Blocker-SELEX: a structure-guided strategy for developing inhibitory aptamers disrupting undruggable transcription factor interactions.

Despite the well-established significance of transcription factors (TFs) in pathogenesis, their utilization as pharmacological targets has been limited by the inherent challenges in modulating their protein interactions. The lack of defined small-molecule binding pockets and the nuclear localization of TFs do not favor the use of traditional tools. Aptamers possess large molecular weights, expansive blocking surfaces and efficient cellular internalization, making them compelling tools for modulating TF interactions.

Synthesis and Biological Evaluation of 3-Amino-4,4-Dimethyl Lithocholic Acid Derivatives as Novel, Selective, and Cellularly Active Allosteric SHP1 Activators.

Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1), a non-receptor member of the protein tyrosine phosphatase (PTP) family, negatively regulates several signaling pathways that are responsible for pathological cell processes in cancers. In this study, we report a series of 3-amino-4,4-dimethyl lithocholic acid derivatives as SHP1 activators. The most potent compounds, , showed low micromolar activating effects (EC: 1.

Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design.

G protein-coupled receptors (GPCRs) are the most common proteins targeted by approved drugs. A complete mechanistic elucidation of large-scale conformational transitions underlying the activation mechanisms of GPCRs is of critical importance for therapeutic drug development. Here, we apply a combined computational and experimental framework integrating extensive molecular dynamics simulations, Markov state models, site-directed mutagenesis, and conformational biosensors to investigate the conformational landscape of the angiotensin II (AngII) type 1 receptor (AT receptor) - a prototypical class A GPCR-activation.

Design, Synthesis, and In Vitro Evaluation of Benzofuro[3,2-]Quinoline Derivatives as Potential Antileukemia Agents.

Herein, we design and synthesize an array of benzofuro[3,2-]quinolines starting from 3-(2-methoxyphenyl)quinolin-4(1)ones via a sequential chlorination/demethylation, intramolecular cyclization pathway. This sequential transformation was efficient, conducted under metal-free and mild reaction conditions, and yielded corresponding benzofuro[3,2-]quinolines in high yields. In vitro biological evaluation indicated that such type of compounds showed excellent antileukemia activity and selectivity, and therefore may offer a promising hit compound for developing antileukemia compounds.

DNA methylation modifier LSH inhibits p53 ubiquitination and transactivates p53 to promote lipid metabolism.

Background: The stability of p53 is mainly controlled by ubiquitin-dependent degradation, which is triggered by the E3 ubiquitin ligase MDM2. The chromatin modifier lymphoid-specific helicase (LSH) is essential for DNA methylation and cancer progression as a transcriptional repressor. The potential interplay between chromatin modifiers and transcription factors remains largely unknown.

GIAT4RA functions as a tumor suppressor in non-small cell lung cancer by counteracting Uchl3-mediated deubiquitination of LSH.

Elucidating mechanisms in tumor suppressors and epigenetic modifiers are needed to gain insights into the etiology and treatment of cancer, the interplay between long intergenic non-coding RNAs (lncRNAs) and chromatin remodeling remains unclear. Here, we showed that GIAT4RA, a poorly characterized lncRNA LOC102723729, was significantly decreased in lung cancer cells and tissues; while no association was observed with clinical risk factors, expression was linked with clinical stage and lymphatic metastasis. Higher expression of GIAT4RA was linked with overall survival in NSCLC.

Correction to: Long noncoding RNA LINC00336 inhibits ferroptosis in lung cancer by functioning as a competing endogenous RNA.

Since publication of this article, the authors reported that the names of the corresponding authors had been placed in the wrong order.

Determining the protective effects of Yin-Chen-Hao Tang against acute liver injury induced by carbon tetrachloride using 16S rRNA gene sequencing and LC/MS-based metabolomics.

Yin-Chen-Hao Tang (YCHT), consisting of Artemisia annua L., Gardenia jasminoides Ellis, and Rheum Palmatum L., has been used to relieve liver diseases in China for thousands of years.

1-Phenyl-dihydrobenzoindazoles as novel colchicine site inhibitors: Structural basis and antitumor efficacy.

The colchicine site inhibitors (CSIs) showed promising prospects as antitumor agents due to their vascular disrupting activities besides antimitotic activities. 1-Phenyl-dihydrobenzoindazole was found as a novel scaffold of CSI without the cis-trans isomerization problem. The X-ray co-crystal structure of the lead compound with tubulin was determined, which revealed the binding mode including special water-bridged hydrogen bonds.

Metabonomics Study on the Hepatoprotective Effect of Leaf Saponins Using UPLC/Q-TOF-MS Analysis.

Alcohol liver disease is a major public health problem associated with lifestyle. Our recent study demonstrated that the roots of saponins (PNS) exert hepatoprotective effects against alcohol consumption. Considering that the leaves of saponins (LPNS) have similar chemical ingredients with PNS, increased attention should be given to the hepatoprotective effects of LPNS.

Lycofargesiines A-F, further Lycopodium alkaloids from the club moss Huperzia fargesii.

Six undescribed Lycopodium alkaloids (LAs) comprising four lycodine-type (lycofargesiines A-D), one lycopodine-type (lycofargesiine E), and a phlegmarine-type (lycofargesiine F), together with 16 known ones were isolated from the club moss Huperzia fargesii. Their structures and absolute configurations were determined by extensive spectroscopic methods, electronic circular dichroism (ECD) analysis, and density functional theory (DFT) calculations. (7S,8R,12R,13R)-Lycofargesiine A is a rare naturally occurring LA possessing an exocyclic double bond between C-15 and C-16, with ring A being a rare 2,3-dihyropyridone motif.

Long noncoding RNA LINC00336 inhibits ferroptosis in lung cancer by functioning as a competing endogenous RNA.

The regulatory loop between long noncoding RNAs (lncRNAs) and microRNAs has a dynamic role in transcriptional and translational regulation, and is involved in cancer. However, the regulatory circuitry between lncRNAs and microRNAs in tumorigenesis remains elusive. Here we demonstrate that a nuclear lncRNA LINC00336 is upregulated in lung cancer and functions as an oncogene by acting as a competing endogenous RNA (ceRNAs).

Evaluation of the chemical consistency of Yin-Chen-Hao-Tang prepared by combined and separated decoction methods using high-performance liquid chromatography and quadrupole time-of-flight mass spectrometry coupled with multivariate statistical analysis.

In this study, Yin-Chen-Hao-Tang prepared by two decoction methods, namely, combined decoction (modern decoction method) and separated decoction (traditional decoction method), was analyzed by high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry. The acquired datasets containing sample codes, t -m/z pairs and ion intensities were processed with multivariate statistical analyses, such as principal component analysis and an orthogonal partial least squared discriminant analysis model, to globally compare the chemical differences between the different decoction samples. Then, the chemical differences between the combined and separated decoctions were screened out by S-plots generated from the orthogonal partial least squared discriminant analysis model and compared with chemical information from an established in-house library.

Wenshen Zhuanggu formula mitigates breast cancer bone metastasis through the signaling crosstalk among the Jagged1/Notch, TGF-β and IL-6 signaling pathways.

Ethnopharmacological Relevance: Advanced breast cancer frequently metastasizes to the bone, resulting in patient morbidity and mortality. The interaction of tumor cells with osteoclasts and osteoblasts seriously affects the occurrence and development of bone metastasis in breast cancer. The signaling crosstalk among the Jagged1/Notch, TGF-β and IL-6 signaling pathways plays a significant role in the context of bone metastasis.

Absorption, Metabolism, and Pharmacokinetics Profiles of Norathyriol, an Aglycone of Mangiferin, in Rats by HPLC-MS/MS.

Norathyriol, an aglycone of mangiferin, is a bioactive tetrahydroxyxanthone present in mangosteen and many medicinal plants. However, the biological fate of norathyriol in vivo remains unclear. In this study, the absorption and metabolism of norathyriol in rats were evaluated through HPLC-MS/MS.

A preclinical overview of metformin for the treatment of type 2 diabetes.

Type 2 diabetes (T2D) is the most common type of diabetes mellitus and is mainly characterized by insulin resistance, β-cell dysfunction, and elevated hepatic glucose output. Metformin is a first-line antihyperglycemic agent that works mainly by regulating hepatic glucose production and peripheral insulin sensitivity. Metformin has been clinically applied for more than half a century, although the underlying pharmacological mechanisms remain elusive.

Synthesis of novel tetrandrine derivatives and their inhibition against NSCLC A549 cells.

A series of novel tetrandrine (Tet) derivatives were synthesized through Suzuki -Miyaura reaction and evaluated for their cytotoxicity against human non-small cell lung carcinoma (NSCLC) A549 cells. Interestingly, most of derivatives showed similar cytotoxicity to Tet against NSCLC A549 cells, and particularly, compounds Y5, Y6, Y9 and Y11 showed the most significant cytotoxic effects with IC values ranging from 3.87 to 4.

Activation of AhR with nuclear IKKα regulates cancer stem-like properties in the occurrence of radioresistance.

Most cancer patients receive radiotherapy in the course of their disease and the occurrence of radioresistance is associated with poor prognosis. The molecular pathways that drive enhanced tumorigenic potential during the development of radioresistance are poorly understood. Here, we demonstrate that aryl hydrocarbon receptor (AhR) plays a vital role in the maintenance of cancer stem-like properties.

A G3BP1-Interacting lncRNA Promotes Ferroptosis and Apoptosis in Cancer via Nuclear Sequestration of p53.

Long noncoding RNAs (lncRNA) have been associated with various types of cancer; however, the precise role of many lncRNAs in tumorigenesis remains elusive. Here we demonstrate that the cytosolic lncRNA P53RRA is downregulated in cancers and functions as a tumor suppressor by inhibiting cancer progression. Chromatin remodeling proteins LSH and Cfp1 silenced or increased P53RRA expression, respectively.

A sensitive HPLC-MS/MS method for the simultaneous determination of anemoside B4, anemoside A3 and 23-hydroxybetulinic acid: Application to the pharmacokinetics and liver distribution of Pulsatilla chinensis saponins.

Pulsatilla chinensis saponins, the major active components in the herb, have drawn great attention as potential hepatitis B virus infection and hepatoma treatments. Here, a sensitive and accurate HPLC-MS/MS method was established for simultaneous determination of three saponins - anemoside B4, anemoside A3 and 23-hydroxybetulinic acid - in rat plasma and liver, and fully validated. The method was successfully applied to a pharmacokinetics and liver distribution study of P.

EGLN1/c-Myc Induced Lymphoid-Specific Helicase Inhibits Ferroptosis through Lipid Metabolic Gene Expression Changes.

Ferroptosis is a newly discovered form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms underlying ferroptosis remain poorly defined. First, we demonstrated that lymphoid-specific helicase (LSH), which is a DNA methylation modifier, interacted with WDR76 to inhibit ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and ferroptosis related genes SCD1 and FADS2, in turn, involved in the Warburg effect.

Annotinolide F and lycoannotines A-I, further Lycopodium alkaloids from Lycopodium annotinum.

Seven lycopodine-type (annotinolide F and lycoannotines A-F), two lycodine-type (lycoannotines G and H), and one fawcettimine-type (lycoannotine I) previously undescribed naturally occurring Lycopodium alkaloids together with thirteen known ones were isolated from the whole plant of Lycopodium annotinum. Their structures and absolute configurations were determined by extensive spectroscopic methods, single-crystal X-ray diffraction, chemical transformation, and electronic circular dichroism (ECD) calculations. Among the isolates, annotinolide F, lycoannotines A and B are unusual 7,8-seco-lycopodane derivatives, and annotinolide F even further possesses a rare 8,5-lactone framework through a lactonization after the C-7/C-8 bond cleavage.

Palhicerines A-F, Lycopodium alkaloids from the club moss Palhinhaea cernua.

Four fawcettimine-type (palhicerines A-D, resp.) and two lycopodine-type (palhicerines E and F) Lycopodium alkaloids together with twenty known ones were isolated from the whole plant of Palhinhaea cernua. The structures and absolute configurations of the palhicerines A-F were determined by extensive spectroscopic methods, single-crystal X-ray diffraction analyses, chemical transformation, and electronic circular dichroism (ECD) calculations or induced electronic circular dichroism (IECD) spectra.

Allosteric Modulation of Sigma-1 Receptors Elicits Rapid Antidepressant Activity.

Aims: Sigma-1 receptors are involved in the pathophysiological process of several neuropsychiatric diseases such as epilepsy, depression. Allosteric modulation represents an important mechanism for receptor functional regulation. In this study, we examined antidepressant activity of the latest identified novel and selective allosteric modulator of sigma-1 receptor 3-methyl-phenyl-2, 3, 4, 5-tetrahydro-1H-benzo[d]azepin-7-ol (SOMCL-668).

A 20(S)-protopanoxadiol derivative overcomes multi-drug resistance by antagonizing ATP-binding cassette subfamily B member 1 transporter function.

In cancer cells, failure of chemotherapy is often caused by the ATP-binding cassette subfamily B member 1 (ABCB1), and few drugs have been successfully developed to overcome ABCB1-mediated multi-drug resistance (MDR). To suppress ABCB1 activity, we previously designed and synthesized a new series of derivatives based on 20(S)-protopanoxadiol (PPD). In the present study, we investigated the role of PPD derivatives in the function of ABC transporters.