Potential Targets and Molecular Mechanism of Quercetin Against Knee Osteoarthritis

Objective The objective of this study was to clarify the potential mechanism of quercetin against knee osteoarthritis(KOA)based on network pharmacology and molecular docking.Methods The targets of quercetin were predicted by PubChem and Swiss Target Prediction databases,and the targets of KOA were obtained by DisGeNET,OMIM,and GeneCards databases.Then,the targets of quercetin and KOA were intersected to find the potential targets of quercetin against KOA.The protein–protein interaction network was constructed through the STRING database,and the core targets were screened.Gene ontology(GO)functions enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed using DAVID database.The drug–target–pathway–disease network was constructed by Cytoscape software,and the molecular docking verification was performed by Vina.Results There were 49 potential targets for quercetin against KOA,including 10 core targets.GO functions enrichment analysis showed that the biological process of quercetin against KOA mainly involved the negative regulation of apoptotic process,collagen catabolic process,and extracellular matrix disassembly.KEGG pathway enrichment analysis showed that quercetin against KOA was closely related to PI3K-Akt signaling pathway,Rap 1 signaling pathway,FoxO signaling pathway,Ras signaling pathway,TNF signaling pathway,and ErbB signaling pathway.The results of molecular docking showed that the binding energies between ligand and receptors were less than−5 kcal·mol−1.Conclusions The molecular mechanism of quercetin against KOA involves many targets and pathways,which can regulate the proliferation and apoptosis of chondrocytes,degradation of extracellular matrix,and inflammatory reaction.Quercetin can stably bind to the active pockets of core target proteins,thereby exerting the effect against KOA.

Mcl-1 as a Potential Therapeutic Target for Human Hepatocelluar Carcinoma

Hepatocellular carcinoma（HCC） is a major cause of cancer-related mortality in part due to its high resistance to chemotherapeutic drugs. The anti-apoptotic Mcl-1 expression has been reported as a resistance factor in various types of tumors. Here, we investigated the expression of Mcl-1 in hepatoma cells and HCC tissues and its relationship with p53, and analyzed the possibility of the gene as a molecular target for HCC therapy. HCC specimens of 30 patients were examined by immunohistochemistry for Mcl-1 and p53 expression. Mcl-1 expression in hepatoma cell lines was measured by RT-PCR and Western blotting. The suppression of Mcl-1 by RNA interference or specific phosphatidylinositol-3 kinase（PI3K） inhibitor, LY294002, was evaluated as monotherapy, and it was combined with mitomycin C（MMC） in treating hepatoma cell line Hep G2. Cell viability and apoptosis were assessed by MTT and FACS analysis. Finally, changes of Mcl-1 or p53 expression in various hepatoma cell lines were examined after transfection with Mcl-1 si RNA, the Mcl-1 expression plasmid, or the wide-type p53 expression plasmid, respectively. Mcl-1 protein was remarkably enhanced in HCC tissues as compared with adjacent non-tumor liver tissues. In addition, Mcl-1 was prominently expressed in Hep G2 and Hep3 B cells, weakly in SMMC7721 cells, and not in L02 cells. P53 protein was also overexpressed in HCC tissues and there was a significant correlation between the expression of p53 and Mcl-1. Silencing Mcl-1 by RNAi or LY294002 downregulated Mcl-1 expression and led to decreased cell viability and increased apoptosis. Combination of MMC and Mcl-1 RNAi or LY294002 exhibited a significant chemosensitizing effect. The expression of p53 was not influenced by Mcl-1 si RNA in Hep G2 cells or transfection with the Mcl-1 expression plasmid in L02 cells. Furthermore, the expression of Mcl-1 in Hep3 B cells was also not significantly changed after transfection with the wild-type p53 expression plasmid. It is concluded that Mcl-1 is overexpressed in HCC tissues. The mechanisms by which silencing Mcl-1 sensitizes hepatoma cells towards chemotherapy may be not attributed to the upregulated expression of p53 but the dysfunction of p53 through Mcl-1/p53 interaction. Mcl-1 may be a potential target of gene therapy for HCC.

Programmed cell death and natural killer cells in multiple sclerosis: new potential therapeutic targets?

Multiple sclerosis（MS）is a chronic,severe and complex disease of still uncertain etiopathogenesis,with lesions in the cerebral white matter and spinal cord.The disease is heterogeneous,but is characterized by neuroinflammatory and neurodegenerative processes,usually associated with altered activation of the immune system following presumable stimulation by still unknown autoantigens.

Reducing intrathecal pressure after traumatic spinal cord injury: a potential clinical target to promote tissue survival

Spinal cord injury （SCI） is an unexpected event that is both devastating and debilitating, resulting in not just motor and sensory loss, but also autonomic dysfunction of the bladder, bowel and sexual organs. Currently, there are no treatments available to improve outcome follow- ing SCI, leaving individuals with permanent and lifelong physical disability. Worldwide it is estimated that more than 500,000 people sustain a SCI each year, with average lifetime cost of paraplegia and quadriplegia estimated at $5 million and $9.5 million respectively. We therefore urgently need effective therapies to improve quality of life following SCI, and this requires a greater understanding of how cell and axonal injury develops after the traumatic event.

The Olfactory Receptor Pseudo-pseudogene: A Potential Therapeutic Target in Human Diseases

Recently, Prieto-Godino et al.[1] found that the olfactory receptor 75a （Ir75a） gene is a functional pseudo-pseudogene in Drosophila sechellia. For a long time, Ir75a has been regarded as an acetic acid receptor that detects acetic acid and induces obvious olfactory responses in olfactory sensory neurons （OSNs）f2J. Nonetheless, Prieto-Godino et al. confirmed that Ir75a lost its sensitivity to acetic acid in D. sechellia. Thus, the D. sechelfia Ir75a gene is generally recognized as a pseudogene in OSNs.

Relevance and therapeutic potential of Cyp A targeting to block apoptosis inducing factor-mediated neuronal cell death

Programmed cell death （PCD） signaling pathways are import- ant contributors to acute neurological insults such as hypox- ic-ischemic brain damage, traumatic brain injury, stroke etc. The pathogenesis of all these diseases is closely linked with ab- erration of apoptotic cell death pathways. Mitochondria play a crucial role during PCD, acting as both sensors of death signals, and as initiators of biochemical path- ways, which cause cell death （Bras et al., 2005）. Cytochrome c was the firstly identified apoptogenic factor released from mitochondria into the cytosol, where it induces apoptosome formation through the activation of caspases. Other proteins, such as apoptosis inducing factor （AIF）, have been subsequently identified as mitochondrial released factors. AIF contributes to apoptotic nuclear DNA damage （Bras et al., 2005）. in a caspase-independent way

Consequences of hepatic damage after traumatic brain injury: current outlook and potential therapeutic targets

Traumatic brain injury（TBI）triggers liver inflammation：TBI is a serious pathology affecting around 10 million people annually,being a persistent public health and medical problem Forceful impact while playing sports,falls,physical assault,or traffic accidents are common causes of head injury.

MicroRNA-216a: a potential therapeutic target for drug resistance and recurrent of liver cancer

The Editor welcomes submissions for possible publication in the Letters to the Editor section.Letters commenting on an article published in the Journal or other interesting pieces will be considered if they are received within 6 weeks of the time the article was published.Authors of the article being commented on will be given an opportunity to offer a timely response to the letter.Authors of letters will be notified that the letter has been received.Unpublished letters cannot be returned.

Regenerative potential of targeting glycogen synthase kinase-3 signaling in neural tissues

Multiple roles of glycogen synthase kinase-3（GSK-3）in neural tissues：GSK-3 is a serine/threonine kinase that has two isoforms encoded by two different genes,GSK-3αand GSK-3β,in mammals.GSK-3 has several sites of serine and tyrosine phosphorylation.

SLP-2: a potential new target for improving mitochondrial function in Parkinson's disease

Parkinson＇s disease （PD） is a progressive neurodegenerative disease, which is generally considered a multifactorial disorder that arises owing to a combination of genes and environmental factors. While most cases are idiopathic, in about 10% of the patients a genetic cause can be detected, ascribable to mutations in more than a dozen genes. PD is characterized clinically by tremor, rigidity, reduced mo- tor activity （bradykinesia）, and postural instability and pathological- ly by loss of dopaminergic （DA） neurons in the substantia nigra pars compacta, loss of DA innervation in the striatum, and the presence of a-synuclein positive aggregates in the form of Lewy bodies. The symptomatic treatment of PD with levodopa, which aims at replac- ing dopamine, remains the gold standard, and no neuroprotective or disease-modifying therapy is available. During treatment, the disease continues to progress, and long-term use of levodopa has import- ant limitations including motor complications termed dyskinesias. Therefore, a pharmacological therapy able to prevent or halt the neu- rodegenerative process is urgently required.

Application and prospects of proteomic technology in inflammation:a review

Proteomics is a new technology that has been widely applied in the field of life and health science.It effectively addresses issues related to the impact of dietary structure on organs,tissues,and cells,as well as the changes in proteins in various organs,tissues,and cells under disease conditions.The differential proteins identified through proteomics can serve as disease biomarkers and target proteins affecting health and can be used for disease diagnosis and health regulation.In this paper,the application of proteomics in the field of infl ammation in recent years was summarized,especially in the therapeutic target and mechanism of action,which opens up a new way for more effective prevention,diagnosis,and treatment of inflammation,and provides medical protection for human life and health.

Identification and functional prediction of long intergenic noncoding RNAs in fetal porcine longissimus dorsi muscle

Pigs are globally farmed animals which provide protein for human consumption in the form of skeletal muscle. To better understand the function of long intergenic noncoding RNAs(linc RNAs) in porcine skeletal muscle growth and development, we collected RNA-seq data from porcine longissimus dorsi muscle(LDM) during embryonic development. We identified a total of 739 linc RNA transcripts, which were distributed on all chromosomes except the chromosome Y, and analyzed their molecular characteristics. Compared to protein-coding genes, linc RNAs showed shorter transcripts, longer exons, fewer exons and higher tissue specificity. In addition, the abundance of linc RNAs in five embryonic development stages were analyzed and 45 differentially expressed linc RNAs were screened, three of which were highly expressed in LDM during porcine embryonic development. Finally, we predicted the potential target genes and functions of the linc RNAs, and identified 1 537 cis-target genes and 8 571 trans-target genes. Furthermore, we identified two key candidate linc RNAs involved in muscle development, XLOC_024652 and XLOC_001832, for post-trial validation. Our results provide a genome-wide resource of linc RNAs which are potentially involved in porcine embryonic skeletal muscle development and lay a foundation for the further study of their functions.

Network pharmacology-based virtual screening of natural products from Peperomia dindygulensis for the application to treat liver cancer

Traditional Chinese medicine plays an increasingly important role in cancer treatment for the property of the complex components and multi-targets.Peperomia dindygulensis,belonging to Piperaceae family,was proved to be effective to the treatment of cancer,but the action mechanism is incomprehensive.In this study,we employed molecular docking and network pharmacology methods to predict the effective compositions,potential target proteins and potential biological pathways.Six compounds were predicted to have potential activity for liver-cancer target proteins.Meanwhile,we analyzed the biological pathways based on compounds-target network,which may be play an important role in liver cancer.This article is presented to explore the active ingredients of P.dindygulensis and provide crucial material for the further research and development of the plant.

The Mitochondrion:A Potential Therapeutic Target for Alzheimer's Disease

Introduction The mitochondrion is a double-membrane organelle consisting of an outer membrane, intermembrane space, inner membrane, cristae, and matrix. It is the ‘‘energy plant’’ that provides most of the energy for cells. Mitochondria also participate in various processes such as calcium homeosta-

Useful detection of CD147 (EMMPRIN) for pathological diagnosis of early hepatocellular carcinoma in needle biopsy samples

AIM:To make clear whether CD147 (EMMPRIN) expression in pathological tumor samples with a fine-needle aspiration biopsy is useful for pathological diagnosis of early hepatocellular carcinoma (HCC). METHODS:Twenty-two patients (15 men and 7 women; median age 68 years,range 56-81 years) underwent a liver tissue biopsy in order to make a diagnosis of HCC. Paraffin-embedded liver biopsy tissue samples from 22 patients were stained with anti-CD147 antibody,murine monoclonal antibody 12C3 (MAb12C3) for immunohistochemical analysis. An immunohistochemical analysis of CD147 was performed and the degree of staining compared between tumor and non-tumor tissue. In addition,the degree of staining within tumor tissue was compared according to a number of clinicopathological variables. RESULTS:The degree of staining of CD147 was significantly higher in tumor tissues than non-tumor tissues,even in tumors less than 15 mm in diameter.The expression of this protein was significantly elevated in HCC tissue specimens from patients with a low value of serum AST and γ-GTP.

The characteristics, formation and exploration progress of the potash deposits on the Khorat Plateau, Thailand and Laos, Southeast Asia

The giant potash deposit on the Khorat Plateau is one of the most promising targets for exploitation of potassium salts.So far,many researches and geologic survey have been conducted on the giant potash deposits.Hence,it is necessary to make an overall review on the potash deposits.The potash deposit on the Khorat Plateau was formed during the Middle to Late Cretaceous,during which seawater was enriched in Ca2+and depleted in SO42-compared with those of modern seawater.In addition to seawater,continental water and hydrothermal fluids could have affected the evaporite basins.The seawater was probably derived from Tethys ocean,and the brine should have evaporated to some extent before entering into the basin systems based on the evidence of absence of carbonates and unproportionate sulphate compared with chloride salts.The paleo-climate during Middle to Late Cretaceous was characterized as high temperature and extremely arid environment,which is favourable for deposition of potassium-magnesium saline minerals.The major saline minerals are of anhydrite,halite,carnallite,sylvite and,tachyhydrite,with trace amounts of borates.The resources of the potash deposit on the Khorat Plateau could be approximately as much as 400×109 t of carnallite and 7×109 t of sylvite.The evaporite sequences have been deformed and altered by postdepositinal processes,including tectonic movements and chemical alteration.Salt domes were formed in the postdepositional processes.Based on the analyses of geophysical surveys and drilling projects,high-quality sylvinite ores are commonly found at the flanks of those salt domes due to incongruent dissolution of carnallite.The furure potential prospecting areas for the highquality sylvinite ores would be on the edges of the Khorat Plateau.

Mechanistic and therapeutic perspectives for cardiac arrhythmias：beyond ion channels

Cardiac arrhythmias are among the most common causes of death in the world. Foundational studies established the critical role of ion channel disorders in arrhythmias, yet defects in ion channels themselves, such as mutations, may not account for all arrhythmias. Despite the progress made in recent decades, the antiarrhythmic drugs currently available have limited effectiveness,and the majority of these drugs can have proarrhythmic effects. This review describes novel knowledge on cellular mechanisms that cause cardiac arrhythmias, focuses on the dysfunction of subcellular organelles and intracellular logistics, and discusses potential strategies and challenges for developing novel, safe and effective treatments for arrhythmias.

Sulfur speciation defined subcellular localization of coumarin derivatives:Correlation of structural relationship to biological behaviors

Targeted-delivery is of great importance to molecular probes and drugs for cell biology study. Herein we reported 11 sulfur-containing coumarins as cell imaging probes. Different sulfur speciation of the 4 representative coumarins SC1-SC4 renders them significantly different subcellular localizations and cellular uptake pathways： SC1 containing thioether group located in lysosomes, while sulfoxide and sulfone compounds SC2 and SC3 distributed in the whole cell. Furthermore, the cationic sulfonium containing compound SC4 was internalized by clathrin-mediated endocytosis and localized at mitochondria. By analyzing the molecular parameters of all 11 coumarins, we found that different sulfur speciation affected their lipophilicity and electrostatic surface potential. These two key factors play roles in altering biological behaviors of the coumarins. The results revealed the importance of sulfur speciation on the physicochemical properties and thus subcellular localization of bioprobes. This is useful for designing new functional bioprobes.