Liposomal nanostructures for Gemcitabine and Paclitaxel delivery in pancreatic cancer.

Pancreatic cancer (PC) is an incurable disease with a high death rate in the world nowadays. Gemcitabine (GEM) and Paclitaxel (PTX) are considered as references of chemotherapeutic treatments and are commonly used in clinical applications. Factors related to the tumor microenvironment such as insufficient tumor penetration, toxicity, and drug resistance can limit the effectiveness of these therapeutic anticancer drugs.

Structural enzymology of iterative type I polyketide synthases: various routes to catalytic programming.

Time span of literature covered: up to mid-2023Iterative type I polyketide synthases (iPKSs) are outstanding natural chemists: megaenzymes that repeatedly utilize their catalytic domains to synthesize complex natural products with diverse bioactivities. Perhaps the most fascinating but least understood question about type I iPKSs is how they perform the iterative yet programmed reactions in which the usage of domain combinations varies during the synthetic cycle. The programmed patterns are fulfilled by multiple factors, and strongly influence the complexity of the resulting natural products.

C-N bond formation by a polyketide synthase.

Assembly-line polyketide synthases (PKSs) are molecular factories that produce diverse metabolites with wide-ranging biological activities. PKSs usually work by constructing and modifying the polyketide backbone successively. Here, we present the cryo-EM structure of CalA3, a chain release PKS module without an ACP domain, and its structures with amidation or hydrolysis products.

Does Involution Cause Anxiety? An Empirical Study from Chinese Universities.

The debate over whether involution causes anxiety has persisted because no studies have attempted to quantify introversion and study its relationship to anxiety. This study quantified involution and explored its relationship with anxiety, provided evidence about whether involution was related to anxiety, and created a foundation for other scholars to carry out research on involution. Interviews and questionnaires were conducted to investigate the characteristics of 535 Chinese college students' involution behavior and its relationship with anxiety.

Codelivery of SARS-CoV-2 Prefusion-Spike Protein with CBLB502 by a Dual-Chambered Ferritin Nanocarrier Potentiates Systemic and Mucosal Immunity.

Thousands of breakthrough infections are confirmed after intramuscular (i.m.) injection of the approved vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Catalytic trajectory of a dimeric nonribosomal peptide synthetase subunit with an inserted epimerase domain.

Nonribosomal peptide synthetases (NRPSs) are modular assembly-line megaenzymes that synthesize diverse metabolites with wide-ranging biological activities. The structural dynamics of synthetic elongation has remained unclear. Here, we present cryo-EM structures of PchE, an NRPS elongation module, in distinct conformations.

Structural basis for the biosynthesis of lovastatin.

Statins are effective cholesterol-lowering drugs. Lovastatin, one of the precursors of statins, is formed from dihydromonacolin L (DML), which is synthesized by lovastatin nonaketide synthase (LovB), with the assistance of a separate trans-acting enoyl reductase (LovC). A full DML synthesis comprises 8 polyketide synthetic cycles with about 35 steps.

DNA phosphorothioate modification facilitates the dissemination of mcr-1 and bla in drinking water supply systems.

The mechanism driving the dissemination of antibiotic resistance genes (ARGs) in drinking water supply systems (DWSSs) with multiple barriers remains poorly understood despite several recent efforts. Phosphorothioate (PT) modifications, governed by dndABCDE genes, occur naturally in various bacteria and involve the incorporation of sulfur into the DNA backbone. PT is regarded as a mild antioxidant in vivo and is known to provide protection against bacterial genomes.

Defense Mechanism of Phosphorothioated DNA under Peroxynitrite-Mediated Oxidative Stress.

DNA phosphorothioation (PT) exists in many pathogenic bacteria; however, the mechanism of PT-DNA resistance to the immune response is unclear. In this work, we meticulously investigated the peroxynitrite (PN) tolerance using PT-bioengineered strains. The experiment confirms that the S strain survives better than the S strain under moderately oxidative stress.

An in vitro DNA phosphorothioate modification reaction.

Phosphorothioation (PT) involves the replacement of a nonbridging phosphate oxygen on the DNA backbone with sulfur. In bacteria, the procedure is both sequence- and stereo-specific. We reconstituted the PT reaction using purified DndCDE from Salmonella enterica and IscS from Escherichia coli.

Phosphorothioated DNA Is Shielded from Oxidative Damage.

DNA is the carrier of genetic information. DNA modifications play a central role in essential physiological processes. Phosphorothioation (PT) modification involves the replacement of an oxygen atom on the DNA backbone with a sulfur atom.

Regulation of Gene Expression in .

DNA sulfur modification is a unique modification occurring in the sugar-phosphate backbone of DNA, with a nonbridging oxygen atom substituted with sulfur in a sequence-specific and p stereo-specific manner. Bioinformatics, RNA-seq, and transcriptional analyses have shown that DNA sulfur modification may be involved in epigenetic regulation. However, the evidence supporting this assertion is not convincing.

Recycling of Overactivated Acyls by a Type II Thioesterase during Calcimycin Biosynthesis in Streptomyces chartreusis NRRL 3882.

Type II thioesterases typically function as editing enzymes, removing acyl groups that have been misconjugated to acyl carrier proteins during polyketide secondary metabolite biosynthesis as a consequence of biosynthetic errors. NRRL 3882 produces the pyrrole polyether ionophoric antibiotic, and we have identified the presence of a putative type II thioesterase-like sequence, , within the biosynthetic gene cluster involved in the antibiotic's synthesis. However, targeted gene mutagenesis experiments in which was inactivated in the organism did not lead to a decrease in calcimycin production but rather reduced the strain's production of its biosynthetic precursor, cezomycin.

Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882.

Calcimycin, N-demethyl calcimycin, and cezomycin are polyether divalent cation ionophore secondary metabolites produced by A thorough understanding of the organization of their encoding genes, biosynthetic pathway(s), and cation specificities is vitally important for their efficient future production and therapeutic use. So far, this has been lacking, as has information concerning any biosynthetic relationships that may exist between calcimycin and cezomycin. In this study, we observed that when a Cal ( mutant) derivative of a calcimycin-producing strain of (NRRL 3882) was grown on cezomycin, calcimycin production was restored.

DNA Backbone Sulfur-Modification Expands Microbial Growth Range under Multiple Stresses by its anti-oxidation function.

DNA phosphorothioate (PT) modification is a sulfur modification on the backbone of DNA introduced by the proteins DndA-E. It has been detected within many bacteria isolates and metagenomic datasets, including human pathogens, and is considered to be widely distributed in nature. However, little is known about the physiological function of this modification, and thus its evolutionary significance and application potential remains largely a mystery.

Mechanistic Investigation on ROS Resistance of Phosphorothioated DNA.

Phosphorothioated DNA (PT-DNA) exhibits a mild anti-oxidant property both in vivo and in vitro. It was found that 8-OHdG and ROS levels were significantly lower in dnd+ (i.e.

DNA Phosphorothioate Modification Plays a Role in Peroxides Resistance in Streptomyces lividans.

DNA phosphorothioation, conferred by dnd genes, was originally discovered in the soil-dwelling bacterium Streptomyces lividans, and thereafter found to exist in various bacterial genera. However, the physiological significance of this sulfur modification of the DNA backbone remains unknown in S. lividans.

Two nucleoside receptors from Streptomyces coelicolor: expression of the genes and characterization of the recombinant proteins.

Streptomyces coelicolor is a soil-dwelling bacterium that undergoes an intricate, saprophytic lifecycle. The bacterium takes up exogenous nucleosides for nucleic acid synthesis or use as carbon and energy sources. However, nucleosides must pass through the membrane with the help of transporters.

Cdc45 (cell division cycle protein 45) guards the gate of the Eukaryote Replisome helicase stabilizing leading strand engagement.

DNA replication licensing is now understood to be the pathway that leads to the assembly of double hexamers of minichromosome maintenance (Mcm2-7) at origin sites. Cell division control protein 45 (Cdc45) and GINS proteins activate the latent Mcm2-7 helicase by inducing allosteric changes through binding, forming a Cdc45/Mcm2-7/GINS (CMG) complex that is competent to unwind duplex DNA. The CMG has an active gate between subunits Mcm2 and Mcm5 that opens and closes in response to nucleotide binding.

Analysis of Streptomyces coelicolor membrane proteome using two-dimensional native/native and native/sodium dodecyl sulfate gel electrophoresis.

Analysis of the oligomeric state of a protein may provide insights into its physiological functions. Because membrane proteins are considered to be the workhorses of energy generation and polypeptide and nutrient transportation, in this study we characterized the membrane-associated proteome of Streptomyces coelicolor by two-dimensional (2D) blue native/sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), high-resolution clear native/native PAGE, and native/SDS-PAGE. A total of 77 proteins were identified, and 20 proteins belonging to 15 complexes were characterized.

[Cloning, expression and purification of dptC, a DNA phosphorothioate modification related gene from Salmonella enteric serovar Cerro 87].

Objective: DNA phosphorothioate modification means substituting a non-bridging oxygen with a sulfur in DNA. The modification endows DNA with such chemical property that protects the hosting bacteria against peroxide. The modification is controlled by a dnd gene cluster.

Mutasynthesis of pyrrole spiroketal compound using calcimycin 3-hydroxy anthranilic acid biosynthetic mutant.

The five-membered aromatic nitrogen heterocyclic pyrrole ring is a building block for a wide variety of natural products. Aiming at generating new pyrrole-containing derivatives as well as to identify new candidates that may be of value in designing new anticancer, antiviral, and/or antimicrobial agents, we employed a strategy on pyrrole-containing compound mutasynthesis using the pyrrole-containing calcimycin biosynthetic gene cluster. We blocked the biosynthesis of the calcimycin precursor, 3-hydroxy anthranilic acid, by deletion of calB1-3 and found that two intermediates containing the pyrrole and the spiroketal moiety were accumulated in the culture.

[Mutagenesis of cysteine residues in dptC from Salmonella enteric serovar Cerro 87 and its effects on DNA phosphorothioate modification].

Objective: DNA phosphorothioate modification (DNA sulfur modification, a non-bridging oxygen swapped with a sulfur) exists in diverse bacteria. Salmonella enterica serovar Cerro 87 is one of the bacteria that harbor the DNA sulfur modification. The modification is carried out by the products of a four-membered gene cluster, dptBCDE.

Characterization of the N-methyltransferase CalM involved in calcimycin biosynthesis by Streptomyces chartreusis NRRL 3882.

Calcimycin is a rare divalent cation specific ionophore antibiotic that has many biochemical and pharmaceutical applications. We have recently cloned and sequenced the Streptomyces chartreusis calcimycin biosynthesis gene cluster as well as identified the genes required for the synthesis of the polyketide backbone of calcimycin. Additional modifying or decorating enzymes are required to convert the polyketide backbone into the biologically active calcimycin.

A novel target of IscS in Escherichia coli: participating in DNA phosphorothioation.

Many bacterial species modify their DNA with the addition of sulfur to phosphate groups, a modification known as DNA phosphorothioation. DndA is known to act as a cysteine desulfurase, catalyzing a key biochemical step in phosphorothioation. However, bioinformatic analysis revealed that 19 out of the 31 known dnd gene clusters, contain only four genes (dndB-E), lacking a key cysteine desulfurase corresponding gene.