Search Results (12)

Genetic constructs must be delivered selectively to target tissues and intracellular compartments at the necessary concentrations in order to achieve the maximum therapeutic effect in gene therapy. Development of targeted carriers for non-viral delivery of nucleic acids into cells, including those in muscle, which is one of the most challenging tissues to transfect in vivo, remains a topical issue. We have studied ternary complexes of plasmid DNA and an arginine–histidine-rich peptide-based carrier coated with a glutamate–histidine-rich polymer bearing skeletal muscle targeting peptide (SMTP) for the gene delivery to muscle tissue. The relaxation of the ternary complexes after polyanion treatment was assessed using the ethidium bromide displacement assay. The developed polyplexes were used to transfect C2C12 myoblasts in full-media conditions, followed by analysis of their toxic properties using the Alamar Blue assay and expression analysis of lacZ and GFP reporter genes. After delivering plasmids containing the GFP and lacZ genes into the femoral muscles of mdx mice, which are model of Duchenne muscular dystrophy, GFP fluorescence and β-galactosidase activity were detected. We observed that the modification of ternary polyplexes with 10 mol% of SMTP ligand resulted in a 2.3-fold increase in lacZ gene expression when compared to unmodified control polyplexes in vivo. Thus, we have demonstrated that the developed DNA/carrier complexes and SMTP-modified coating are nontoxic, are stable against polyanion-induced relaxation, and can provide targeted gene delivery to muscle cells and tissues. The results of this study are useful for a range of therapeutic applications, from immunization to amelioration of inherited neuromuscular diseases. Full article

Cybersecurity is a critical issue in today’s internet world. Classical security systems, such as firewalls based on signature detection, cannot detect today’s sophisticated zero-day attacks. Machine learning (ML) based solutions are more attractive for their capabilities of detecting anomaly traffic from benign traffic, but to develop an ML-based anomaly detection system, we need meaningful or realistic network datasets to train the detection engine. There are many public network datasets for ML applications. Still, they have limitations, such as the data creation process and the lack of diverse attack scenarios or background traffic. To create a good detection engine, we need a realistic dataset with various attack scenarios and various types of background traffic, such as HTTPs, streaming, and SMTP traffic. In this work, we have developed realistic network data or datasets considering various attack scenarios and diverse background/benign traffic. Furthermore, considering the importance of distributed denial of service (DDoS) attacks, we have compared the performance of detecting anomaly traffic of some classical supervised and our prior developed unsupervised ML algorithms based on the convolutional neural network (CNN) and pseudo auto-encoder (AE) architecture based on the created datasets. The results show that the performance of the CNN-Pseudo-AE is comparable to that of many classical supervised algorithms. Hence, the CNN-Pseudo-AE algorithm is promising in actual implementation. Full article

SMTP-44D has been reported to have anti-oxidative and anti-inflammatory reactions, including reduced expression of receptor for advanced glycation end products (RAGE) in experimental diabetic neuropathy. Although activation of RAGE with its ligands, and advanced glycation end products (AGEs), play a crucial role in atherosclerotic cardiovascular disease, a leading cause of death in diabetic patients, it remains unclear whether SMTP-44D could inhibit experimental atherosclerosis by suppressing the AGEs–RAGE axis. In this study, we investigated the effects of SMTP-44D on atherosclerotic plaque formation and expression of AGEs in apolipoprotein-E null (Apoe^−/−) mice. We further studied here whether and how SMTP-44D inhibited foam cell formation of macrophages isolated from Apoe^−/− mice ex vivo. Although administration of SMTP-44D to Apoe^−/− mice did not affect clinical or biochemical parameters, it significantly decreased the surface area of atherosclerotic lesions and reduced the atheromatous plaque size, macrophage infiltration, and AGEs accumulation in the aortic roots. SMTP-44D bound to immobilized RAGE and subsequently attenuated the interaction of AGEs with RAGE in vitro. Furthermore, foam cell formation evaluated by Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and gene expression of RAGE, cyclin-dependent kinase 5 (Cdk5) and CD36 in macrophages isolated from SMTP-44D-treated Apoe^−/− mice were significantly decreased compared with those from saline-treated mice. Gene expression levels of RAGE and Cdk5 were highly correlated with each other, the latter of which was also positively associated with that of CD36. The present study suggests that SMTP-44D may inhibit atherosclerotic plaque formation in Apoe^−/− mice partly by blocking the AGEs-RAGE-induced ox-LDL uptake into macrophages via the suppression of Cdk5-CD36 pathway. Full article

This study introduces the Live Spam Beater (LiSB) framework for the execution of email filtering techniques during SMTP (Simple Mail Transfer Protocol) transactions. It aims to increase the effectiveness and efficiency of existing proactive filtering mechanisms, mainly based on simple blacklists. Since it implements some proactive filtering schemes (during SMTP transaction), when an email message is classified as spam, the sender can be notified by an SMTP response code as a result of the transaction itself. The presented framework is written in Python programming language, works as an MTA (Mail Transfer Agent) server that implements an SMTP (Simple Mail Transfer Protocol) reverse proxy and allows the use of plugins to easily incorporate new filtering techniques designed to operate proactively. We also include a plugin to perform proactive content-based filtering through the analysis of words included in the body of the email message. Finally, we measured the performance of the plugin and the framework (time required for operation and accuracy) obtaining values suitable for their use during SMTP transactions. Full article

SMTP (the name SMTP is derived from Stachybotrys microspora triprenyl phenol) is a family of triprenyl phenol secondary metabolites from a black mold, Stachybotrys microspora. Some SMTP congeners exhibit anti-inflammatory and profibrinolytic activities that, in combination, contribute to the treatment of ischemic stroke. The final step in the SMTP biosynthesis is a non-enzymatic amine conjugation with an o-phthalaldehyde moiety of the precursor pre-SMTP, which can form adducts with proteins and nucleic acids. Thus, pre-SMTP formation should be a precisely regulated, rate-limiting step in the SMTP biosynthesis. To address the mechanism backing this regulation, we purified a metabolite that rapidly disappeared following amine feeding, identifying a novel compound, pri-SMTP. Furthermore, an enzyme, designated as pri-SMTP oxidase, responsible for pri-SMTP conversion to pre-SMTP, was purified. The formation of pri-SMTP, which is regulated by nitrogen and carbon nutrients, occurred in particular septate mycelia. Although pri-SMTP oxidase was expressed constitutively, the consumption of pri-SMTP was accelerated only when a primary amine was fed. Thus, SMTP biosynthesis is regulated by at least three mechanisms: (i) pri-SMTP formation affected by nutrients, (ii) the compartmentalization of pri-SMTP formation/storage, and (iii) amine-regulated pri-SMTP oxidation. Amine-regulated SMTP formation (i.e., amine-capturing with pre-SMTP) may play a role in the nitrogen acquisition/assimilation strategy in S. microspora, since pri-SMTP synthesis occurs on non-preferred nitrogen. Full article

Compound 1 (SMTP-7, also FGFC1), an isoindolone alkaloid from marine fungi Starchbotrys longispora FG216 and fungi Stachybotrys microspora IFO 30018, possessed diverse bioactivities such as thrombolysis, anti-inflammatory and anti-oxidative properties, and so on. It may be widely used for the treatment of various diseases, including cerebral infarction, stroke, ischemia/reperfusion damage, acute kidney injury, etc. Especially in cerebral infarction, compound 1 could reduce hemorrhagic transformation along with thrombolytic therapy, as the traditional therapies are accompanied with bleeding risks. In the latest studies, compound 1 selectively inhibited the growth of NSCLC cells with EGFR mutation, thus demonstrating its excellent anti-cancer activity. Herein, we summarized pharmacological activities, preparation of staplabin congeners—especially compound 1—and the mechanism of compound 1, with potential therapeutic applications. Full article

Diabetic neuropathy (DN) is a major complication of diabetes mellitus. We have previously reported the efficacy of Stachybotrys microspora triprenyl phenol-44D (SMTP-44D) for DN through its potential antioxidant and anti-inflammatory activities. However, the mechanisms underlying the antioxidant and anti-inflammatory activities of SMTP-44D remain unclear. The present study aimed to explore the mechanism of these effects of SMTP-44D in regard to its inhibition of soluble epoxide hydrolase (sEH) in immortalized mouse Schwann cells (IMS32) following high glucose treatment. IMS32 cells were incubated in a high glucose medium for 48 h and then treated with SMTP-44D for 48 h. After incubation, the ratio of epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), oxidative stress markers, such as NADPH oxidase-1 and malondialdehyde, inflammatory factors, such as the ratio of nuclear to cytosolic levels of NF-κB and the levels of IL-6, MCP-1, MMP-9, the receptor for the advanced glycation end product (RAGE), and apoptosis, were evaluated. SMTP-44D treatment considerably increased the ratio of EETs to DHETs and mitigated oxidative stress, inflammation, RAGE induction, and apoptosis after high glucose treatment. In conclusion, SMTP-44D can suppress the induction of apoptosis by exerting antioxidant and anti-inflammatory effects, possibly through sEH inhibition. SMTP-44D can be a potential therapeutic agent against DN. Full article

Considering the nature of marine accidents, even a single accident can result in significant damage to the environment and property, as well as loss of life. Therefore, the initial response should be rapid and accurate, and various decision support systems have been developed to achieve this. Research on simulating progressive flooding on board immediately after an accident is being actively conducted, but this requires high levels of computing power. In this study, a methodology for converting simulated ship motion data into a ship motion database is presented. The model of a training ship from the Korea Institute of Maritime and Fisheries Technology and KRISO in-house code SMTP was used for ship motion computations. The short-time Fourier transform was used to convert time-series motion data into a spectrogram motion database. A methodology for deriving a predicted location of the damage center is presented. The candidate locations of the damage centers were obtained by comparing the root mean square error values of the ship motion database from the simulation and real-time ship motion data. Finally, a probability function was suggested to confirm the predicted location of the damage center. Using 100 randomly selected test cases, our method showed 95% accuracy. Full article

Gene therapy is a good alternative for determined congenital disorders; however, there are numerous limitations for gene delivery in vivo including targeted cellular uptake, intracellular trafficking, and transport through the nuclear membrane. Here, a modified G5 polyamidoamine (G5 PAMAM) dendrimer–DNA complex was developed, which will allow cell-specific targeting to skeletal muscle cells and transport the DNA through the intracellular machinery and the nuclear membrane. The G5 PAMAM nanocarrier was modified with a skeletal muscle-targeting peptide (SMTP), a DLC8-binding peptide (DBP) for intracellular transport, and a nuclear localization signaling peptide (NLS) for nuclear uptake, and polyplexed with plasmid DNA containing the GFP-tagged microdystrophin (µDys) gene. The delivery of µDys has been considered as a therapeutic modality for patients suffering from a debilitating Duchenne muscular dystrophy (DMD) disorder. The nanocarrier–peptide–DNA polyplexes were prepared with different charge ratios and characterized for stability, size, surface charge, and cytotoxicity. Using the optimized nanocarrier polyplexes, the transfection efficiency in vitro was determined by demonstrating the expression of the GFP and the µDys protein using fluorescence and Western blotting studies, respectively. Protein expression in vivo was determined by injecting an optimal nanocarrier polyplex formulation to Duchenne model mice, mdx^4Cv. Ultimately, these nanocarrier polyplexes will allow targeted delivery of the microdystrophin gene to skeletal muscle cells and result in improved muscle function in Duchenne muscular dystrophy patients. Full article

Alternaria alternata isolates C1, S1, and X3 were isolated respectively from the weeds Convolvulus arvensis, Sonchus oleraceus, and Xanthium strumarium in Algiers during 2016 and identified by morphological and molecular analyses. The aim of this investigation was to chemically characterize the exometabolome of these fungi and to evaluate the myco-herbicidal potential of their culture filtrates, crude extracts, or fractions towards target weeds. Results revealed a great heterogeneity in the biochemical profiles of the exometabolome with the remarkable presence of two compounds: tenuazonic acid (TeA) and triprenyl phenol-7 (SMTP-7). To the best of our knowledge, SMTP-7—found in all the isolates—as well as 12-methoxycitromycin detected in the culture filtrate of isolate C1, have never been reported to be produced by A. alternata. Some fractions of isolates C1 and S1 showed symptoms (necrosis and chlorosis) on the detached leaves of C. arvensis and S. oleraceus, respectively with up to 100% phytotoxic effect at low concentration. In conclusion, biochemical characterization revealed great difference of C1, S1, and X3 exometabolome that is likely to explain the difference in their phytotoxic activity. Some fractions (d₁, e₁, h₁, i₁, a₂, and f₂) of isolates C1 and S1 of A. alternata caused severe necrosis and chlorosis on the injured detached leaves of C. arvensis and S. oleraceus, respectively. Full article

Complexes of trivalent lanthanides (Ln) with the hydridotris(1-pyrazolyl)borato (Tp) ligand Ln[η³-HB(N₂C₃H₃)₃]₃ (LnTp₃) were subjected to a joint experimental–theoretical analysis. X-ray diffraction experiments have been performed on CeTp₃, NdTp₃, SmTp₃, GdTp₃, and TbTp₃ in the nine-fold coordination and on DyTp₃, HoTp₃, ErTp₃, TmTp₃, YbTp₃, and LuTp₃ in the eight-fold coordination form. Density functional theory (DFT) calculations were carried out for all 15 LnTp₃ complexes. They extended the X-ray diffraction data available on the LnTp₃ compounds and facilitated a straightforward interpretation of trends in the structural parameters. As a result of the joint analysis, significant steric strain in the equatorial coordination sites of the nine-coordinate structures was recognized. Trends in the bonding properties were elucidated by energy decomposition and quantum theory of atoms in molecules (QTAIM) analysis of the electron density distribution. These results revealed the major electrostatic character of the Ln…Tp bonding and fine variation of charge transfer effects across the Ln row. Full article

Stachybotrys microspora triprenyl phenol (SMTP) is a large family of small molecules derived from the fungus S. microspora. SMTP acts as a zymogen modulator (specifically, plasminogen modulator) that alters plasminogen conformation to enhance its binding to fibrin and subsequent fibrinolysis. Certain SMTP congeners exert anti-inflammatory effects by targeting soluble epoxide hydrolase. SMTP congeners with both plasminogen modulation activity and anti-inflammatory activity ameliorate various aspects of ischemic stroke in rodents and primates. A remarkable feature of SMTP efficacy is the suppression of hemorrhagic transformation, which is exacerbated by conventional thrombolytic treatments. No drug with such properties has been developed yet, and SMTP would be the first to promote thrombolysis but suppress disease-associated bleeding. On the basis of these findings, one SMTP congener is under clinical study and development. This review summarizes the discovery, mechanism of action, pharmacological activities, and development of SMTP. Full article