ABSTRACT
OBJECTIVES: Laparoscopic resection for rectal cancer is currently the predominant treatment modality for rectal tumors, with an ongoing focus on reducing the incidence of postoperative complications. In an effort to decrease the occurrence of anastomotic leakage, two additional steps worth considering are reinforcing the anastomosis with a barbed suture and retaining an anal drain as part of the procedure. The results of the operation were analyzed by comparing them to cases where the anastomosis was performed with a stapler alone. METHODS: This study retrospectively analyzed patients who underwent laparoscopic radical rectal cancer surgery between July 2020 and March 2023. The patients were categorized into three cohorts based on the postoperative management following instrumented anastomosis: cohort A, the instrumented anastomosis alone group; cohort B, the reinforced suture group; and cohort C, the reinforced suture and indwelling transanal drainage tube group. Propensity score matching was performed twice in a 1:1 ratio, comparing cohort B to cohort A and cohort C to cohort B. The objective was to compare the benefits and drawbacks among the different groups in terms of operative time, postoperative outcomes and operative costs. RESULTS: 529 patients with laparoscopic resection for rectal cancer were eligible for inclusion. the instrumented anastomosis alone group, reinforced suture group and the reinforced suture and indwelling transanal drainage tube group were performed in 205 patients, 198 patients and 126 patients, respectively. Cohort A and Cohort B differed in three variables after PSM: total operative time (p = 0.018), postoperative hospital stay (p < 0.001) and incidence of anastomotic leakage (p = 0.038). Cohort B had a longer total operative time, shorter postoperative hospital stay and a lower incidence of anastomotic leakage. Similarly, cohort C had less postoperative drainage (P = 0.01) and a longer postoperative hospital stay (P = 0.003) when cohort B and cohort C were matched for propensity scores. There was no significant difference in the cost of surgery between the three cohorts. CONCLUSIONS: The incorporation of barbed suture reinforcement significantly reduces the occurrence of postoperative anastomotic leakage in rectal cancer surgeries. On the other hand, although trans-anal drainage was used as an additional measure to the reinforcement suture of the anastomosis, the utilization of trans-anal drainage tubes does not demonstrate a significant improvement in surgical outcomes.
Subject(s)
Laparoscopy , Rectal Neoplasms , Humans , Anastomotic Leak/epidemiology , Anastomotic Leak/etiology , Anastomotic Leak/prevention & control , Propensity Score , Retrospective Studies , Rectal Neoplasms/surgery , Rectal Neoplasms/pathology , Anastomosis, Surgical/methods , Drainage/methods , Laparoscopy/adverse effects , Sutures/adverse effectsABSTRACT
The Periodic Table, and the unique chemical behavior of the first element in a column (group), were discovered simultaneously one and a half centuries ago. Half a century ago, this unique chemistry of the light homologs was correlated to the then available atomic orbital (AO) radii. The radially nodeless 1s, 2p, 3d, 4f valence AOs are particularly compact. The similarity of r(2s)≈r(2p) leads to pronounced sp-hybrid bonding of the light p-block elements, whereas the heavier p elements with n≥3 exhibit r(ns) ⪠r(np) of approximately -20 to -30 %. Herein, a comprehensive physical explanation is presented in terms of kinetic radial and angular, as well as potential nuclear-attraction and electron-screening effects. For hydrogen-like atoms and all inner shells of the heavy atoms, r(2s) â« r(2p) by +20 to +30 %, whereas r(3s)â³r(3p)â³r(3d), since in Coulomb potentials radial motion is more radial orbital expanding than angular motion. However, the screening of nuclear attraction by inner core shells is more efficient for s than for p valence shells. The uniqueness of the 2p AO is explained by this differential shielding. Thereby, the present work paves the way for future physical explanations of the 3d, 4f, and 5g cases.
ABSTRACT
Staphylococcus aureus is a major and dangerous human pathogen that causes a range of clinical manifestations of varying severity, and is the most commonly isolated pathogen in the setting of skin and soft tissue infections, pneumonia, suppurative arthritis, endovascular infections, foreign-body associated infections, septicemia, osteomyelitis, and toxic shocksyndrome. Honokiol, a pharmacologically active natural compound derived from the bark of Magnolia officinalis, has antibacterial activity against Staphylococcus aureus which provides a great inspiration for the discovery of potential antibacterial agents. Herein, honokiol derivatives were designed, synthesized and evaluated for their antibacterial activity by determining the minimum inhibitory concentration (MIC) against S. aureus ATCC25923 and Escherichia coli ATCC25922 in vitro. 7c exhibited better antibacterial activity than other derivatives and honokiol. The structure-activity relationships indicated piperidine ring with amino group is helpful to improve antibacterial activity. Further more, 7c showed broad spectrum antibacterial efficiency against various bacterial strains including eleven gram-positive and seven gram-negative species. Time-kill kinetics against S. aureus ATCC25923 in vitro revealed that 7c displayed a concentration-dependent effect and more rapid bactericidal kinetics better than linezolid and vancomycin with the same concentration. Gram staining assays of S. aureus ATCC25923 suggested that 7c could destroy the cell walls of bacteria at 1×MIC and 4×MIC.
Subject(s)
Anti-Bacterial Agents/pharmacology , Biphenyl Compounds/pharmacology , Lignans/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/chemistry , Cell Wall/drug effects , Cyclization , Drug Design , Escherichia coli/drug effects , Kinetics , Lignans/chemical synthesis , Lignans/chemistry , Linezolid/pharmacology , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Structure-Activity Relationship , Vancomycin/pharmacologyABSTRACT
The periodic table provides a fundamental protocol for qualitatively classifying and predicting chemical properties based on periodicity. While the periodic law of chemical elements had already been rationalized within the framework of the nonrelativistic description of chemistry with quantum mechanics, this law was later known to be affected significantly by relativity. We here report a systematic theoretical study on the chemical bonding pattern change in the coinage metal dimers (Cu2, Ag2, Au2, Rg2) due to the relativistic effect on the superheavy elements. Unlike the lighter congeners basically demonstrating ns- ns bonding character and a 0g+ ground state, Rg2 shows unique 6d-6d bonding induced by strong relativity. Because of relativistic spin-orbit (SO) coupling effect in Rg2, two nearly degenerate SO states, 0g+ and 2u, exist as candidate of the ground state. This relativity-induced change of bonding mechanism gives rise to various unique alteration of chemical properties compared with the lighter dimers, including higher intrinsic bond energy, force constant, and nuclear shielding. Our work thus provides a rather simple but clear-cut example, where the chemical bonding picture is significantly changed by relativistic effect, demonstrating the modified periodic law in heavy-element chemistry.
ABSTRACT
SrZn(1-x) (WO4)2:xTb3+, yCe3+ green fluorescent phosphors for near ultraviolet excitation were prepared using chemical co-precipitation. The phases of different doping ratio samples were characterized by the X-ray diffraction (XRD). The emission spectrum and excitation spectrum of samples were characterized by fluorescence spectroscopy (PL). The luminescence properties of the rare-earth Tb3+ ion doped and Ce3+ and Tb3+ ion codoped samples were discussed. XRD analysis shows that the main diffraction peaks of samples were consistent with the standard card (JCPDS 08-0490 and the JCPDS 15-0774) of the diffraction peak data. This showed that the doping rare earth ions did not change matrix lattice structure. The excitation spectrum showed that the excitation spectrum peaks at 223 nm which is assigned to the 7F-7D absorption transitions of Tb3+. The emission spectrum excited by 223 nm exhibits sharp lines peaking at 543 nm which was assigned to the 5D4-7F5 transitions of the Tb3+ ions. With Tb3+ and Ce3+ co-doping, the spectrum didn't change much. The intensity of fluorescence reached the strongest when the concentration of Tb3+:Ce3+ arrived at 0.06:0.02 which may means that there was energy transfer between the ions of Ce3+ and Tb3+.
ABSTRACT
Background: Cancer risk is influenced by calcium signaling in intracellular and intercellular signaling pathways. However, the relationship between the calcium signaling pathway and colorectal cancer risk remains unknown. We aim to evaluate the role of genetic variants in calcium signaling pathway genes in colorectal cancer risk through the tumor microenvironment. Methods: An analysis of genetic variants in the calcium signaling pathway was conducted using a case-control study that included 1150 colorectal cancer patients and 1342 non-cancer patients. Using the regression model, we assessed whether single-nucleotide polymorphisms (SNPs) increase the risk of colorectal cancer. We also performed a dual luciferase reporter gene assay using HCT116 cell lines and DLD1 cell lines to demonstrate the regulatory relationship between SNP and candidate risk gene. We evaluated the expression of candidate risk gene in different populations. In addition, we also evaluated candidate risk gene and 22 immune cells correlation studies. Results: There was a significant association between the PDE1C rs12538364 T allele and colorectal cancer risk [odds ratio (OR) = 1.57, 95% confidence interval (CI) = 1.30 - 1.90, P = 3.07 × 10-6, P FDR = 0.004]. Mutation of intron region rs1538364 C to T locus reduces promoter activity of PDE1C in DLD1 and HCT116 cell lines (P < 0.05). We identified that PDE1C is significantly down-regulated in colorectal cancer, closely associated with 22 immune cells. Finally, we found that PDE1C could be the biomarker for individual immunotherapy of colorectal cancer. Conclusion: According to our findings, PDE1C may be a key factor contributing to colorectal cancer, thus improving individual immunotherapy for the disease. The potential mechanism by which polymorphisms in the calcium signaling pathway genes may participate in the pathogenesis of colorectal cancer through the tumor microenvironment.
ABSTRACT
Hepatitis represents a ubiquitous human health problem but effective therapies with limited side effects are still lacking. In this study, we investigated the effect and mechanism of TP-58, a novel thienopyridine derivative, on a murine fulminant hepatitis model induced by concanavalin A (ConA). We found TP-58 markedly alleviated ConA-caused liver injury and increased survival ratio of mice injected with a lethal dose of ConA. Oral administration of TP-58 significantly alleviated ConA-caused liver injury in mice by the reduction of serum aminotransferases and liver necrosis.The analysis of proinflammatory cytokines showed that TP-58 decreased both hepatic mRNA expressions and serum protein levels of TNF-α and IL-6. And the result from LPS-stimulated RAW 264.7 cells showed TP-58 suppressed the production of TNF-α, IL-6, and Nitro Oxide (NO) in the supernatant of LPS-stimulated RAW 264.7 cells. The study of activation of nuclear factor-κB (NF-κB) by electrophoretic mobility shift assay (EMSA) showed that TP-58 inhibited the activation of NF-κB both in vivo and in vitro. The inhibitory effect was also accompanied by a parallel reduction of IκB phosphorylation. These results indicate that TP-58 protects against liver injury by inhibition of the NF-κB-mediated inflammation and suggest a potential role of TP-58 against acute liver injury and other inflammatory diseases.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Chemical and Drug Induced Liver Injury/prevention & control , Inflammation/pathology , Liver/drug effects , Pyridines/pharmacology , Thiophenes/pharmacology , Administration, Oral , Animals , Cell Line , Chemical and Drug Induced Liver Injury/pathology , Concanavalin A , Cytokines/blood , Cytokines/genetics , Disease Models, Animal , Female , I-kappa B Proteins/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Interleukin-6/blood , Interleukin-6/genetics , Lipopolysaccharides , Liver/metabolism , Mice , Mice, Inbred BALB C , NF-kappa B/metabolism , Nitric Oxide/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Pyridines/chemistry , Pyridines/therapeutic use , Thiophenes/chemistry , Thiophenes/therapeutic use , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/geneticsABSTRACT
Hexagonal-phase NaYF(4):Yb(3+),Er(3+) up-conversion nanocrystals (UCNCs) are synthesized by a combination of refluxing and hydrothermal treatment. This strategy leads to only a slight increase in particle size, from 4.5 to ca. 10 nm, during the cubic-to-hexagonal phase transition. The hexagonal UCNCs can be internalized by HeLa cells and exhibit visible emission in the cells under near-infrared excitation.
Subject(s)
Biosensing Techniques , Erbium/chemistry , Fluorides/chemistry , Nanoparticles/chemistry , Nanotechnology/methods , Ytterbium/chemistry , Yttrium/chemistry , Cell Proliferation , Cell Survival , Fluorescent Dyes/chemistry , Fluorescent Dyes/pharmacology , HeLa Cells , Humans , In Vitro Techniques , Lanthanoid Series Elements/chemistry , Luminescence , Microscopy, Confocal/methods , Microscopy, Electron, Transmission/methods , X-Ray DiffractionABSTRACT
BACKGROUND AND AIM: (Z)2-(5-(4-methoxybenzylidene)-2, 4-dioxothiazolidin-3-yl) acetic acid (MDA) is an aldose reductase (AR) inhibitor. Recent studies suggest that AR contributes to the pathogenesis of inflammation by affecting the nuclear factor κB (NF-κB)-dependent expression of cytokines and chemokines and therefore could be a novel therapeutic target for inflammatory pathology. The current study evaluated the in vivo role of MDA in protecting the liver against injury and fibrogenesis caused by CCl(4) in rats, and the underlying mechanisms. METHODS: A single injection of CCl(4) induced acute hepatitis, and repeated injections were used to induce hepatic fibrosis in rats. Therapeutic efficacy was assessed by comparison of the severity of hepatic injury and fibrosis in MDA-treated rats versus untreated controls. RESULTS: MDA significantly protected the liver from injury by reducing the activity of serum alanine aminotransferase, and improving the histological architecture of the liver. MDA modulated NF-κB-dependent activation of inflammatory cytokines by reducing hepatic mRNA levels of tumor necrosis factor-α, interleukin-1ß, inducible nitric oxide (NO) synthase and transforming growth factor-ß. In addition, MDA attenuated oxidative stress by increasing the content of hepatic glutathione. These favorable changes were associated with suppressed hepatic NF-κB activation by MDA. MDA treatment improved liver fibrosis in rats that received repeated CCl(4) injections. In vitro, MDA attenuated phosphorylation of IκB and activation of NF-κB, and thus prevented biosynthesis of NO in lipopolysaccharide-activated RAW264.7 cells. CONCLUSIONS: The present study suggests that AR is a novel therapeutic anti-inflammatory target for the treatment of hepatitis and liver fibrosis.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/prevention & control , Enzyme Inhibitors/therapeutic use , Liver Cirrhosis, Experimental/metabolism , Liver Cirrhosis, Experimental/prevention & control , Thiazolidinediones/therapeutic use , Alanine Transaminase/blood , Animals , Carbon Tetrachloride , Cells, Cultured , Chemical and Drug Induced Liver Injury/pathology , Enzyme Inhibitors/pharmacology , Glutathione/metabolism , I-kappa B Proteins/metabolism , Interleukin-1beta/metabolism , Liver/metabolism , Liver/pathology , Liver Cirrhosis, Experimental/pathology , Macrophages/drug effects , Macrophages/metabolism , Male , NF-kappa B/drug effects , NF-kappa B/metabolism , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , Oxidative Stress/drug effects , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Thiazolidinediones/pharmacology , Transforming Growth Factor beta/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: PD-1 inhibitors in combination with fruquintinib have not previously been reported as neoadjuvant therapy for patients with colorectal cancer. In this case report, the combination of a PD-1 inhibitor and fruquintinib demonstrated good efficacy in patients with MSI-H colorectal cancer. CASE SUMMARY: The patient was a young man in his 30s who had MSI-H type colon cancer. The patient underwent four cycles of neoadjuvant therapy with a PD-1 inhibitor combined with fruquintinib before surgery, resulting in regression of the mass and a successful surgery. CONCLUSION: Some patients with colorectal cancer have the MSI-H type, and the first-line chemotherapy regimen is not effective. However, PD-1 monoclonal antibody immunotherapy has a good therapeutic effect, which can be improved by combination therapy with fruquintinib. We recommend that patients with a history of colon or rectal cancer receive universal MSI testing; then, neoadjuvant therapy should be used.
ABSTRACT
Background: 7-Methylguanosine(m7G) contributes greatly to its pathogenesis and progression in colorectal cancer. We proposed building a prognostic model of m7G-related LncRNAs. Our prognostic model was used to identify differences between hot and cold tumors. Methods: The study included 647 colorectal cancer patients (51 cancer-free patients and 647 cancer patients) from The Cancer Genome Atlas (TCGA). We identified m7G-related prognostic lncRNAs by employing the univariate Cox regression method. Assessments were conducted using univariate Cox regression, multivariate Cox regression, receiver operating characteristics (ROC), nomogram, calibration curves, and Kaplan-Meier analysis. All of these procedures were used with the aim of confirming the validity and stability of the model. Besides these two analyses, we also conducted half-maximal inhibitory concentration (IC50), immune analysis, principal component analysis (PCA), and gene set enrichment analysis (GSEA). The entire set of m7G-related (lncRNAs) with respect to cold and hot tumors has been divided into two clusters for further discussion of immunotherapy. Results: The risk model was constructed with 17 m7G-related lncRNAs. A good correlation was found between the calibration plots and the prognosis prediction in the model. By assessing IC50 in a significant way across risk groups, systemic treatment can be guided. By using clusters, it may be possible to distinguish hot and cold tumors effectively and to aid in specific therapeutic interventions. Cluster 1 was identified as having the highest response to immunotherapy drugs and thus was identified as the hot tumor. Conclusion: This study shows that 17 m7G-related lncRNA can be used in clinical settings to predict prognosis and use them to determine whether a tumor is cold or hot in colorectal cancer and improve the individualization of treatment.
ABSTRACT
The concept of metalla-aromaticity proposed by Thorn-Hoffmann (Nouv. J. Chim. 1979, 3, 39) has been expanded to organometallic molecules of transition metals that have more than one independent electron-delocalized system. Lanthanides, with highly contracted 4f atomic orbitals, are rarely found in multiply aromatic systems. Here we report the discovery of a doubly aromatic triatomic lanthanide-boron molecule PrB2 - based on a joint photoelectron spectroscopy and quantum chemical investigation. Global minimum structural searches reveal that PrB2 - has a C 2v triangular structure with a paramagnetic triplet 3B2 electronic ground state, which can be viewed as featuring a trivalent Pr(III,f2) and B2 4-. Chemical bonding analyses show that this cyclo-PrB2 - species is the smallest 4f-metalla-aromatic system exhibiting σ and π double aromaticity and multiple Pr-B bonding characters. It also sheds light on the formation of the rare B2 4- tetraanion by the high-lying 5d orbitals of the 4f-elements, completing the isoelectronic B2 4-, C2 2-, N2, and O2 2+ series.
ABSTRACT
Deltonin, a steroidal saponin, isolated from Dioscorea zingiberensis Wright (DZW), has shown high-cytotoxic activity in cancer cells. However, its mechanisms and in vivo anti-cancer effects remain unknown. In the present study, we evaluated the effects and explored the anti-tumor mechanisms of deltonin on a panel of colon cancer cell lines and in a mouse model of murine colon cancer C26. Deltonin had more cytotoxic effect on C26 cells than 5-fluorouracil had, promoting dramatic G2-M phase arrest and apoptosis in C26 cells in a concentration-dependent manner; oral administration of deltonin significantly inhibited the tumor growth and prolonged survival of the tumor bearing mice. The deltonin treatment caused a noticeable apoptosis in tumor tissue, which associated with increased levels of Bax, activated caspase-3, caspase-9, and cleaved poly (ADPribose) polymerase, decreased pro-caspase-8, pro-caspase-9, Bcl-2 expression levels and extracellular signal-regulated kinase-1/2 activity; and dose-dependently inhibit angiogenesis. In conclusion, the findings in this study demonstrated that deltonin is an effective natural agent for cancer therapy, which may be mediated, in part, by induction of apoptosis, as well as involve mitogen-activated protein kinase pathways, and inhibition of angiogenesis.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Apoptosis/drug effects , Colonic Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Spirostans/therapeutic use , Angiogenesis Inhibitors/chemistry , Animals , Caspase 3/metabolism , Caspase 8/metabolism , Caspase 9/metabolism , Cell Line, Tumor , Colonic Neoplasms/blood supply , Disease Models, Animal , Humans , Male , Mice , Mice, Inbred BALB C , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Platelet Endothelial Cell Adhesion Molecule-1/immunology , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Poly(ADP-ribose) Polymerases/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Saponins/therapeutic use , Spirostans/chemistry , bcl-2-Associated X Protein/metabolismABSTRACT
The critical role of phosphoinositide 3-kinase gamma (PI3Kgamma) in inflammatory cell activation and recruitment makes it an attractive target for immunomodulatory therapy. 5-Quinoxilin-6-methylene-1,3-thiazolidine-2,4-dione (AS605240), a potent PI3Kgamma inhibitor, has been reported to ameliorate chronic inflammatory disorders including rheumatoid arthritis, systemic lupus erythematosus, and atherosclerosis. However, its in vivo effect on intestinal inflammation remains unknown. Here we evaluated the protective and therapeutic potentials of AS605240 in mice with dextran sodium sulfate (DSS)-induced acute and chronic colitis. Our results showed that AS605240 improved survival rate, disease activity index, and histological damage score in mice administered DSS in both preventive and therapeutic studies. AS605240 treatment also significantly inhibited the increase in myeloperoxidase levels, macrophage infiltration, and CD4(+) T-cell number in the colon of DSS-fed mice. The DSS-induced overproduction of colonic proinflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor-alpha, and interferon-gamma was significantly suppressed in mice undergoing AS605240 therapy, whereas colonic anti-inflammatory cytokines such as IL-4 were up-regulated. The down-regulation of the phospho-Akt level in immunological cells from the inflamed colon tissue and spleen of AS605240-treated mice was detected both by immunohistochemical analysis and Western blotting. These findings demonstrate that AS605240 may represent a promising novel agent for the treatment of inflammatory bowel disease by suppressing leukocyte infiltration as well as by immunoregulating the imbalance between proinflammatory and anti-inflammatory cytokines.
Subject(s)
Colitis/prevention & control , Enzyme Inhibitors/therapeutic use , Phosphoinositide-3 Kinase Inhibitors , Quinoxalines/therapeutic use , Thiazolidinediones/therapeutic use , Acute Disease , Animals , Blotting, Western , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/cytology , Chronic Disease , Colitis/chemically induced , Colitis/enzymology , Colitis/immunology , Colitis/pathology , Colon/drug effects , Colon/enzymology , Colon/immunology , Colon/pathology , Cytokines/biosynthesis , Cytokines/immunology , Dextran Sulfate , Disease Models, Animal , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Flow Cytometry , Fluorescent Antibody Technique , Immunohistochemistry , Intestinal Mucosa/drug effects , Intestinal Mucosa/enzymology , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Male , Mice , Mice, Inbred C57BL , Organ Size , Quinoxalines/administration & dosage , Quinoxalines/pharmacology , Severity of Illness Index , Spleen/drug effects , Spleen/immunology , Thiazolidinediones/administration & dosage , Thiazolidinediones/pharmacologyABSTRACT
With the improvement of gene vectors, the rise of chimeric antigen receptor T cell immunotherapy and breakthroughs in the genome editing technology, gene therapy had once again returned to the central stage of disease treatment. It had brought new choices to clinical therapy of diseases such as tumors and genetic diseases, and had changed the status quo of treatment for monogenic disorders and diffuse large B-cell lymphoma. Until August 2019, 22 gene medicines had been approved by the drug regulatory agencies from various countries, but there were few relevant reviews of combing these drugs systematically. Consequently, this review summarizes the gene therapy drugs approved worldwide from 1998 to 2019 in details, including names, indications, dates of approval, companies, vectors, the applied technologies and mechanisms of gene therapy drugs, etc. Furthermore, the gene therapy drugs were classified and addressed in accordance with the employed vectors. Gene therapy had gradually been accepted by the government and the public since 1980s, and have become a new and important alternative to existing treatments for human diseases in the past few years. Therefore, gene therapy drugs, with safe vectors and advanced biotechnologies, would play a greater role in the prevention and treatment of human diseases in future.
Subject(s)
Genetic Therapy , Gene Editing , Genetic Vectors , Humans , Immunotherapy , Neoplasms/therapyABSTRACT
Ionizing irradiation kills pathogens by destroying nucleic acids without protein structure destruction. However, how pathogens respond to irradiation stress has not yet been fully elucidated. Here, we observed that Pseudomonas aeruginosa PAO1 could release nucleic acids into the extracellular environment under X-ray irradiation. Using scanning electron microscopy (SEM) and transmission electron microscopy (TEM), X-ray irradiation was observed to induce outer membrane vesicle (OMV) formation in P. aeruginosa PAO1. The size distribution of the OMVs of the irradiated PAO1 was similar to that of the OMVs of the non-irradiated PAO1 according to nanoparticle tracking analysis (NTA). The pyocin-related proteins are involved in OMV production in P. aeruginosa PAO1 under X-ray irradiation conditions, and that this is regulated by the key SOS gene recA. The OMV production was significantly impaired in the irradiated PAO1 Δlys mutant, suggesting that Lys endolysin is associated with OMV production in P. aeruginosa PAO1 upon irradiation stress. Meanwhile, no significant difference in OMV production was observed between PAO1 lacking the pqsR, lasR, or rhlR genes and the parent strain, demonstrating that the irradiation-induced OMV biosynthesis of P. aeruginosa was independent of the Pseudomonas quinolone signal (PQS).
ABSTRACT
A pivotal role of phosphoinositide 3-kinase-gamma (PI3Kgamma) in inflammatory cell activation and recruitment makes it an attractive target for immunomodulatory therapy. In present study we investigated the therapeutic efficiency of AS605240, a selective PI3Kgamma inhibitor, on hepatitis and liver fibrosis in murine models induced by concanavalin A (ConA). Orally administration of AS605240 significantly improved survival, decreased the serum levels of alanine aminotransaminase (ALT), prevented inflammatory infiltration to liver in ConA-induced hepatitis. TNF-alpha and IFN-gamma at protein levels in serum and mRNA levels in liver were markedly reduced. Downregulated phospho-Akt level of inflammatory cells infiltrating the liver by AS605240 treatment was detected by immunohistochemistry analysis in liver and further confirmed by Western blotting analysis in splenocytes. In ConA-induced chronic liver fibrosis model, accumulation of smooth-muscle actin (SMA)-expressing cells was partially inhibited by AS605240 treatment. These observations suggest that AS605240 might be of therapeutic value for the treatment of ConA-induced hepatic injury.
Subject(s)
Chemical and Drug Induced Liver Injury/drug therapy , Enzyme Inhibitors/therapeutic use , Liver/enzymology , Phosphoinositide-3 Kinase Inhibitors , Quinoxalines/therapeutic use , Thiazolidinediones/therapeutic use , Acute Disease , Animals , Chemical and Drug Induced Liver Injury/complications , Chemical and Drug Induced Liver Injury/pathology , Class Ib Phosphatidylinositol 3-Kinase , Concanavalin A/toxicity , Cytokines/biosynthesis , Isoenzymes/antagonists & inhibitors , Liver/drug effects , Liver/pathology , Liver Cirrhosis/etiology , Liver Cirrhosis/pathology , Liver Cirrhosis/prevention & control , Mice , Mitogens/toxicity , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
OBJECTIVE: To investigate the therapeutic effect of PI3Kgamma inhibitor AS605240 on autoimmune myocarditis in mice. METHODS: BALB/c mice were randomly divided into three groups, AS605240 group and vehicle group were injected subcutaneously with emulsions containing CFA and 100 ng peptide which derived from murine cardiac alpha-myosin heavy chain on day 0 and 7 while control group were injected with emulsions containing CFA and PBS. AS605240 group received the oral administration of AS605240 50 mg/(kg x d). The vehicle group received the oral administration of an equal volume of 0.5% carboxymethylcellulose. 21 days after the first immunization, mice were sacrificed, heart and body weight were measured. Myocarditis severity was evaluated according to a semi-quantitative scoring system in heart sections. Immunohistochemistry was performed to determine the effect of AS605240 on myocardium macrophage infiltration; TNF-alpha levels in myocardium were determined by ELISA. In vitro and in vivo chemotaxis assays were performed to determine the effect of AS605240 on MCP-1-induced macrophage chemotaxis. RESULTS: Histological examination of the heart showed that AS605240 significantly relieved the murine myocarditis and reduced heart/body weight ratios in experimental autoimmune myocarditis (EAM) (P< 0.01). Immunohistochemical detection showed that AS605240 significantly suppressed macrophage infiltration into the heart with EAM. ELISA demonstrated that AS605240 down-regulated TNF-alpha levels in myocardium (P<0.01). In vitro and in vivo chemotaxis assays indicated that AS605240 significantly suppressed MCP-1-induced macrophage chemotaxis (P<0.01). CONCLUSION: AS605240 may be an effective drug for autoimmune myocarditis, of which the mechanism is relating to suppress macrophage chemotaxis and macrophage infiltration into myocardium, and to decrease TNF-alpha levels in myocardium.
Subject(s)
Autoimmune Diseases/drug therapy , Myocarditis/drug therapy , Phosphoinositide-3 Kinase Inhibitors , Quinoxalines/therapeutic use , Thiazolidinediones/therapeutic use , Tumor Necrosis Factor-alpha/metabolism , Animals , Autoimmune Diseases/immunology , Chemokine CCL2/metabolism , Class Ib Phosphatidylinositol 3-Kinase , Down-Regulation/drug effects , Isoenzymes/antagonists & inhibitors , Male , Mice , Mice, Inbred BALB C , Myocarditis/immunology , Random AllocationABSTRACT
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
ABSTRACT
DspI, a putative enoyl-coenzyme A (CoA) hydratase/isomerase, was proposed to be involved in the synthesis of cis-2-decenoic acid (CDA), a quorum sensing (QS) signal molecule in the pathogen Pseudomonas aeruginosa (P. aeruginosa). The present study provided a structural basis for the dehydration reaction mechanism of DspI during CDA synthesis. Structural analysis reveals that Glu126, Glu146, Cys127, Cys131 and Cys154 are important for its enzymatic function. Moreover, we show that the deletion of dspI results in a remarkable decreased in the pyoverdine production, flagella-dependent swarming motility, and biofilm dispersion as well as attenuated virulence in P. aeruginosa PA14. This study thus unravels the mechanism of DspI in diffusible signal factor (DSF) CDA biosynthesis, providing vital information for developing inhibitors that interfere with DSF associated pathogenicity in P. aeruginosa.