A Stereoselective Decarboxylative Aromatase/Cyclase Directs the Biosynthesis of an Axially Chiral Biphenyl Framework in Fasamycin.

Aromatic polyketides are an important class of natural products with various bioactivities, and their structural diversity arises from modifications to their aromatic frameworks. In this study, we identify a stereoselective aromatase/cyclase (ARO/CYC) FasU, which is responsible for forming the axial chiral biphenyl framework in fasamycin. FasU catalyzes sequential decarboxylation and cyclization/aromatization with strict -stereospecificity on a previously unidentified biosynthetic intermediate.

Strategy of employing plug-and-play vectors and LC-MS screening to facilitate the discovery of natural products using Aspergillus oryzae.

Aspergillus oryzae is a widely used host for heterologous expression of fungal natural products. However, the vectors previously developed are not convenient for use and screening positive transformants by PCR and fermentation is time- and effort-consuming. Hence, three plug-and-play vectors were developed here for multi-gene expression and liquid chromatography mass spectrometry detection was introduced to screen positive transformants.

A nucleobase-driven P450 peroxidase system enables regio- and stereo-specific formation of C─C and C─N bonds.

P450 peroxidase activities are valued for their ability to catalyze complex chemical transformations using economical HO; however, they have been largely underexplored compared to their monooxygenase and peroxygenase activities. In this study, we identified an unconventional P450 enzyme, PtmB, which catalyzes the dimerization of purine nucleobases and tryptophan-containing diketopiperazines (TDKPs), yielding C3-nucleobase pyrroloindolines and nucleobase-TDKP dimers. Unlike typical TDKP P450 enzymes reliant on NAD(P)H cofactors and electron transfer systems, PtmB, and its analogs exhibit remarkable peroxidase activity in synthesizing adenine and other modified 6-aminopurine nucleobase-TDKP dimers.

One-day examination of triple nuclear medicine imaging and application in evaluating transarterial embolization.

A diagnosis based on multiple nuclear medicine imaging (NMI) was more comprehensive in approaching the nature of pathological changes. In this research, a method to realize triple NMIs within one day was developed based on the reasonable arrangements of Ga-RGD PET/CT specialized on neovascularization, Tc-HL-91 SPECT/CT specialized on hypoxia and F-FDG PET/CT specialized on tumor metabolism. Feasibility was verified in evaluating the therapeutic effects of transarterial embolization (TAE) performed on rabbit models with VX2 tumor.

Analyzing and engineering of the biosynthetic pathway of mollemycin A for enhancing its production.

Mollemycin A (MOMA) is a unique glyco-hexadepsipeptide-polyketide that was isolated from a sp. derived from the Australian marine environment. MOMA exhibits remarkable inhibitory activity against both drug-sensitive and multidrug-resistant malaria parasites.

An unusual aromatase/cyclase programs the formation of the phenyldimethylanthrone framework in anthrabenzoxocinones and fasamycin.

Aromatic polyketides are renowned for their wide-ranging pharmaceutical activities. Their structural diversity is mainly produced via modification of limited types of basic frameworks. In this study, we characterized the biosynthesis of a unique basic aromatic framework, phenyldimethylanthrone (PDA) found in (+)/(-)-anthrabenzoxocinones (ABXs) and fasamycin (FAS).

Sublethal heat treatment enhances lactic acid uptake in macrophages via MCT1, leading to reduced paraspeckle formation and a subsequent decrease in macrophage pyroptosis.

Introduction: Heat ablation is one of the key modalities in treating liver cancer, yet the residual cancer tissues suffering sublethal heat treatment possess a potential for increased malignancy. This study conducts a comprehensive analysis of cellular dynamics, metabolic shifts, and macrophage polarization within the tumor microenvironment following sublethal heat treatment.

Methods: We observed significant acidification in tumor cell supernatants, attributed to increased lactic acid production.

A large conserved family of small-molecule carboxyl methyltransferases identified from microorganisms.

Small-molecule carboxyl methyltransferases (CbMTs) constitute a small proportion of the reported methyltransferases, but they have received extensive attention due to their important physiological functions. Most of the small-molecule CbMTs isolated to date originate from plants and are members of the SABATH family. In this study, we identified a type of CbMT (OPCMT) from a group of , which has a distinct catalytic mechanism from the SABATH methyltransferases.

Engineering the Substrate Specificity of a P450 Dimerase Enables the Collective Biosynthesis of Heterodimeric Tryptophan-Containing Diketopiperazines.

Heterodimeric tryptophan-containing diketopiperazines (HTDKPs) are an important class of bioactive secondary metabolites. Biosynthesis offers a practical opportunity to access their bioactive structural diversity, however, it is restricted by the limited substrate scopes of the HTDKPs-forming P450 dimerases. Herein, by genome mining and investigation of the sequence-product relationships, we unveiled three important residues (F387, F388 and E73) in these P450s that are pivotal for selecting different diketopiperazine (DKP) substrates in the upper binding pocket.

Formation and Loading of a (2S)-2-Ethylmalonamyl Starter Unit in the Assembly Line of Polyketide-Nonribosomal Peptide Hybrid Sanglifehrin A.

Sanglifehrin A (SFA) is a spirolactam-conjugated, 22-membered macrolide with remarkable immunosuppressive and antiviral activities. This macrolide is a result of a hybrid polyketide synthase (PKS)-nonribosomal peptide synthetase (NRPS) assembly line that utilizes (2S)-2-ethylmalonamyl as a starter unit. Here, we report that the formation and loading of this starter unit in the SFA assembly line involve two unusual enzymatic reactions that occur on a discrete acyl carrier protein (ACP), SfaO.

Biosynthesis of Tetronates by a Nonribosomal Peptide Synthetase-Polyketide Synthase System.

A cryptic tetronate biosynthetic pathway was identified in DSM 44781 via heterologous expression. Distinct from the currently known biosynthetic pathways, this system utilizes a partially functional nonribosomal peptide synthetase and a broadly selective polyketide synthase to direct the assembly and lactonization of the tetronate scaffold. By employing a permissive crotonyl-CoA reductase/carboxylase to provide different extender units, seven new tetronates (kitaniitetronins A-G) were obtained via precursor-directed biosynthesis.

Combined iodine-125 seed strand, portal vein stent, transarterial chemoembolization, lenvatinib and anti-PD-1 antibodies therapy for hepatocellular carcinoma and Vp4 portal vein tumor thrombus: A propensity-score analysis.

Objective: To evaluate the safety and efficacy of interventional therapy (iodine-125[I] seed strand and portal vein stent [PVS] implantation plus transarterial chemoembolization [TACE]) combined with systemic therapy (lenvatinib plus anti-PD-1 antibody) as first-line treatment for hepatocellular carcinoma (HCC) patients with Vp4 portal vein tumor thrombus (PVTT).

Patients And Methods: From December 2018 to October 2021, 87 HCC patients with Vp4 PVTT were included in this single-center retrospective study. Forty-seven patients underwent interventional therapy combined with lenvatinib and anti-PD-1 antibody (group A), while 40 cases underwent interventional therapy combined with lenvatinib only (group B).

Hepatectomy After Conversion Therapy Using Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibody Therapy for Patients with Unresectable Hepatocellular Carcinoma.

Background: Combined treatment with tyrosine kinase inhibitors (TKI) plus anti-PD-1 antibodies showed high anti-tumor efficacy and made conversion resection possible for patients with unresectable hepatocellular carcinoma (HCC). However, long-term survival has not been reported.

Methods: A cohort of consecutive patients who received combined TKI/anti-PD-1 antibodies as first-line treatment for initially unresectable HCC at the authors' hospital between August 2018 and September 2020 was eligible for this study.

Norditerpenoids biosynthesized by variediene synthase-associated P450 machinery along with modifications by the host cell .

The chemical diversity of terpenoids is typically established by terpene synthase-catalyzed cyclization and diversified by post-tailoring modifications. Fungal bifunctional terpene synthase (BFTS) associated P450 enzymes have shown significant catalytic potentials through the development of various new terpenoids with different biological activities. This study discovered the BFTS and its related gene cluster from the plant endophytic fungus 17020.

Transcatheter arterial embolization-salvaged ALPPS, a novel ALPPS procedure especially for patients with hepatocellular carcinoma and severe fibrosis/cirrhosis.

Background: The associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for hepatocellular carcinoma (HCC) with fibrosis/cirrhosis is often associated with limited growth of future liver remnant (FLR). We introduced a new procedure named transcatheter arterial embolization-salvaged ALPPS (TAE-salvaged ALPPS) which was shown to be especially suitable for HCC patients with cirrhosis or fibrosis who failed adequately to respond to conventional ALPPS. The short-term efficacy and safety for the TAE-salvaged ALPPS on patients with HCC and fibrosis/cirrhosis were studied.

Biosynthesis of pyrroloindoline-containing natural products.

Covering: up to 2022Pyrroloindoline is a privileged tricyclic indoline motif widely present in many biologically active and medicinally valuable natural products. Thus, understanding the biosynthesis of this molecule is critical for developing convenient synthetic routes, which is highly challenging for its chemical synthesis due to the presence of rich chiral centers in this molecule, especially the fully substituted chiral carbon center at the C3-position of its rigid tricyclic structure. In recent years, progress has been made in elucidating the biosynthetic pathways and enzymatic mechanisms of pyrroloindoline-containing natural products (PiNPs).