Global analysis of lysine acetylation in the brain cortex of K18-hACE2 mice infected with SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected hundreds of millions of people all over the world and thus threatens human life. Clinical evidence shows that SARS-CoV-2 infection can cause several neurological consequences, but the existing antiviral drugs and vaccines have failed to stop its spread. Therefore, an understanding of the response to SARS-CoV-2 infection of hosts is vital to find a resultful therapy. Here, we employed a K18-hACE2 mouse infection model and LC-MS/MS to systematically evaluate the acetylomes of brain cortexes in the presence and absence of SARS-CoV-2 infection. Using a label-free strategy, 3829 lysine acetylation (Kac) sites in 1735 histone and nonhistone proteins were identified. Bioinformatics analyses indicated that SARS-CoV-2 infection might lead to neurological consequences via acetylation or deacetylation of important proteins. According to a previous study, we found 26 SARS-CoV-2 proteins interacted with 61 differentially expressed acetylated proteins with high confidence and identified one acetylated SARS-CoV-2 protein nucleocapsid phosphoprotein. We greatly expanded the known set of acetylated proteins and provide the first report of the brain cortex acetylome in this model and thus a theoretical basis for future research on the pathological mechanisms and therapies of neurological consequences after SARS-CoV-2 infection.

Sustainable production of dimethyl-protected cyclic lysine over Pd/m-Al2O3-Si catalysts and its application in synthesis of antibacterial nylon‑6 copolymers

• Pd/ m- Al 2 O 3 -Si catalyst exhibited high efficiency in converting α- amino -ε- caprolactam (α- ACL) to dimethyl-protected cyclic lysine (DMCL). • The lack of Brönsted acid sites on Pd/ m- Al 2 O 3 -Si surface facilitated the formation of DMCL and suppressed undesirable reaction process. • Pd/ m- Al 2 O 3 -Si catalyst with microspherical morphology performed excellent stability and physical strength during the catalytic process. • The nylon‑6 copolymers produced from the as-synthesized DMCL exhibited a great potential in the synthesis of self-cleaning antibacterial materials. Antibacterial monomers are prerequisites for synthesizing antibacterial polymers, especially during the current COVID-19 pandemic. Dimethyl-protected cyclic lysine (DMCL) is a promising functional monomer for nylon-6 based self-cleaning antibacterial polymers. However, the production of DMCL still faces formidable challenges, such as harsh reaction conditions and low catalyst activities. In this study, we developed a Pd/ m -Al 2 O 3 -Si catalyst, which exhibited high efficiency in converting α -amino- ε -caprolactam (α -ACL) to DMCL, affording a yield of as high as 97.1% at 100 °C and 1 MPa H 2. The lack of Brönsted acid sites on the catalyst surface facilitated the formation of DMCL and suppressed undesirable hydrolysis or cracking by-products from the lactam-based reactant. The recycled experiments showed that Pd/ m -Al 2 O 3 -Si performed excellent stability and physical strength with essentially no damage to its microspheres after the reaction. The nylon‑6 copolymers produced from the as-synthesized DMCL exhibited similar structure and thermal stability with pure nylon-6, showing great potential in synthesizing the self-cleaning antibacterial polymers. This work provides a sustainable and efficient method for producing DMCL and other lysine-based antibacterial monomers, showing a great prospect for the utilization of bio-based chemicals in synthesizing functional polymers. [ FROM AUTHOR] Copyright of Chemical Engineering Journal is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Emerging Roles of SIRT5 in Metabolism, Cancer, and SARS-CoV-2 Infection.

Sirtuin 5 (SIRT5) is a predominantly mitochondrial enzyme catalyzing the removal of glutaryl, succinyl, malonyl, and acetyl groups from lysine residues through a NAD+-dependent deacylase mechanism. SIRT5 is an important regulator of cellular homeostasis and modulates the activity of proteins involved in different metabolic pathways such as glycolysis, tricarboxylic acid (TCA) cycle, fatty acid oxidation, electron transport chain, generation of ketone bodies, nitrogenous waste management, and reactive oxygen species (ROS) detoxification. SIRT5 controls a wide range of aspects of myocardial energy metabolism and plays critical roles in heart physiology and stress responses. Moreover, SIRT5 has a protective function in the context of neurodegenerative diseases, while it acts as a context-dependent tumor promoter or suppressor. In addition, current research has demonstrated that SIRT5 is implicated in the SARS-CoV-2 infection, although opposing conclusions have been drawn in different studies. Here, we review the current knowledge on SIRT5 molecular actions under both healthy and diseased settings, as well as its functional effects on metabolic targets. Finally, we revise the potential of SIRT5 as a therapeutic target and provide an overview of the currently reported SIRT5 modulators, which include both activators and inhibitors.

Expedient Synthesis of Ubiquitin‐like Protein ISG15 Tools through Chemo‐Enzymatic Ligation Catalyzed by a Viral Protease Lbpro

Ubiquitin (Ub)‐like protein ISG15 (interferon‐stimulated gene 15) regulates innate immunity and links with the evasion of host response by viruses such as SARS‐CoV‐2. Dissecting ISGylation pathways recently received increasing attention which can inform related disease interventions, but such studies necessitate the preparation and development of various ISG15 protein tools. Here, we find that the leader protease (Lbpro) encoded by foot‐and‐mouth disease virus can promote ligation reactions between recombinant ISG15 and synthetic glycyl compounds, generating protein tools such as ISG15‐propargylamide and ISG15‐rhodamine110, which are needed for cellular proteomic studies of deISGylases, and the screening and evaluation of inhibitors against SARS‐CoV‐2 papain‐like protease (PLpro). Furthermore, this strategy can be also used to load ISG15 onto the lysine of a synthetic peptide through an isopeptide bond, and prepare Ub and NEDD8 (ubiquitin‐like protein Nedd8) protein tools.

Electroporation: An Effective Method For In Vivo Gene Delivery

Background: Gene therapy is a promising approach for the treatment of various diseases, including cancer, hereditary disorders, and some viral infections. The development of efficient and safe gene delivery systems is essential for facilitating gene transfer to various organs and tissues in vivo. Objective: In this review, we briefly describe the principal mechanisms of gene delivery systems, particularly electroporation, and discuss the latest advancements in the application of electro-poration for in vivo gene transfer. Methods: A narrative review of all the relevant publication known to the authors was conducted. Results: In recent years, electroporation-based strategies have emerged as an auspicious and versa-tile platform for efficient and controlled delivery of various biomolecules, including nucleic acids. Applying electric pulses of enough magnitude leads to the formation of hydrophilic pores in the cell membrane and allows the entry of otherwise membrane-impermeant molecules, such as DNA. Alt-hough electroporation has been initially developed for in vitro transfection of cells, it has recently advanced to preclinical in vivo applications and finally to clinical trials. Conclusion: Electroporation has already entered the clinical practice for antitumor therapy and may be an essential part of future personalized treatments. Given the ability of electroporation to deliver multiple genes in a single event, it will also certainly be further developed both as a stand-alone delivery approach and when coupled with other technologies.

Effects of reducing the standardized ileal digestible lysine and tryptophan to lysine ratio to slow growth of finishing pigs.

The COVID-19 global pandemic greatly affected pork processing plants in the United States. These pork processing plants were forced to either temporarily close or operate at reduced capacity due to the increased number of health-related employee absences. Because finishing pigs could not be timely marketed, methods to reduce growth performance were required to keep pigs from becoming too heavy at slaughter weight. Therefore, our objective was to determine the extent that reducing dietary standardized ileal digestible (SID) Lys and tryptophan-to-lysine ratio (Trp:Lys) ratio would slow finishing pig average daily gain (ADG) in a commercial setting. A total of 1,080 finishing pigs (327 × 1050, PIC; initially 32.3 kg) were used in a 119-d growth trial. Pigs were allotted by initial body weight (BW) and randomly assigned to 1 of 4 dietary treatments in a completely randomized block design with 27 pigs per pen and 10 pens per treatment. Three dietary regimes were formulated to contain either 100%, 90%, or 80% of the estimated SID Lys requirement for pigs in this facility, with a SID Trp:Lys ratio of 19%, with the exception of the last dietary phase formulated to 17% SID Trp:Lys. Seven different dietary phases were fed. The SID Lys concentrations in the 100% diets were: 1.10%, 1.01%, 0.91%, 0.83%, 0.79%, 0.71%, or 0.67% SID Lys from 32 to 40, 40 to 51, 51 to 72, 72 to 85, 85 to 98, 98 to 112, and 112 to 130 kg, respectively. A fourth regime was formulated to 80% SID Lys with a SID Trp:Lys ratio of 16% (80-16% SID Trp:Lys) throughout all phases. Overall from d 0 to 119, ADG (linear, P < 0.001), final BW (linear, P < 0.001), and gain-to-feed (G:F) decreased (linear, P = 0.087) as SID Lys decreased from 100% to 80% of the estimated requirement. Pigs fed the 80-16% SID Trp:Lys diets had an additional decrease in ADG (P < 0.05) and G:F (P < 0.10) compared with pigs fed 80% of the SID Lys requirement with the normal Trp:Lys ratio. The reduction in SID Lys (from 100% to 80%) and reduction in SID Lys and Trp:Lys ratio resulted in an 8.6 and 11.7 kg, respectively, decrease in final BW compared with pigs fed Lys and Trp at the requirement (100%). This study provides alternatives for pork producers to reduce growth rate of finishing pigs.

Novel Lung Targeting Cell Penetrating Peptides as Vectors for Delivery of Therapeutics

Rationale: Cell-penetrating peptides are able to cross membranes and deliver cargoes in a functional form. Our prior work identified a 12-amino acid, cardiac targeting peptide (APWHLSSQYSRT). Studies into its mechanism of transduction led to the identification of two lung targeting peptides (LTPs), S7A and R11A. Here we report on a) the comparative lung uptake of S7A versus R11A, b) complete biodistribution of R11A, c) show that cyclic versions are -100-fold more efficient than linear counterparts, d) uptake is via a non-endocytic pathway, and e) cyclic R11A's (cR11A) ability to deliver siRNA targeting structural proteins of SARS-CoV-2 and act as an anti-viral. Methods: Linear LTPs were synthesized with N-terminal labeled with Cyanine 5.5 (Cy5.5). Cyclic versions were synthesized with lysine added to the N-terminus, cyclized through a peptide bond, with a side NH-group labeled with Cy5.5. cR11A was conjugated to siRNA duplexes via a DTME linker. Wild-type, CD1 mice, were injected with S7A or R11A at 10, 5, and 1mg/Kg, peptides allowed to circulate for 15mins, mice euthanized, lung along with multiple other organs dissected and imaged using In Vivo Imaging Systems (IVIS, Perkin-Elmer) followed by confocal microscopy. CD1 mice were injected with R11A, 5mg/Kg, and euthanized at different time intervals for biodistribution studies. Endocytosis studies were done using serum-starved human bronchial epithelial cells (HBEC) incubated with fluorescently labeled transferrin and LTP-S7A or LTP- R11A. Lastly, anti-viral activity was tested in HBECs pre-treated with cR11A-siRNA followed by viral infection. Results: Mice injected with LTP-S7A or LTP-R11A showed robust uptake of the peptides by lung tissue, with R11A showing an increasingly favorable lung:liver ratio with decreasing dose. Lung uptake of R11A peaked at 120mins with complete dissipation of fluorescence by 24 hours. In Vitro studies in HBECs showed no co-localization of transferrin with LTPs, ruling out endocytosis as a mechanism of uptake. Comparison of linear versus cyclic peptides using FACS showed cyclic peptides had -100-fold increased transduction efficiency over their linear counterparts. cR11A conjugated to ant-spike, and anti-envelop proteins showed an anti-viral effect with EC90 of 0.6uM and 1.0μM, respectively. Conclusions: We have identified two novel lung-targeting peptides capable of acting as delivery vectors. Peak uptake of R11A occurred at 120mins. Furthermore, this uptake was not via endocytosis, and cyclic versions were -100-fold more efficiently taken up. Lastly, as proof of concept, we show cR11A acts as a vector and delivers siRNA to HBECs in a functional form, and act as anti-virals.

Why Omicron Variant of SARS-CoV-2 is Less Fatal?

The article published by Nie et al. addressed one of the two key questions regarding the Omicron variant of SARS-CoV-2, while the underpinning for the less deadly nature of the variant remains unexplained. The proteins of the Omicron variant have numerous mutations, notably several substitutions of other amino acids by lysine residues. Glycine and valine attract calcium and enhance the formation of stressful, insoluble, and stiff calcium oxalate. Lysine residues in proteins build up chloride via ionic bonds which solubilizes insoluble and rigid divalent salts. The aforementioned mutations have weakened the lethalness of the Omicron variant perhaps via a biochemical mechanism. Despite net gain in favorable mutations versus deleterious mutations, the overall valine plus glycine content is still high in the proteins of Omicron variant of SARS-CoV-2, which remains a public health concern.

Adapt-Kcr: a novel deep learning framework for accurate prediction of lysine crotonylation sites based on learning embedding features and attention architecture.

Protein lysine crotonylation (Kcr) is an important type of posttranslational modification that is associated with a wide range of biological processes. The identification of Kcr sites is critical to better understanding their functional mechanisms. However, the existing experimental techniques for detecting Kcr sites are cost-ineffective, to a great need for new computational methods to address this problem. We here describe Adapt-Kcr, an advanced deep learning model that utilizes adaptive embedding and is based on a convolutional neural network together with a bidirectional long short-term memory network and attention architecture. On the independent testing set, Adapt-Kcr outperformed the current state-of-the-art Kcr prediction model, with an improvement of 3.2% in accuracy and 1.9% in the area under the receiver operating characteristic curve. Compared to other Kcr models, Adapt-Kcr additionally had a more robust ability to distinguish between crotonylation and other lysine modifications. Another model (Adapt-ST) was trained to predict phosphorylation sites in SARS-CoV-2, and outperformed the equivalent state-of-the-art phosphorylation site prediction model. These results indicate that self-adaptive embedding features perform better than handcrafted features in capturing discriminative information; when used in attention architecture, this could be an effective way of identifying protein Kcr sites. Together, our Adapt framework (including learning embedding features and attention architecture) has a strong potential for prediction of other protein posttranslational modification sites.

Identification of a Conserved Intracellular Loop (CIL) Structure That Scaffolds PIP3 to Amplify Oncogenic Signaling during Malignant B-Cell Transformation

Background: Within seconds of antigen-encounter, B-cell receptor (BCR) signaling induces dramatic changes of cell membrane lipid composition, including >40-fold increases of local PIP3-concentrations within lipid rafts. While several structural elements, including pleckstrin homology (PH) domains have been identified as PIP3-binding proteins, the underlying mechanisms that amplify BCR-signaling to assemble large signaling complexes within lipid rafts within 15 to 30 seconds, remained elusive. To understand the mechanistic and biophysical requirements for PIP3 accumulation during normal B-cell activation and acute oncogenic transformation, we identified PIP3-interacting proteins by cell-surface proteomic analyses. Results: In addition to proteins known to bind PIP3 with their PH-domains, we identified the short 133 aa protein IFITM3 (interferon-inducible transmembrane protein 3) as a top-ranking PIP3 scaffold. This was unexpected because IFITM3 was previously identified as endosomal protein that blocks viral infection by stiffening endosomal membranes to firmly contain viral cargo. Previous studies revealed that polymorphisms that lead to the expression of truncated IFITM3 are associated with increased susceptibility to viral infections, including SARS-CoV2. Among known cell membrane lipids, PIP3 has the highest negative charge. Instead of a PH-domain, IFITM3 laterally sequestered PIP3 through electrostatic interactions with two basic lysine residues (K83 and K104) located at the membrane-solution interface. Together with three other basic lysine and arginine residues K83 and K104 form a conserved intracellular loop (CIL), which enable IFITM3 to efficiently capture two PIP3 molecules. Bivalent PIP3-binding of the IFITM3-CIL enables a crosslinking mechanism that results in dramatic amplification of B-cell activation signals and clustering of large signaling complexes within lipid rafts. In normal resting B-cells, Ifitm3 was minimally expressed and mainly localized in endosomes. However, B-cell activation and oncogenic kinases induced phosphorylation at IFITM3-Y20, resulting in translocation of IFITM3 from endosomes and massive accumulation at the cell surface. Ifitm3ˉ /ˉ naïve B-cells developed at normal numbers, however, activation by antigen encounter was compromised. In Ifitm3ˉ /ˉ B-cells, lipid rafts were depleted of PIP3, resulting in defective expression of >60 lipid raft-associated surface receptors and impaired PI3K-signaling. Ifitm3ˉ /ˉ B-cells were unable to undergo affinity maturation and di not contribute to germinal center formation upon immunization. Analyses of gene expression and clinical outcome data from patients in six clinical cohorts for pediatric and adult B-ALL, mantle cell lymphoma, CLL and DLBCL, we consistently identified IFITM3 as a top-ranking predictor of poor clinical outcome. Inducible activation of BCR-ABL1 and NRAS G12D rapidly induced development of B-ALL but failed to transform and initiate B-ALL from Ifitm3ˉ /ˉ B-cell precursors. Conversely, the phospho-mimetic IFITM3-Y20E mutation, mimicking phosphorylation of the IFITM3 N-terminus at Y20 induced constitutive membrane localization of IFITM3, spontaneous aggregation of large oncogenic signaling complexes and readily initiated transformation in a genetic model of pre-malignant B-cells. Conclusions: We conclude that phosphorylation of IFITM3 upon B-cell activation induces a dynamic switch from antiviral effector functions in endosomes to oncogenic signal-amplification at the cell-surface. IFITM3-dependent amplification of PI3K-signaling is critical to enable rapid expansion of activated B-cells. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3-dependent signaling complexes and amplify PI3K-signaling for malignant transformation and initiation of B-lymphoid leukemia and lymphoma. [Formula presented] Disclosures: Weinstock: SecuraBio: Consultancy;ASELL: Consultancy;Bantam: Consultancy;Abcuro: Research Funding;Verastem: Research Funding;Daiichi Sankyo: Consultancy, Research Funding;AstraZeneca: Consultanc ;Travera: Other: Founder/Equity;Ajax: Other: Founder/Equity.

Pityriasis rosea-like cutaneous eruption as a possible dermatological manifestation after Oxford-AstraZeneca vaccine: Case report and brief literature review.

Pityriasis rosea (PR) has been manifested in patients suffering from COVID-19 as well as after vaccine protocols against SARS-CoV-2. It has a possible association with the HHV-6B virus (roseola infantum) and can be controlled by antivirals such as acyclovir as well as by the amino acid l-Lysine that showed a positive result in reducing the number of lesions and healing time. The aim of this study was to report a case of PR after a second dose of Oxford-AstraZeneca, the adopted therapy and a brief literature review. A 53-year-old woman, phototype II, presented an erythematous lesion in the posterior right thigh 15 days after the second dose of Oxford-AstraZeneca vaccine. Eight days after the initial injury, new injuries appeared in the calf, buttocks and thighs. The diagnosis was PR with a 5-week eruption cycle. The treatment consisted of the use of l-Lysine, 3 grams loading dose and 500 mg for 30 days and moisturizing/healing lotion, starting 14 days after the herald patch. After the 5th week of the disease cycle, there were no new eruptions and the repair cycle continued for up to 8 weeks leaving some residual skin spots. It is concluded that the patient may be a carrier a latent virus, HHV-6, and the vaccine administration with immune system stimulation, would have activated the possible virus causing PR. l-Lysine helped to control the manifestation by limiting the number of lesions and their location, which were restricted to the legs, thighs and buttocks.

Effects of Basic Amino Acids and Their Derivatives on SARS-CoV-2 and Influenza-A Virus Infection.

Amino acids have been implicated with virus infection and replication. Here, we demonstrate the effects of two basic amino acids, arginine and lysine, and their ester derivatives on infection of two enveloped viruses, SARS-CoV-2, and influenza A virus. We found that lysine and its ester derivative can efficiently block infection of both viruses in vitro. Furthermore, the arginine ester derivative caused a significant boost in virus infection. Studies on their mechanism of action revealed that the compounds potentially disturb virus uncoating rather than virus attachment and endosomal acidification. Our findings suggest that lysine supplementation and the reduction of arginine-rich food intake can be considered as prophylactic and therapeutic regimens against these viruses while also providing a paradigm for the development of broad-spectrum antivirals.

Synthesis of pH and Glucose Responsive Silk Fibroin Hydrogels.

Silk fibroin (SF) has attracted much attention due to its high, tunable mechanical strength and excellent biocompatibility. Imparting the ability to respond to external stimuli can further enhance its scope of application. In order to imbue stimuli-responsive behavior in silk fibroin, we propose a new conjugated material, namely cationic SF (CSF) obtained by chemical modification of silk fibroin with ε-Poly-(L-lysine) (ε-PLL). This pH-responsive CSF hydrogel was prepared by enzymatic crosslinking using horseradish peroxidase and H2O2. Zeta potential measurements and SDS-PAGE gel electrophoresis show successful synthesis, with an increase in isoelectric point from 4.1 to 8.6. Fourier transform infrared (FTIR) and X-ray diffraction (XRD) results show that the modification does not affect the crystalline structure of SF. Most importantly, the synthesized CSF hydrogel has an excellent pH response. At 10 wt.% ε-PLL, a significant change in swelling with pH is observed. We further demonstrate that the hydrogel can be glucose-responsive by the addition of glucose oxidase (GOx). At high glucose concentration (400 mg/dL), the swelling of CSF/GOx hydrogel is as high as 345 ± 16%, while swelling in 200 mg/dL, 100 mg/dL and 0 mg/dL glucose solutions is 237 ± 12%, 163 ± 12% and 98 ± 15%, respectively. This shows the responsive swelling of CSF/GOx hydrogels to glucose, thus providing sufficient conditions for rapid drug release. Together with the versatility and biological properties of fibroin, such stimuli-responsive silk hydrogels have great potential in intelligent drug delivery, as soft matter substrates for enzymatic reactions and in other biomedical applications.

Phytoconstituents from ten natural herbs as potent inhibitors of main protease enzyme of SARS-COV-2: In silico study.

Background: Lack of treatment of novel Coronavirus disease led to the search of specific antivirals that are capable to inhibit the replication of the virus. The plant kingdom has demonstrated to be an important source of new molecules with antiviral potential. Purpose: The present study aims to utilize various computational tools to identify the most eligible drug candidate that have capabilities to halt the replication of SARS-COV-2 virus by inhibiting Main protease (Mpro) enzyme. Methods: We have selected plants whose extracts have inhibitory potential against previously discovered coronaviruses. Their phytoconstituents were surveyed and a library of 100 molecules was prepared. Then, computational tools such as molecular docking, ADMET and molecular dynamic simulations were utilized to screen the compounds and evaluate them against Mpro enzyme. Results: All the phytoconstituents showed good binding affinities towards Mpro enzyme. Among them laurolitsine possesses the highest binding affinity i.e. -294.1533 kcal/mol. On ADMET analysis of best three ligands were simulated for 1.2 ns, then the stable ligand among them was further simulated for 20 ns. Results revealed that no conformational changes were observed in the laurolitsine w.r.t. protein residues and low RMSD value suggested that the Laurolitsine-protein complex was stable for 20 ns. Conclusion: Laurolitsine, an active constituent of roots of Lindera aggregata, was found to be having good ADMET profile and have capabilities to halt the activity of the enzyme. Therefore, this makes laurolitsine a good drug candidate for the treatment of COVID-19.

A weak COPI binding motif in the cytoplasmic tail of SARS-CoV-2 spike glycoprotein is necessary for its cleavage, glycosylation, and localization.

The SARS-CoV-2 spike glycoprotein (spike) mediates viral entry by binding ACE2 receptors on host cell surfaces. Spike glycan processing and cleavage, which occur in the Golgi network, are important for fusion at the plasma membrane, promoting both virion infectivity and cell-to-cell viral spreading. We show that a KxHxx motif in the cytosolic tail of spike weakly binds the COPß' subunit of COPI coatomer, which facilitates some recycling of spike within the Golgi, while releasing the remainder to the cell surface. Although histidine (KxHxx) has been proposed to be equivalent to lysine within di-lysine endoplasmic reticulum (ER) retrieval sequences, we show that histidine-to-lysine substitution (KxKxx) retains spike at the ER and prevents glycan processing, protease cleavage, and transport to the plasma membrane.

Cyclodextrin pendant polymer as an efficient drug carrier for scutellarin.

A novel ß-cyclodextrin pendant polymer (ε-PL-CD), composed of poly(ε-lysine) (ε-PL) main chain and glycine-ß-cyclodextrin (Gly-CD) side chains, was prepared by a simple two-step procedure. The ε-PL-CD was investigated as a drug carrier of hydrophobic drug scutellarin (SCU). The characterization and complexation mode of the SCU:ε-PL-CD were researched in both solution and solid state by means of photoluminescence spectroscopy, 1H and 2D NMR, X-Ray powder diffraction (XRPD), thermal gravimetric analysis, Particle size and Zeta potential. The solubility test indicated that the solubilizing ability of SCU:ε-PL-CD was significantly improved compared with SCU:ß-CD and free SCU. Besides, in vitro cell experiment, it was found that SCU:ε-PL-CD has a strong inhibitory effect on the growth and invasion of tumor cells. The present study provides useful information for ε-PL-CD as a drug carrier material.

Computationally predicted SARS-COV-2 encoded microRNAs target NFKB, JAK/STAT and TGFB signaling pathways.

Recently an outbreak that emerged in Wuhan, China in December 2019, spread to the whole world in a short time and killed >1,410,000 people. It was determined that a new type of beta coronavirus called severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) was causative agent of this outbreak and the disease caused by the virus was named as coronavirus disease 19 (COVID19). Despite the information obtained from the viral genome structure, many aspects of the virus-host interactions during infection is still unknown. In this study we aimed to identify SARS-CoV-2 encoded microRNAs and their cellular targets. We applied a computational method to predict miRNAs encoded by SARS-CoV-2 along with their putative targets in humans. Targets of predicted miRNAs were clustered into groups based on their biological processes, molecular function, and cellular compartments using GO and PANTHER. By using KEGG pathway enrichment analysis top pathways were identified. Finally, we have constructed an integrative pathway network analysis with target genes. We identified 40 SARS-CoV-2 miRNAs and their regulated targets. Our analysis showed that targeted genes including NFKB1, NFKBIE, JAK1-2, STAT3-4, STAT5B, STAT6, SOCS1-6, IL2, IL8, IL10, IL17, TGFBR1-2, SMAD2-4, HDAC1-6 and JARID1A-C, JARID2 play important roles in NFKB, JAK/STAT and TGFB signaling pathways as well as cells' epigenetic regulation pathways. Our results may help to understand virus-host interaction and the role of viral miRNAs during SARS-CoV-2 infection. As there is no current drug and effective treatment available for COVID19, it may also help to develop new treatment strategies.

Natural products as LSD1 inhibitors for cancer therapy.

Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent technological advances, natural product-based drug discovery is now reaching a new era. Natural products have also shown promise in epigenetic drug discovery, some of them have advanced into clinical trials or are presently being used in clinic. The histone lysine specific demethylase 1 (LSD1), an important class of histone demethylases, has fundamental roles in the development of various pathological conditions. Targeting LSD1 has been recognized as a promising therapeutic option for cancer treatment. Notably, some natural products with different chemotypes including protoberberine alkaloids, flavones, polyphenols, and cyclic peptides have shown effectiveness against LSD1. These natural products provide novel scaffolds for developing new LSD1 inhibitors. In this review, we mainly discuss the identification of natural LSD1 inhibitors, analysis of the co-crystal structures of LSD1/natural product complex, antitumor activity and their modes of action. We also briefly discuss the challenges faced in this field. We believe this review will provide a landscape of natural LSD1 inhibitors.