Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer

AbstractStatins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) inhibitors decreasing serum cholesterol and have shown promise in cancer prevention. In this study, we demonstrated the oncogenic role of HMGR in colorectal cancer (CRC) by disclosing increased HMGR activity in CRC patients and its enhancement of anti-apoptosis and stemness. Our previous studies showed that statins containing carboxylic acid chains possessed activity against histone deacetylases (HDACs), and strengthened their anti-HDAC activity through designing HMGR-HDAC dual inhibitors, JMF compounds. These compounds exerted anti-cancer effect in CRC cells as well as in AOM-DSS and ApcMin/+ CRC mouse models. JMF mostly regulated the genes related to apoptosis and inflammation through genome-wide ChIP-on-chip analysis, and Ingenuity Pathways Analysis (IPA) predicted their respective regulation by NR3C1 and NF-κB. Furthermore, JMF inhibited metastasis, angiogenesis and cancer stemness, and potentiated the effect of oxaliplatin in CRC mouse models. Dual HMGR-HDAC inhibitor could be a potential treatment for CRC

Cost-effectiveness analysis of quadrivalent versus trivalent influenza vaccine in Taiwan: A lifetime multi-cohort model

A government-funded trivalent influenza vaccine (TIV) program to prevent seasonal influenza was implemented in Taiwan since 1998. However, mismatch between the vaccine and circulating strains may occur. Alternatively, a quadrivalent influenza vaccine (QIV) includes all 4 influenza lineages could minimize the risk of mismatches. Therefore, QIV could be considered as an alternative strategy to enhance protection against seasonal influenza. The objective of the study was to analyze, from a governmental perspective, the cost-effectiveness of using QIV vs. TIV as a vaccination strategy in Taiwan. A lifetime multi-cohort, static Markov model was constructed with 9 age groups to assess the costs and effectiveness of QIV vs. TIV. Direct costs were obtained from a database released by the Ministry of Health and Welfare. Outcomes included life-years gained, quality-adjusted life years (QALYs) gained, influenza cases avoided and incremental cost-effectiveness ratios (ICERs). The discount rate of costs and effectiveness was set at 3.5% and the time horizon used in the model was 100 y. Results show that a vaccination strategy utilizing QIV instead of TIV would bring an additional 10,557 QALYs at an extra cost of US$39.4 million, yielding an ICER of US$3,015.07 per QALY gained. When setting the willingness-to-pay threshold at US$10,000, compared to TIV, the probability that QIV would be cost-effective was 98%. Sensitivity analyses show that ICER was sensitive to the changes of circulation of influenza virus subtypes and vaccine mismatch. From a governmental perspective, the QIV vaccination could be considered as a cost-effective strategy within the context of public health in Taiwan

Mechanical characterization of nanoindented graphene via molecular dynamics simulations

Abstract The mechanical behavior of graphene under various indentation depths, velocities, and temperatures is studied using molecular dynamics analysis. The results show that the load, elastic and plastic energies, and relaxation force increased with increasing indentation depth and velocity. Nanoindentation induced pile ups and corrugations of the graphene. Resistance to deformation decreased at higher temperature. Strong adhesion caused topological defects and vacancies during the unloading process.</p

Curcumin-Loaded Hydrophobic Surface-Modified Hydroxyapatite as an Antioxidant for Sarcopenia Prevention

Oxidative stress and later-induced chronic inflammation have been reported to play an important role on the progression of sarcopenia. Current treatments for sarcopenia are mainly administered to patients whom sarcopenia already developed. However, there has been no promising results shown in therapy. Therefore, the development of therapeutic and preventive strategies against sarcopenia would be necessary. Curcumin is a traditional medicine that possesses anti-inflammatory and antioxidative properties. In the present study, hydroxyapatite was subjected to hydrophobic surface modifications for curcumin loading (Cur-SHAP). It was, subsequently, utilized for delivery to the patient’s body via intramuscular injection in order to achieve constant release for more than 2 weeks, preventing the progression of the sarcopenia or even leading to recovery from the early stage of the illness. According to the results of WST-1, LIVE/DEAD, DCFDA, and gene expression assays, Cur-SHAP exhibited good biocompatibility and showed great antioxidant/anti-inflammatory effects through the endocytic pathway. The results of the animal studies showed that the muscle endurance, grip strength, and fat/lean mass ratio were all improved in Cur-SHAP-treated rats from LPS-induced sarcopenia. In summary, we successfully synthesized hydrophobic surface modification hydroxyapatite for curcumin loading (Cur-SHAP) and drug delivery via the IM route. The LPS-induced sarcopenia rats were able to recover from disease after the Cur-SHAP treatment

Site-specific His/Asp phosphoproteomic analysis of prokaryotes reveals putative targets for drug resistance

Abstract Background Phosphorylation of amino acid residues on proteins is an important and common post-translational modification in both eukaryotes and prokaryotes. Most research work has been focused on phosphorylation of serine, threonine or tyrosine residues, whereas phosphorylation of other amino acids are significantly less clear due to the controversy on their stability under standard bioanalytical conditions. Results Here we applied a shotgun strategy to analyze the histidine and aspartate phosphorylations in different microbes. Our results collectively indicate that histidine and aspartate phosphorylations frequently occur also in proteins that are not part of the two-component systems. Noticeably, a number of the modified proteins are pathogenesis-related or essential for survival in host. These include the zinc ion periplasmic transporter ZnuA in Acinetobacter baumannii SK17, the multidrug and toxic compound extrusion (MATE) channel YeeO in Klebsiella pneumoniae NTUH-K2044, branched amino acid transporter AzlC in Vibrio vulnificus and the RNA-modifying pseudouridine synthase in Helicobacter pylori. Conclusions In summary, histidine and aspartate phosphorylation is likely to be ubiquitous and to take place in proteins of various functions. This work also sheds light into how these functionally important proteins and potential drug targets might be regulated at a post-translational level

Phosphoproteomic analysis of Methanohalophilus portucalensis FDF1(T) identified the role of protein phosphorylation in methanogenesis and osmoregulation

Methanogens have gained much attention for their metabolic product, methane, which could be an energy substitute but also contributes to the greenhouse effect. One factor that controls methane emission, reversible protein phosphorylation, is a crucial signaling switch, and phosphoproteomics has become a powerful tool for large-scale surveying. Here, we conducted the first phosphorylation-mediated regulation study in halophilic Methanohalophilus portucalensis FDF1(T), a model strain for studying stress response mechanisms in osmoadaptation. A shotgun approach and MS-based analysis identified 149 unique phosphoproteins. Among them, 26% participated in methanogenesis and osmolytes biosynthesis pathways. Of note, we uncovered that protein phosphorylation might be a crucial factor to modulate the pyrrolysine (Pyl) incorporation and Pyl-mediated methylotrophic methanogenesis. Furthermore, heterologous expression of glycine sarcosine N-methyltransferase (GSMT) mutant derivatives in the osmosensitive Escherichia coli MKH13 revealed that the nonphosphorylated T68A mutant resulted in increased salt tolerance. In contrast, mimic phosphorylated mutant T68D proved defective in both enzymatic activity and salinity tolerance for growth. Our study provides new insights into phosphorylation modification as a crucial role of both methanogenesis and osmoadaptation in methanoarchaea, promoting biogas production or reducing future methane emission in response to global warming and climate change

Additional file 2: Table S1. of Site-specific His/Asp phosphoproteomic analysis of prokaryotes reveals putative targets for drug resistance

Phospho probabilities, process method, leading protein identifier, UniProt No. (if available), protein description, and protein functional class of the identified phosphopeptides (PDF 539 kb)

Additional file 1: of Site-specific His/Asp phosphoproteomic analysis of prokaryotes reveals putative targets for drug resistance

MS/MS Spectra. Spectra of the identified phosphopeptides (PDF 4714 kb)