CRISPR-Cas9-based genome-editing technologies in engineering bacteria for the production of plant-derived terpenoids.

Terpenoids are widely used as medicines, flavors, and biofuels. However, the use of these natural products is largely restricted by their low abundance in native plants. Fortunately, heterologous biosynthesis of terpenoids in microorganisms offers an alternative and sustainable approach for efficient production.

Interleukin 15-Presenting Nanovesicles with Doxorubicin-Loaded Ferritin Cores for Cancer Immunochemotherapy.

Interleukin 15 (IL15) is crucial for fostering the survival and proliferation of nature killer (NK) cells and cytotoxic T lymphocytes (CTLs), playing a pivotal role in tumor control. However, IL15 supplementary therapy encounters challenges such as systemic inflammation and non-specific stimulation of cancer cells. Herein, a nanovesicle termed DoxFILN, comprising a membrane presenting IL15/IL15 receptor α complexes (IL15c) and a core of doxorubicin-loaded ferritin (Dox-Fn) are reported.

Mass balance, metabolism, and pharmacokinetics of [C]amdizalisib, a clinical-stage novel oral selective PI3Kδ inhibitor for the treatment of non-hodgkin's lymphoma, in healthy Chinese volunteers.

Introduction: Amdizalisib (HMPL-689) is an ATP-competitive PI3Kδ inhibitor currently under investigation for treating Hodgkin's lymphoma. This study aimed to evaluate the metabolism, excretion, pharmacokinetics, and safety profile of amdizalisib in healthy human subjects to support its clinical application.

Methods: This Phase I clinical trial included six healthy Chinese male volunteers who received a single oral dose of 30 mg/100 µCi [C]amdizalisib suspension.

Structural insights into endogenous ligand selectivity and activation mechanisms of FFAR1 and FFAR2.

Free fatty acid receptors (FFARs) play critical roles in metabolic regulation and are potential therapeutic targets for metabolic and inflammatory diseases. A comprehensive understanding of the activation mechanisms and endogenous ligand selectivity of FFARs is essential for drug discovery. Here, we report two cryoelectron microscopy structures of the human FFAR1 bound to the endogenous ligand docosahexaenoic acid (DHA) and G protein as well as FFAR2 in complex with butyrate and G at 3.

Novel chitosan/lignin hydrogel prepared by the Mannich reaction for Pb(II) and Cu(II) removal from aqueous solution.

Green and high-performance biomass-based adsorbents have a good application prospect for the removal of heavy metals. At present, the preparation of chitosan/lignin biomass adsorbents mainly adopts dissolution-drying method, and the obtained adsorbents show relatively poor adsorption performance for heavy metals. To overcome this problem, a novel chitosan/lignin hydrogel (CSL) is prepared by a simple one-pot method through the Mannich reaction.

Structure-guided development of selective caseinolytic protease P agonists as antistaphylococcal agents.

Methicillin-resistant Staphylococcus aureus is a ubiquitous pathogen, posing a serious threat to human health worldwide. Thus, there is a high demand for antibiotics with distinct targets. Caseinolytic protease P (ClpP) is a promising target for combating staphylococcal infections; however, selectively activating S.

Ring expansion of 3-hydroxyoxindoles to 4-quinolones palladium-catalyzed C-C(acyl) bond cleavage.

We report herein the construction of 4-quinolones palladium-catalyzed regioselective β-acyl elimination of 3-hydroxyoxindoles and a subsequent Camps cyclization process. This protocol is highly efficient and various 4-quinolone derivatives are obtained in high yields. The construction of the core skeleton of the 4-quinolone antibiotics demonstrated the synthetic utility of this method.

Slow Metabolism-Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone-Induced Obesity-Specific Liver Injury.

Obesity and nonalcoholic fatty liver disease (NAFLD) are established risk factors for drug-induced liver injury (DILI). The previous study demonstrates that benzbromarone (BBR), a commonly prescribed pharmaceutical agent for managing gout and hyperuricemia, exacerbates hepatic steatosis and liver injury specifically in obese individuals. However, the precise mechanism underpinning this adverse effect remains incompletely elucidated.

Modification of the active centre of nattokinase to enhance its thermostability using a strategy based on molecular dynamics simulation, steered dynamics simulation, and conservative prediction.

Introduction: The poor thermostability of nattokinase represents a significant limitation in its potential applications. Additionally, there is a notable absence of studies focused on modifying residues within the active site region of nattokinase with the aim of enhancing its catalytic properties. Furthermore, the direct utilisation of directed evolution often yields unfavourable outcomes, with a considerable workload being a common consequence.

Discovery of Thiochroman Derivatives as Potent, Oral Selective Estrogen Receptor Degraders and Antagonists for the Treatment of Endocrine-Resistant Breast Cancer.

Selective estrogen receptor degraders (SERDs) deplete the ER signaling pathway via antagonism and degradation of ERα and represent a promising strategy to tackle endocrine resistance. Here, we report a new class of SERDs by pharmacological evolution of a selective estrogen receptor modulator, lasofoxifene. The structure-activity relationship study and efforts to circumvent the issue of human ether-a-go-go-related gene led to the identification of compounds .

Conformation Influences Biological Fates of Peptide-Based Nanofilaments by Modulating Protein Adsorption and Interfilament Entanglement.

Filamentous structures exert biological functions mediated by multivalent interactions with their counterparts in sharp contrast with spherical ones. The physicochemical properties and unique behaviors of nanofilaments that are associated with multivalent interaction with protein are poorly understood. Here, peptide-based nanofilaments containing different homotetrapeptidic inserts are reported and their protein adsorption and biological fates are tested.

New diketopiperazine dimers and 4-hydroxyphenylacetates from an endolichenic fungus Aspergillus sp.

Two novel diketopiperazine dimers (1 and 2) and two new 4-hydroxyphenylacetates (5 and 6), along with two previously known diketopiperazine dimers were isolated from the culture of the endolichenic fungus Aspergillus sp. CPCC 400810. Their structures were determined through comprehensive spectroscopic analysis, including high-resolution electrospray ionization mass spectrometry (HRESIMS) and 1D and 2D nuclear magnetic resonance (NMR) data.

SurfDock is a surface-informed diffusion generative model for reliable and accurate protein-ligand complex prediction.

Accurately predicting protein-ligand interactions is crucial for understanding cellular processes. We introduce SurfDock, a deep-learning method that addresses this challenge by integrating protein sequence, three-dimensional structural graphs and surface-level features into an equivariant architecture. SurfDock employs a generative diffusion model on a non-Euclidean manifold, optimizing molecular translations, rotations and torsions to generate reliable binding poses.

Protective Effects of Isostrictiniin Against High-Fat, High-Sugar Diet-Induced Steatosis in MASLD Mice via Regulation of the AMPK/SREBP-1c/ACC Pathway.

Objectives: Isostrictiniin (ITN), a natural polyphenol extracted from (snow-white waterlily), has antioxidant and hepatoprotective activities that may be beneficial in treating metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to investigate the protective effects of ITN on high-fat, high-sugar diet (HFSD)-induced steatosis in MASLD mice and its mechanisms.

Methods: Kunming mice were randomly divided into normal control and HFSD groups.

Advancements in -Based Anti-Tumor Gene Therapy Research.

The gene is one of the genes most closely associated with human tumors and has become a popular target for tumor drug design. Currently, -based gene therapy techniques have been developed, but these therapies face challenges such as immaturity, high safety hazards, limited efficacy, and low patient acceptance. However, researchers are no less enthusiastic about the treatment because of its theoretical potential to treat cancer.

RNAi Screen Identifies AXL Inhibition Combined with Cannabinoid WIN55212-2 as a Potential Strategy for Cancer Treatment.

: Cannabinoids are commonly used as adjuvant cancer drugs to overcome numerous adverse side effects for patients. The aim of this study was to identify the target genes that show a synergistic anti-tumor role in combination with the cannabinoid WIN55212-2 in vitro and in vivo. : A human kinome RNAi library was used to screen the targeted gene that silencing plus WIN55212-2 treatment synergistically inhibited cancer cell growth in an INCELL Analyzer 2000.

Panobinostat Attenuates Experimental Autoimmune Encephalomyelitis in Mice via Suppressing Oxidative Stress-Related Neuroinflammation and Mitochondrial Dysfunction.

Multiple sclerosis (MS) is an autoimmune disease mediated by T helper cells, which is characterized by neuroinflammation, axonal or neuronal loss, demyelination, and astrocytic gliosis. Histone deacetylase inhibitors (HDACis) are noted for their roles in easing inflammatory conditions and suppressing the immune response. Panobinostat, an HDACi, is now being used in treating multiple myeloma.

Age-related decline in CD8 tissue resident memory T cells compromises antitumor immunity.

Aging compromises antitumor immunity, but the underlying mechanisms remain elusive. Here, we report that aging impairs the generation of CD8 tissue resident memory T (T) cells in nonlymphoid tissues in mice, thus compromising the antitumor activity of aged CD8 T cells, which we also observed in human lung adenocarcinoma. We further identified that the apoptosis regulator BFAR was highly enriched in aged CD8 T cells, in which BFAR suppressed cytokine-induced JAK2 signaling by activating JAK2 deubiquitination, thereby limiting downstream STAT1-mediated T reprogramming.

miCGR: interpretable deep neural network for predicting both site-level and gene-level functional targets of microRNA.

MicroRNAs (miRNAs) are critical regulators in various biological processes to cleave or repress translation of messenger RNAs (mRNAs). Accurately predicting miRNA targets is essential for developing miRNA-based therapies for diseases such as cancer and cardiovascular disease. Traditional miRNA target prediction methods often struggle due to incomplete knowledge of miRNA-target interactions and lack interpretability.

BET inhibitor and CDK4/6 inhibitor synergistically inhibit breast cancer by suppressing BRD4 stability and DNA damage repair.

CDK4/6 inhibitors have shown clinical benefits in hormone receptor positive breast cancer. However, monotonous indications and unclear resistance mechanisms greatly limit the clinical application of these inhibitors. We attempt to improve the therapeutic effect of CDK4/6 inhibitors against breast cancer by combination with BET inhibitors.