A regio-specific 4--methyltransferase from regiospecifically catalyzing 8-prenylkeampferol to icaritin.

is widely used in traditional Chinese medicine and contains rich bioactive compounds. These compounds often have a methyl group at their 4'-OH position catalyzed by methyltransferases. Therefore, studying methyltransferases in plants is of great significance.

Pharmacokinetics and related gender difference studies of four active components of Codonopsis Pilosula by LC-MS/MS determination.

Ethnopharmacological Relevance: Codonopsis pilosula (C. pilosula), commonly known as Dangshen in Chinese, had been used to regulate the immune, digestive, and circulatory systems of human. The reported pharmacokinetic studies on C.

Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response.

Immunotherapy successfully complements traditional cancer treatment. However, primary and acquired resistance might limit efficacy. Reduced antigen presentation by MHC-I has been identified as potential resistance factor.

Cabozantinib-encapsulated and maytansine-conjugated high-density lipoprotein for immunotherapy in colorectal cancer.

Advanced colorectal cancer (CRC) responds poorly to current adjuvant therapies, partially due to its immunosuppressive intestinal microenvironment. We found that myeloid-derived suppressor cells (MDSCs) were enriched in orthotopic tumors due to treatment-induced succinate release, which activated tuft cells and upregulated interleukin 25 (IL-25) and interleukin 13 (IL-13). We engineered a cabozantinib (Cabo)-encapsulated and maytansine (DM1)-conjugated synthetic high-density lipoprotein (CD-sHDL) to modulate the tumor microenvironment.

Germacrane-type sesquiterpenes from Artemisia atrovirens and their anti-inflammatory activity.

Artemisia plants are well-known for their abundant sesquiterpene compounds, which encompass various structural types and exhibit a range of biological activities. In this study, a systematic investigation of Artemisia atrovirens revealed the presence of germacrane-type sesquiterpenes for the first time. This included the discovery of 10 new compounds and three known analogues, among which were two rare dimeric germacrane-type compounds.

A dTDP-L-rhamnose 4-epimerase required for glycopeptidolipid biosynthesis in Mycobacterium abscessus.

Mycobacterium abscessus causes severe lung infections in cystic fibrosis patients and exhibits smooth (S) or rough (R) morphotypes. Disruption of glycopeptidolipid (GPL) production results in the S-to-R transition but the underlying molecular mechanisms of this transition remain incompletely understood. Herein, we characterized MAB_4111c in relation to GPL synthesis and investigated the effects of MAB_4111c deletion in M.

Discovery of benzo[c]phenanthridine derivatives with potent activity against multidrug-resistant .

(Mtb), the pathogen responsible for tuberculosis (TB), is the leading cause of bacterial disease-related death worldwide. Current antibiotic regimens for the treatment of TB remain dated and suffer from long treatment times as well as the development of drug resistance. As such, the search for novel chemical modalities that have selective or potent anti-Mtb properties remains an urgent priority, particularly against multidrug-resistant (MDR) Mtb strains.

Selective ligand recognition and activation of somatostatin receptors SSTR1 and SSTR3.

Somatostatin receptors (SSTRs) exert critical biological functions such as negatively regulating hormone release and cell proliferation, making them popular targets for developing therapeutics to treat endocrine disorders, especially neuroendocrine tumors. Although several panagonists mimicking the endogenous ligand somatostatin are available, the development of more effective and safer somatostatinergic therapies is limited due to a lack of molecular understanding of the ligand recognition and regulation of divergent SSTR subtypes. Here, we report four cryoelectron microscopy structures of G-coupled SSTR1 and SSTR3 activated by distinct agonists, including the FDA-approved panagonist pasireotide as well as their selective small molecule agonists L-797591 and L-796778.

Quantitative proteomics combined independent PRM analysis reveals the mitochondrial and synaptic mechanism underlying norisoboldine's antidepressant effects.

Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests.

Discovery of Imidazo[1,2-]pyrazine Derivatives as Potent ENPP1 Inhibitors.

ENPP1 acts as a negative regulator of the cGAS-STING pathway through the hydrolysis of 2'3'-cGAMP. Inhibitors of ENPP1 are regarded as promising agents for stimulating the immune response in cancer immunotherapy. This study describes the identification and optimization of imidazo[1,2-]pyrazine derivative as a highly potent and selective ENPP1 inhibitor.

Discovery of CZL-046 with an ()-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma.

E1A binding protein (p300) is a promising therapeutic target for the treatment of cancer. Herein, we report the discovery of a series of novel inhibitors with an ()-3-fluoropyrrolidin-2-one scaffold targeting p300 bromodomain. The best compound (CZL-046) shows potent inhibitory activity of p300 bromodomain (IC = 3.

Neuroinflammation inhibition and neuroprotective effects of purpurin, a potential anti-AD compound, screened via network proximity and gene enrichment analyses.

Alzheimer's disease (AD) is a complex neurodegenerative disease without any effective preventive or therapeutic drugs. Natural products with stable structures and pharmacological characteristics are valuable sources for the development of novel drugs for many complex diseases. This study aimed to discover potential natural compounds for the treatment of AD using new technologies and methods and explore the efficacy and mechanism of candidate compounds.

Sirtuin 1/sirtuin 3 are robust lysine delactylases and sirtuin 1-mediated delactylation regulates glycolysis.

Lysine lactylation (Kla), an epigenetic mark triggered by lactate during glycolysis, including the Warburg effect, bridges metabolism and gene regulation. Enzymes such as p300 and HDAC1/3 have been pivotal in deciphering the regulatory dynamics of Kla, though questions about additional regulatory enzymes, their specific Kla substrates, and the underlying functional mechanisms persist. Here, we identify SIRT1 and SIRT3 as key "erasers" of Kla, shedding light on their selective regulation of both histone and non-histone proteins.

F qNMR based pharmacokinetics, metabolism and mass balance studies of SARS-CoV-2-3CL protease inhibitor simnotrelvir (SIM0417) in humans.

Simnotrelvir (SIM0417), an inhibitor of the 3CL protease of SARS-CoV-2, has been identified as a CYP3A sensitive substrate. This study investigated the pharmacokinetics, metabolism, and mass balance of simnotrelvir following a single oral dose of 750 mg in six healthy Chinese male subjects, co-administered with four doses of 100 mg ritonavir. Analysis using F qNMR combined with LC-MS/MS showed that the parent drug M0 constituted over 90% of the drug-related components in plasma.

Intermolecular sulfur atom transfer cascade enabled late-stage introduction of sulfilimines into peptides.

Sulfilimines, a privileged class of -S(iv)[double bond, length as m-dash]N- functional groups found in nature, have been exploited as valuable building blocks in organic synthesis and as pharmacophores in drug discovery, and have aroused significant interest in the chemical community. Nevertheless, strategies for late-stage introduction of sulfilimines into peptides and proteins have still met with limited success. Herein, we have developed a method of introducing biological sulfilimine fragments into peptides by an intermolecular sulfur atom transfer cascade reaction, utilizing hydroxylamine condensed with the acid moieties of peptides and varied diaryl disulfides.

Structural Optimization of Isoquinoline Derivatives from Lycobetaine and Their Inhibitory Activity against Neuroendocrine Prostate Cancer Cells.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive cancer that is resistant to hormone therapy and characterized by poor prognosis, as well as limited therapeutic options. Since the natural product lycobetaine was reported to exhibit good antitumor activities against various types of cancers, we initially simplified the scaffold of lycobetaine to obtain the active compound , an isoquinoline derivative with an aryl moiety substitution at the 4-position, which showed apparent antiproliferative activities against NPEC cell line LASCPC-01 in vitro. Subsequently, we carried out structural optimization and systematic structure-activity relationship (SAR) studies on compound , leading to the discovery of compound , which demonstrated potent inhibitory activities against the LASCPC-01 cell line with an IC value of 0.

Phenylethanol Glycoside from Attenuates BSA-Induced Liver Fibrosis in Rats by Modulating the Gut Microbiota-Liver Axis.

This study aimed to investigate the effect of phenylethanol glycoside from (CPhGs) on the prevention of bovine serum albumin (BSA)-induced hepatic fibrosis in rats. Investigation of the mechanisms of the anti-hepatic fibrosis effect was focused on CPhGs' influence on the "gut-liver" regulation, including the gut microbiota, intestinal barrier, systemic lipopolysaccharide (LPS) concentration, and LPS-related signaling pathway. The results show that CPhGs restored the diversity of gut microbiota, increased the relative abundance of , and decreased the relative abundance of and in the fibrotic rats.

Maltol Improves Peripheral Nerve Function by Inhibiting Schwann Cell Apoptosis via the PERK/eIF2α/CHOP Pathway and MME Upregulation in Diabetic Peripheral Neuropathy.

Diabetic peripheral neuropathy (DPN) is the most prevalent chronic complication among diabetic patients and a primary risk factor contributing to the deterioration of diabetic foot conditions. The pathogenesis of DPN remains complex and not fully understood, and there are hardly any effective treatment drugs. Maltol (3-hydroxy-2-methyl-4-pyranone) has demonstrated antioxidant and anti-inflammatory properties.

Progress in Research of Nanotherapeutics for Overcoming Multidrug Resistance in Cancer.

Chemotherapy has been widely applied in oncotherapy. However, the development of multidrug resistance (MDR) has diminished the effectiveness of anticancer drugs against tumor cells. Such resistance often results in tumor recurrence, metastasis, and patient death.