Recent advances in the culture-independent discovery of natural products using metagenomic approaches.

Natural products derived from bacterial sources have long been pivotal in the discovery of drug leads. However, the cultivation of only about 1% of bacteria in laboratory settings has left a significant portion of biosynthetic diversity hidden within the genomes of uncultured bacteria. Advances in sequencing technologies now enable the exploration of genetic material from these metagenomes through culture-independent methods.

Tapcin, an In Vivo Active Dual Topoisomerase I/II Inhibitor Discovered by Synthetic Bioinformatic Natural Product (Syn-BNP)-Coupled Metagenomics.

DNA topoisomerases are attractive targets for anticancer agents. Dual topoisomerase I/II inhibitors are particularly appealing due to their reduced rates of resistance. A number of therapeutically relevant topoisomerase inhibitors are bacterial natural products.

A Family of Antibiotics That Evades Resistance by Binding Polyprenyl Phosphates.

Cilagicin is a Gram-positive active antibiotic that has a dual polyprenyl phosphate binding mechanism that impedes resistance development. Here we bioinformatically screened predicted non-ribosomal polypeptide synthetase encoded structures to search for antibiotics that might similarly avoid resistance development. Synthesis and bioactivity screening of the predicted structures that we identified led to three antibiotics that are active against multidrug-resistant Gram-positive pathogens, two of which, paenilagicin and virgilagicin, did not lead to resistance even after prolonged antibiotic exposure.

Multiplexed mobilization and expression of biosynthetic gene clusters.

Bacterial genomes contain large reservoirs of biosynthetic gene clusters (BGCs) that are predicted to encode unexplored natural products. Heterologous expression of previously unstudied BGCs should facilitate the discovery of additional therapeutically relevant bioactive molecules from bacterial culture collections, but the large-scale manipulation of BGCs remains cumbersome. Here, we describe a method to parallelize the identification, mobilization and heterologous expression of BGCs.

Discovery of Paenibacillaceae Family Gram-Negative-Active Cationic Lipopeptide Antibiotics Using Evolution-Guided Chemical Synthesis.

Cationic nonribosomal lipopeptides (CNRLPs) from spp. have been a rewarding source of Gram-negative-active antibiotics. Here we systematically screened sequenced bacterial genomes for CNRLP biosynthetic gene clusters (BGCs) that we predicted might encode additional Gram-negative-active antibiotics.

Bioinformatic prospecting and synthesis of a bifunctional lipopeptide antibiotic that evades resistance.

Emerging resistance to currently used antibiotics is a global public health crisis. Because most of the biosynthetic capacity within the bacterial kingdom has remained silent in previous antibiotic discovery efforts, uncharacterized biosynthetic gene clusters found in bacterial genome-sequencing studies remain an appealing source of antibiotics with distinctive modes of action. Here, we report the discovery of a naturally inspired lipopeptide antibiotic called cilagicin, which we chemically synthesized on the basis of a detailed bioinformatic analysis of the biosynthetic gene cluster.

Lapcin, a potent dual topoisomerase I/II inhibitor discovered by soil metagenome guided total chemical synthesis.

In natural product discovery programs, the power of synthetic chemistry is often leveraged for the total synthesis and diversification of characterized metabolites. The synthesis of structures that are bioinformatically predicted to arise from uncharacterized biosynthetic gene clusters (BGCs) provides a means for synthetic chemistry to enter this process at an early stage. The recent identification of non-ribosomal peptides (NRPs) containing multiple ρ-aminobenzoic acids (PABAs) led us to search soil metagenomes for BGCs that polymerize PABA.

A naturally inspired antibiotic to target multidrug-resistant pathogens.

Gram-negative bacteria are responsible for an increasing number of deaths caused by antibiotic-resistant infections. The bacterial natural product colistin is considered the last line of defence against a number of Gram-negative pathogens. The recent global spread of the plasmid-borne mobilized colistin-resistance gene mcr-1 (phosphoethanolamine transferase) threatens the usefulness of colistin.

Analysis of risk factors related to breast cancer metastasis: a retrospective nested case-control study.

Purpose: To explore the laboratory indexes related to breast cancer metastasis, so as to provide scientific basis for the control of breast metastasis.

Methods: A retrospective cohort-based nested case-control study was used to screen 732 breast cancer patients recorded in the First and the Third Hospitals of Jilin University's electronic medical record system between January 2008 through December 2015 without metastasis at admission. Those with subsequent metastasis were classified as the metastasis group and those without metastasis as the control group.

Retracted: Overexpression of Neuregulin-1 (NRG-1) Gene Contributes to Surgical Repair of Brachial Plexus Injury After Contralateral C7 Nerve Root Transfer in Rats.

Retracted on the author's request: "We would like to withdraw our manuscript. We restarted the project for further study last year, we found that the results in this study are not solid enough and need to be further explored." Reference: Zong-Qiang Wang, Dian-Hui Xiu, Gui-Feng Liu, Jin-Lan Jiang.

Metagenome-Guided Analogue Synthesis Yields Improved Gram-Negative-Active Albicidin- and Cystobactamid-Type Antibiotics.

Natural products are a major source of new antibiotics. Here we utilize biosynthetic instructions contained within metagenome-derived congener biosynthetic gene clusters (BGCs) to guide the synthesis of improved antibiotic analogues. Albicidin and cystobactamid are the first members of a new class of broad-spectrum ρ-aminobenzoic acid (PABA)-based antibiotics.

Elucidating the Diversity and Potential Function of Nonribosomal Peptide and Polyketide Biosynthetic Gene Clusters in the Root Microbiome.

Polyketides (PKs) and nonribosomal peptides (NRPs) are two microbial secondary metabolite (SM) families known for their variety of functions, including antimicrobials, siderophores, and others. Despite their involvement in bacterium-bacterium and bacterium-plant interactions, root-associated SMs are largely unexplored due to the limited cultivability of bacteria. Here, we analyzed the diversity and expression of SM-encoding biosynthetic gene clusters (BGCs) in root microbiomes by culture-independent amplicon sequencing, shotgun metagenomics, and metatranscriptomics.

Long non-coding RNA XIST binding to let-7c-5p contributes to rheumatoid arthritis through its effects on proliferation and differentiation of osteoblasts via regulation of STAT3.

Background: Rheumatoid arthritis (RA), a chronic autoimmune disease, affects around 1% population worldwide, with the life quality of patients severely reduced. In this study, it is intended to explore the role of long non-coding RNA X-inactive specific transcript (lncRNA XIST) in RA and the underlying mechanisms associated with let-7c-5p and signal transducer and activator of transcription 3 (STAT3).

Methods: LncRNA XIST, let-7c-5p, and STAT3 expressions were determined in RA and normal cartilage tissues, and their relationship was analyzed in osteoblasts.

[Retracted] Diagnostic and prognostic value of contrast‑enhanced ultrasound combined with diffusion‑weighted magnetic resonance imaging in different subtypes of breast cancer.

Int J Mol Med 42: [Related article:] 105‑114, 2018; DOI: 10.3892/ijmm.2018.

Profiling of apoptosis- and autophagy-associated molecules in human lung cancer A549 cells in response to cisplatin treatment using stable isotope labeling with amino acids in cell culture.

Cis‑diammine‑dichloro‑platinum II‑based adjuvant chemotherapy provides an alternative therapy to improve the survival of patients with lung tumors, especially those with non‑small cell lung cancer (NSCLC). However, drug resistance is a large clinical problem and its underlying mechanism remains unclear. In the present study, NSCLC A549 cells were treated with a low concentration of cisplatin in order to observe and determine the development of chemoresistance, via growth curves, colony forming assays and apoptosis assays.

Downregulation of the long noncoding RNA MBNL1-AS1 protects sevoflurane-pretreated mice against ischemia-reperfusion injury by targeting KCNMA1.

Total knee arthroplasty (TKA) is the most common and cost-effective treatment for older adults with long-standing osteoarthritis. During TKA, muscle cells suffer from prolonged oxygen deficiency, which leads to altered cell metabolism that reduces the energy demand and maintains cell homeostasis before blood flow is restored. This study focused on the role of the lncRNA muscleblind-like 1 antisense RNA 1 (MBNL1-AS1) in protecting sevoflurane-pretreated mice against ischemia-reperfusion (I/R) injury after TKA, as well as the elucidation of the potential associated mechanism.

Overexpression of Neuregulin-1 (NRG-1) Gene Contributes to Surgical Repair of Brachial Plexus Injury After Contralateral C7 Nerve Root Transfer in Rats.

BACKGROUND Surgeons usually transfer the contralateral C7 to the median nerve on the injured side via a nerve graft to recover sensation and movement in a paralyzed hand. The purpose of our study was to determine whether NRG-1 affects the recovery of nerve function in brachial plexus injury after contralateral C7 nerve root transfer in a rat model. MATERIAL AND METHODS An injury model of left brachial plexus and contralateral C7 nerve root transfer was established.

Diagnostic and prognostic values of contrast‑enhanced ultrasound combined with diffusion‑weighted magnetic resonance imaging in different subtypes of breast cancer.

The present study aimed to investigate the diagnostic and prognostic values of contrast‑enhanced ultrasound (CEUS) combined with diffusion‑weighted magnetic resonance imaging (DW‑MRI) in different subtypes of breast cancer (BC). CEUS and DW‑MRI were conducted in 232 patients with BC prior to surgical treatment. Patients were categorized as having the luminal A subtype, the luminal B subtype, triple‑negative subtype or the human epidermal growth factor receptor 2 (Her‑2)‑positive subtype according to their expression of the estrogen receptor (ER), progesterone receptor (PR) and Her‑2, as detected by immunohistochemistry.

Role of lentivirus-mediated overexpression of SOCS3 in proliferation and apoptosis of fibroblasts-like synoviocytes in Lewis rats with adjuvant-induced rheumatoid arthritis.

The purpose of this study is to explore the effects of lentivirus-mediated overexpression of the SOCS3 gene on proliferation and apoptosis of fibroblasts-like synoviocytes (FLSs) in rheumatoid arthritis (RA). A total of 20 Lewis rats were randomly assigned into experimental and normal groups. Rats in the experimental group were modeled with adjuvant arthritisand the normal group was given no treatment.

A network meta-analysis on the short-term efficacy and adverse events of different anti-osteoporosis drugs for the treatment of postmenopausal osteoporosis.

A network meta-analysis was conducted to compare the short-term efficacy and adverse events of different drugs for the treatment of postmenopausal osteoporosis (PMO), providing a more effective treatment for PMO. We initially searched through various databases like PubMed, Cochrane Library, and EMBASE from inception till October 2016. All randomized controlled trials (RCTs) of drugs for the treatment of PMO were included for direct and indirect comparison.

Sumoylation of SMAD 4 ameliorates the oxidative stress-induced apoptosis in osteoblasts.

Oxidative stress-induced mitochondrial function and cell apoptosis to osteoblasts, plays a critical role in the pathophysiology of osteoporosis. However, mechanisms underlying such process remain not yet clear. We aims in this study to investigate a possible role of SMAD (the mothers against decapentaplegic homolog 4 (SMAD4) in the oxidative stress-induced apoptosis, in homo sapiens osteoblast hFOB1.

Resveratrol attenuates testicular apoptosis in type 1 diabetic mice: Role of Akt-mediated Nrf2 activation and p62-dependent Keap1 degradation.

Infertility is a common complication in diabetic men, mainly due to the loss of germ cells by apoptotic cell death. However, effective and safe approaches to prevent diabetic induction of testicular apoptosis for diabetic patients have not been available. Resveratrol (RSV), a group of compounds called polyphenols from plants, has been indicated its promising used clinically for cancers and cardiovascular diseases.

Expanding the Catalytic Promiscuity of Heparinase III from Pedobacter heparinus.

Glycosaminoglycans (GAG) lyases are useful biocatalysts for the preparation of oligosaccharides, but their substrate spectra are limited to the same family. Thus, the degradation activity across families of GAG lyases is advantageous and desirable for various applications. In this study, residue Lys130 at the substrate entrance of monomeric heparinase III from Pedobacter heparinus ATCC 13125 was replaced by cysteine, and the resulting mutant K130C showed novel catalytic activity in degrading hyaluronic acid without affecting its native activity toward heparin and heparan sulfate.

Discovery of a small molecule targeting SET-PP2A interaction to overcome BCR-ABLT315I mutation of chronic myeloid leukemia.

Despite the great success in using tyrosine kinase inhibitors (TKIs) to treat chronic myeloid leukemia (CML), the frequent development of multi-drug resistance, particularly the T315I mutation of BCR-ABL, remains a challenging issue. Enhancement of protein phosphatase 2A (PP2A) activity by dissociating its endogenous inhibitor SET is an effective approach to combat TKI-based resistance. Here, we report the identification of a novel 2-phenyloxypyrimidine compound TGI1002 to specifically disrupt SET-PP2A interaction.