SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ferroptosis susceptibility via FSP1 acetylation.

Ferroptosis, an iron-dependent form of programmed cell death characterized by excessive lipid hydroperoxides accumulation, emerges as a promising target in cancer therapy. Among the solute carrier (SLC) superfamily, the cystine/glutamate transporter system antiporter components SLC3A2 and SLC7A11 are known to regulate ferroptosis by facilitating cystine import for ferroptosis inhibition. However, the contribution of additional SLC superfamily members to ferroptosis remains poorly understood.

PTPN23-dependent activation of PI3KC2α is a therapeutic vulnerability of BRAF-mutant cancers.

BRAF mutations drive initiation and progression of various tumors. While BRAF inhibitors are effective in BRAF-mutant melanoma patients, intrinsic or acquired resistance to these therapies is common. Here, we identify non-receptor-type protein tyrosine phosphatase 23 (PTPN23) as an alternative effective target in BRAF-mutant cancer cells.

Palmitoylation-dependent regulation of GPX4 suppresses ferroptosis.

S-palmitoylation is a reversible and widespread post-translational modification, but its role in the regulation of ferroptosis has been poorly understood. Here, we elucidate that GPX4, an essential regulator of ferroptosis, is reversibly palmitoylated on cysteine 66. The acyltransferase ZDHHC20 palmitoylates GPX4 and increases its protein stability.

N6-methyladenosine modification of 3'tRF-AlaAGC impairs PD-1 blockade efficacy by promoting lactic acid accumulation in the tumor microenvironment of gastric carcinoma.

The balance between CD8 T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) plays a crucial role in the immune checkpoint inhibition (ICI) therapy in gastric carcinoma (GC). However, related factors leading to the disturbance of TME and resistance to ICI therapy remain unknown. In this study, we applied N6-methyladenosine (m6A) small RNA Epitranscriptomic Microarray and screened out 3'tRF-AlaAGC based on its highest differential expression level and lowest inter-group variance.

Pd-Catalyzed Stereospecific Glycosyl Cross-Coupling of Reversed Anomeric Stannanes for Modular Synthesis of Nonclassical -Glycosides.

Nonclassical -glycosides, distinguished by their unique glycosidic bond connection mode, represent a promising avenue for the development of carbohydrate-based drugs. However, the accessibility of nonclassical -glycosides hinders broader investigations into their structural features and modes of action. Herein, we present the first example of Pd-catalyzed stereospecific glycosylation of nonclassical anomeric stannanes with aryl or vinyl halides.

Accessing 7,8-Dihydroquinoline-2,5-diones via Rh-Catalyzed Olefinic C-H Activation/[4+2] Cyclization.

Herein, we report a rhodium-catalyzed C-H activation/[4+2] cyclization reaction between α,β-unsaturated amides and iodonium ylides for the synthesis of novel 7,8-dihydroquinoline-2,5-diones and analogues. This protocol provides a series of pyridones fused with saturated cycles with good functional group compatibility, good water and air tolerance, and good to excellent yields under mild and green reaction conditions. Additionally, scale-up synthesis can be smoothly performed with as low as 0.

Rhodium-Catalyzed Diastereoselective C-H Activation/[4 + 2] Annulation of α,β-Unsaturated Amides with Bicyclic Alkenes.

Herein, we report a rare example of rhodium-catalyzed C-H activation/[4 + 2] annulation of alkenyl amides with bicyclic alkenes under mild and green conditions. The reactivity of the rhodium catalyst in this study differed from that observed in cobalt-catalyzed C-H activation/[3 + 2] annulation between vinylic amides and bicyclic alkenes. In addition, the reaction was performed in EtOH at room temperature, which also displayed excellent diastereoselectivity, good functional group tolerance, and air compatibility.

Discovery and Mechanistic Understanding of a Lipase from Rhizorhabdus dicambivorans for Efficient Ester Aminolysis in Aromatic Amines.

The formation of amide bonds via aminolysis of esters by lipases generates a diverse range of amide frameworks in biosynthetic chemistry. Few lipases have satisfactory activity towards bulky aromatic amines despite numerous attempts to improve the efficiency of this transformation. Here, we report the discovery of a new intracellular lipase (Ndbn) with a broad substrate scope.

Identification of a Potential Antimycobacterial Drug Sensitizer Targeting a Flavin-Independent Methylenetetrahydrofolate Reductase.

The increasing antibiotic resistance of and pathogenic nontuberculosis mycobacteria highlights the urgent need for new prevention and treatment strategies. Recently, the cocrystal structure of a flavin-independent 5,10-methylenetetrahydrofolate reductase (MTHFR) that binds with a reduced nicotinamide adenine dinucleotide (NADH) has been well-determined, providing a structural basis for the screening of antimycobacterial leads targeting MTHFR, a new enzyme involved in tetrahydrofolic acid (THF) biosynthesis. In this study, we identified compound AB131 as a promising candidate that fits well into the NADH binding pocket of MTHFR through virtual screening.

Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2.

A novel series of peptidomimetic aldehydes was designed and synthesized to target 3C protease (3C) of enterovirus 71 (EV71). Most of the compounds exhibited high antiviral activity, and among them, compound demonstrated potent enzyme inhibitory activity and broad-spectrum antiviral activity on a panel of enteroviruses and rhinoviruses. The crystal structure of EV71 3C in complex with determined at a resolution of 1.

α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment.

The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases.

Artificial neural networks accurately predict intra-abdominal infection in moderately severe and severe acute pancreatitis.

Objective: The aim of this study was to evaluate the efficacy of artificial neural networks (ANN) in predicting intra-abdominal infection in moderately severe (MASP) and severe acute pancreatitis (SAP) compared with that of a logistic regression model (LRM).

Methods: Patients suffering from MSAP or SAP from July 2014 to June 2017 in three affiliated hospitals of the Army Medical University in Chongqing, China, were enrolled in this study. A univariate analysis was used to determine the different parameters between patients with and without intra-abdominal infection.

Chemical Resolution of C, N-Unprotected α-Substituted β-Amino Acids Using Stable and Recyclable Proline-Derived Chiral Ligands.

We report the first purely chemical method for the resolution of C, N-unprotected racemic α-substituted β-amino acids (β-AAs) using thermodynamically stable and recyclable chiral proline-derived ligands. The ligands and racemic β-AAs along with Ni(II) could form a pair of Ni(II) complex diastereoisomers with a desirable diastereoselectivity (dr up to 91:9). Enantiomerically pure C, N-unprotected β-AAs could be obtained by simple hydrolysis of an isolated favored Ni(II) complex.

Analysis of crystallographic structures of Ni(ii) complexes of α-amino acid Schiff bases: elucidation of the substituent effect on stereochemical preferences.

In this study, we performed critical analysis of 13 crystallographic structures of various Ni(ii) complexes of amino acid Schiff bases. The major finding of this work is the significance of a parallel displaced type of aromatic interactions between o-amino-benzophenone and Pro N-benzyl rings. The quality of these aromatic interactions was shown to control the steric environment around the amino acid side-chain, rendering variously substituted Ni(ii) complexes of different thermodynamic stabilities.

[Association study between the angiotensin converting enzyme gene insertion/deletion polymorphism and Qinghai Han Chinese with congenital heart disease].

Objective: The aim of this work is to determine whether the angiotensin converting enzyme (ACE) I/D (insertion/deletion) polymorphism is associated with the susceptibility to congenital heart disease (CHD) in the Qinghai Han Chinese.

Methods: This study enrolled 59 CHD patients and 193 CHD controls from Qinghai Cardiovascular Diseases Vocational Hospital. Blood samples were collected from each of the patient and control groups.

Purely Chemical Approach for Preparation of d-α-Amino Acids via (S)-to-(R)-Interconversion of Unprotected Tailor-Made α-Amino Acids.

Unnatural (R)-α-amino acids (α-AAs) are in growing demand in the biomedical research and pharmaceutical industries. In this work, we present development of a purely chemical approach for preparation of (R)-α-AAs via (S)-to-(R)-interconversion of natural and tailor-made (S)-α-AAs. The method can be used on free, unprotected α-AAs and features a remarkable structural generality including substrates bearing tertiary alkyl chains and reactive functional groups.

Recyclable Ligands for the Non-Enzymatic Dynamic Kinetic Resolution of Challenging α-Amino Acids.

Structurally simple and inexpensive chiral tridentate ligands were employed for substantially advancing the purely chemical dynamic kinetic resolution (DKR) of unprotected racemic tailor-made α-amino acids (TM-α-AAs), enabling the first DKR of TM-α-AAs bearing tertiary alkyl chains as well as multiple unprotected functional groups. Owing to the operationally convenient conditions, virtually complete stereoselectivity, and full recyclability of the source of chirality, this method should find wide applications for the preparation of TM-α-AAs, especially on large scale.

Chemical Dynamic Thermodynamic Resolution and S/R Interconversion of Unprotected Unnatural Tailor-made α-Amino Acids.

Described here is an advanced, general method for purely chemical dynamic thermodynamic resolution and S/R interconversion of unprotected tailor-made α-amino acids (α-AAs) through intermediate formation of the corresponding nickel(II)-chelated Schiff bases. The method features virtually complete stereochemical outcome, broad substrate generality (35 examples), and operationally convenient conditions allowing for large-scale preparation of the target α-AAs in enantiomerically pure form. Furthermore, the new type of nonracemizable axially chiral ligands can be quantitatively recycled and reused, rendering the whole process economically and synthetically attractive.

Palladium-catalyzed picolinamide-directed coupling of C(sp(2))-H and C(sp(2))-H: a straightforward approach to quinolinone and pyridone scaffolds.

An unprecedented palladium-catalyzed picolinamide-directed coupling of C(sp(2))-H and C(sp(2))-H has been developed with exclusive formation of the six-membered ring heterocyclics - quinolinone and pyridone. The method employs cyclic hypervalent iodine as oxidant and features good functional-group tolerance. Another advantage of this reaction is that sequential C-H/C-H and C-H/N-H coupling could be achieved.

Palladium-catalyzed difunctionalization of alkynes via C-N and S-N cleavages: a versatile approach to highly functional indoles.

Palladium-catalyzed intramolecular addition of C-N and S-N bond to alkynes with the migration of functional groups has been achieved. A wide range of functional groups including acyl, pyruvoyl, amide, and sulfonyl groups can migrate smoothly and be conveniently introduced at the C-3 postion of indoles in our catalytic system. The operational simplicity and broad substrate scope demonstrate the great potential of this method for the synthesis of highly functional indoles.

Artemether, artesunate, praziquantel and tribendimidine administered singly at different dosages against Clonorchis sinensis: a comparative in vivo study.

We comparatively assessed the in vivo efficacy of artemether, artesunate, praziquantel and tribendimidine against different stages of Clonorchis sinensis. Rats were infected with 40-50 C. sinensis metacercariae, and drugs were administered singly by the oral route at different dosages.

Paragonimiasis in Yongjia County, Zhejiang Province, China: clinical, parasitological and karyotypic studies on Paragonimus westermani.

Paragonimiasis in Yongjia County, Zhejiang Province, China, has been of such public health concern that a specialized Institute for Paragonimiasis Control has been established there. The study reported here involved both parasitological research on Paragonimus westermani in the endemic areas and a clinical analysis of 94 cases of paragonimiasis. Eggs were found in sputum, feces and brain tissue in 45 cases.