spatial and temporal expression patterns, suggesting possible roles of sNPF signaling in the regulation of a wide range of biological processes. Our findings provide the first in-depth information on sNPF signaling for further elucidation of the roles of the Bombyx sNPF/sNPFR system in the regulation of physiological activities.

Metabolic Regulations of Smilax china L. against ß-Amyloid Toxicity in Caenorhabditis elegans.

Smilax china L. (Chinaroot) is a natural herb that has multiple uses, such as being used to make tea and food. Both its roots and leaves have different uses due to their unique components. In this study, we analyzed the extract of S. china. roots using LC-HRMS and evaluated the neuroprotective effects and metabolic regulation of S. china on Caenorhabditis elegans. Chinaroot extract prolonged the life span of healthy nematodes, delayed the paralysis time of transgenic CL4176, and reduced the level of ß-amyloid deposition in transgenic CL2006. The comprehensive analysis of metabolomics and qRT-PCR revealed that Chinaroot extract exerted neuroprotective effects through the valine, leucine and isoleucine degradation and fatty acid degradation pathways. Moreover, we first discovered that the expressions of T09B4.8, ech-7, and agxt-1 were linked to the neuroprotective effects of Chinaroot. The material exerted neuroprotective effects by modulating metabolic abnormalities in AD model C. elegans. Our study provides a new foundation for the development of functional food properties and functions.

High Expression of KIFC1 in Glioma Correlates with Poor Prognosis.

OBJECTIVE: Kinesin family member C1 (KIFC1), a non-essential kinesin-like motor protein, has been found to serve a crucial role in supernumerary centrosome clustering and the progression of several human cancer types. However, the role of KIFC1 in glioma has been rarely reported. Thus, the present study aimed to investigate the role of KIFC1 in glioma progression. METHODS: Online bioinformatics analysis was performed to determine the association between KIFC1 expression and clinical outcomes in glioma. Immunohistochemical staining was conducted to analyze the expression levels of KIFC1 in glioma and normal brain tissues. Furthermore, KIFC1 expression was knocked in the glioma cell lines, U251 and U87MG, and the functional roles of KIFC1 in cell proliferation, invasion and migration were analyzed using cell multiplication, wound healing and Transwell invasion assays, respectively. The autophagic flux and expression levels matrix metalloproteinase-2 (MMP2) were also determined using imaging flow cytometry, western blotting and a gelation zymography assay. RESULTS: The results revealed that KIFC1 expression levels were significantly upregulated in glioma tissues compared with normal brain tissues, and the expression levels were positively associated with tumor grade. Patients with glioma with low KIFC1 expression levels had a more favorable prognosis compared with patients with high KIFC1 expression levels. In vitro, KIFC1 knockdown not only inhibited the proliferation, migration and invasion of glioma cells, but also increased the autophagic flux and downregulated the expression levels of MMP2. CONCLUSION: Upregulation of KIFC1 expression may promote glioma progression and KIFC1 may serve as a potential prognostic biomarker and possible therapeutic target for glioma.

PAK1 inhibition increases TRIM21-induced PD-L1 degradation and enhances responses to anti-PD-1 therapy in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is a common malignancy with a 5-year survival <10 %. Immunosuppressive tumor microenvironment (TME) plays a critical role in the progression of PDA. In recent years, programmed death-ligand 1 (PD-L1)/programmed cell death protein-1 (PD-1) blockade has emerged as a potent anti-tumor immunotherapy, while is yet to achieve significant clinical benefits for PDA patients. P21-Activated kinase 1 (PAK1) is highly upregulated in PDA and has been reported to be involved in the regulation of anti-tumor immunity. This study aims to investigate the combined effect of PAK1 inhibition and anti-PD-1 therapy on PDA and the underlying mechanisms. We have shown that PAK1 expression positively correlated with PD-L1 in PDA patients, and that inhibition of PAK1 downregulated PD-L1 expression of PDA cells. More importantly, we have demonstrated that PAK1 competed with PD-L1 in binding to tripartite motif-containing protein 21 (TRIM21), a ubiquitin E3 ligase, resulting in less ubiquitination and degradation of PD-L1. Moreover, PAK1 inhibition promoted CD8+ T cells activation and infiltration. In a murine PDA model, the combination of PAK1 inhibition and anti-PD-1 therapy showed significant anti-tumor effects compared with the control or monotherapy. Our results indicated that the combination of PAK1 inhibition and anti-PD-1 therapy would be a more effective treatment for PDA patients.