Direct synthesis of α-functionalized amides via heteroatom-hydrogen insertion reactions using amide-sulfoxonium ylides.

α-Functionalized Si-, Ge-, B-, Se-, and S-amide moieties are present in many medicinally active molecules, but their synthesis remains challenging. Here, we demonstrate a high-throughput synthesis using amide-sulfoxonium ylides as carbene precursors in a Si-H, Ge-H, B-H, Se-H, and S-H insertion reactions to target a wide range of α-silyl, α-geryl, α-boryl, α-selenyl, and α-sulfur (hetero)amides. The process is featured as simple operation, mild conditions, broad substrate scope, high functional group compatibility, and excellent chemoselectivity.

On-DNA Three-Component Cycloaddition of Diazo Compounds, Nitrosoarenes, and Alkenes: Syntheses of Isoxazolidines for DNA-Encoded Chemical Libraries.

A DNA-compatible three-component reaction is disclosed for the synthesis of on-DNA polysubstituted isoxazolidines that serve as privileged core scaffolds in numerous natural products and bioactive molecules. This one-pot approach involves the 1,3-dipolar cycloaddition of DNA-tagged styrenes with diazo compounds and nitrosoarenes in an aqueous solution of KOAc. The reaction demonstrates excellent functional group compatibility, providing a conventional protocol for the construction of a DNA-labeled isoxazolidine library.

A new strictosamide-based indolo[2,3-a]quinolizidine alkaloid and two new lignans from the stem bark of Smith.

Phytochemical investigation of Smith. (Rubiaceae), an African ethnomedicinal plant, yielded a new indolo[2,3-a]quinolizidine alkaloid, nauclealatimide , two previously unknown lignans named nauclealignan A and B , as well rhemaneolignan B and spicatolignan A from the hydromethanolic extract obtained after ultrasonication of the stem bark. Their chemical structures were elucidated using IR, NMR (1D and 2D) and HRESIMS spectral evidence as well as comparisons with existing literature data.

An enhanced bioactive chitosan-modified microemulsion for mucosal healing of ulcerative colitis.

The intestinal mucus layer plays a crucial role in the systemic absorption of drugs. While penetration through this layer traditionally constitutes a pivotal phase in drug absorption, the approach for treating ulcerative colitis (UC) shifts towards facilitating the direct delivery of drugs to the colon. In this study, we engineered a chitosan-modified microemulsion encapsulated nobiletin (NOB-CS-ME) characterized by small particle dimensions and positive charge specifically, designed to enable targeted delivery.

Intestinal FXR deficiency induces dysregulation of xanthine oxidase and accounts for sex difference in hyperuricemia.

Overproduction of uric acid caused by increased expression and/or enhanced activity of xanthine oxidase (XO) is one of the major etiologies of hyperuricemia, which had a significant sex differences. As an important enzyme involved in production of reactive oxygen species and uric acid, activity of XO is highly correlated with hyperuricemia and its complications. However, the mechanisms underlying XO dysregulation remain unclear, and sex difference in the prevalence of hyperuricemia has been well known.

Golgi-derived extracellular vesicle production induced by SARS-CoV-2 envelope protein.

Extracellular vesicles facilitate cell-to-cell communication, and some enveloped viruses utilize these vesicles as carriers to mediate viral transmission. SARS-CoV-2 envelope protein (2-E) forms a cation channel and overexpression of 2-E led to the generation of a distinct type of large extracellular vesicles (2-E-EVs). Although 2-E-EVs have been demonstrated to facilitate viral transmission in a receptor-independent way, the characteristics and biogenesis mechanism remain enigmatic.

The structure elucidation and alleviating effect on liver fibrosis in vivo of a pectin-like polysaccharide isolated from Buddleja officinalis.

Buddleja officinalis has been used as a traditional Chinese medicine for years. Although evidence has demonstrated it can enhance liver function, the active material basis remains unknown. We hypothesize polysaccharides from Buddleja officinalis may be the active material against liver disease.

A proteogenomic analysis of cervical cancer reveals therapeutic and biological insights.

Although the incidence of cervical cancer (CC) has been reduced in high-income countries due to human papillomavirus (HPV) vaccination and screening strategies, it remains a significant public health issue that poses a threat to women's health in low-income countries. Here, we perform a comprehensive proteogenomic profiling of CC tumors obtained from 139 Chinese women. Integrated proteogenomic analysis links genetic aberrations to downstream pathogenesis-related pathways and reveals the landscape of HPV-associated multi-omic changes.

White matter lesions contribute to motor and non-motor disorders in Parkinson's disease: a critical review.

Parkinson's disease (PD) is a prevalent neurodegenerative disease, characterized by movement disorders and non-motor symptoms like cognitive impairment and depression. Degeneration of dopaminergic neurons in the substantia nigra and Lewy bodies have long been considered as main neuropathological changes. However, recent magnetic resonance imaging (MRI) studies have shown that white matter lesions (WMLs) were present in PD patients.

Analysis of Herbal Constituents and In Vivo Pharmacokinetics of Gegen-Huangqi Decoction in Rat Plasma Using HPLC-Q-TOF-MS/MS and HPLC-QQQ-MS/MS.

The traditional Chinese medicine (TCM) formula, gegen-huangqi (GH) decoction, has been employed for over 200 years, notably for its therapeutic effects in treating conditions such as atherosclerosis and diabetes mellitus. Despite its long-standing use, comprehensive studies on the chemical constituents of GH and their in vivo pharmacokinetics (PK) remain limited. This study aimed to profile the bioactive compounds present in GH decoction and to explore their PK characteristics using HPLC-Q-TOF-MS/MS.

Discovery of CLPP-1071 as an Exceptionally Potent and Orally Efficacious Human ClpP Activator with Strong In Vivo Antitumor Activity.

caseinolytic protease P (ClpP) is essential for maintaining mitochondrial proteome homeostasis, and its activation is increasingly recognized as a promising cancer therapy strategy. Herein, based on structure-guided drug design, we discovered a series of potent ClpP activators by introducing a methyl group to the imipridone scaffold of the ClpP activator in Phase III clinical trials. Through structural optimization of the lead compound, the most optimal compound, , exhibited exceptionally potent ClpP agonistic activity (EC = 23.

Covalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors.

The COVID-19 pandemic, exacerbated by persistent viral mutations, underscored the urgent need for diverse inhibitors targeting multiple viral proteins. In this study, we utilized covalent DNA-encoded libraries to discover innovative triazine-based covalent inhibitors for the 3-chymotrypsin-like protease (3CL, Nsp5) and the papain-like protease (PL) domains of Nsp3, as well as novel non-nucleoside covalent inhibitors for the nonstructural protein 12 (Nsp12, RdRp). Optimization through molecular docking and medicinal chemistry led to the development of , a nonpeptide 3CL inhibitor with an IC of 0.

Design and synthesis of pyridazin-4-one derivatives as necroptosis inhibitors.

Necroptosis is a regulated inflammatory cell death process that is closely associated with autoimmune diseases, acute ischemic injuries, neurodegenerative disorders, and so on. Due to the crucial role of receptor-interacting protein kinase 1 (RIPK1) in the necroptosis pathway, RIPK1 inhibitors are believed to have great potential in the treatment of necroptosis-related diseases. In this article, we reported a series of pyridazin-4-one derivatives as potent necroptosis inhibitors for both human and mouse cells.

Diterpenoids and lignans from the stems of Tripterygium wilfordii and their anti-inflammatory activities.

Two undescribed diterpenoids (1-2) and three lignans (3a/3b, 4a), together with sixteen known compounds (4b, 5-9, 10a/10b-14a/14b) were obtained from the stems of Tripterygium wilfordii (T. wilfordii). The structures of these new compounds were elucidated by detailed spectroscopic analyses, and their absolute configurations were estabished by ECD calculations.

Integrated global and unique metabolic characteristics to reveal the intervention effect of Yiyi decoction on acute pancreatitis.

Yiyi decoction is a Chinese herbal formula for the treatment of acute pancreatitis that has been used in clinical practice for decades. A previous study has suggested that resveratrol, emodin, rhein and their derivatives might be the potential pharmacodynamic components in Yiyi decoction, and researchers have proposed that resveratrol, emodin and rhein are candidate markers for quality control. The present study investigated the intervention effect of Yiyi decoction and its effective components on murine acute pancreatitis using metabolomic approach that integrated global and unique metabolic characteristics.

Research progress on the association of insulin resistance with type 2 diabetes mellitus and Alzheimer's disease.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by insulin resistance and hyperglycemia. It is also known to be a risk factor for Alzheimer's disease (AD). Insulin plays a crucial role in regulating the body's metabolism and is responsible for activating the Phosphoinotide-3-Kinase (PI3K)/Protein Kinase B (Akt) signaling pathway.

Ucp1 Ablation Improves Skeletal Muscle Glycolytic Function in Aging Mice.

Muscular atrophy is among the systematic decline in organ functions in aging, while defective thermogenic fat functionality precedes these anomalies. The potential crosstalk between adipose tissue and muscle during aging is poorly understood. In this study, it is showed that UCP1 knockout (KO) mice characterized deteriorated brown adipose tissue (BAT) function in aging, yet their glucose homeostasis is sustained and energy expenditure is increased, possibly compensated by improved inguinal adipose tissue (iWAT) and muscle functionality compared to age-matched WT mice.

Comprehensive multi-omics analysis elucidates colchicine-induced toxicity mechanisms and unveils the therapeutic potential of MLN4924 and kinase inhibitors.

Colchicine is a widely prescribed anti-inflammatory drug for the treatment of gout, familial Mediterranean fever and pericarditis, but its narrow therapeutic window presents a significant risk of severe toxicity. Despite its clinical relevance, the molecular mechanisms underlying colchicine's pharmacological effects and associated toxicity and explored potential therapeutic interventions to mitigate its adverse effects. We showed the colchicine's impact on cellular morphology in human umbilical vein endothelial cells (HUVEC) and HeLa cells including cell rounding and detachment following 24 h of exposure that revealed pronounced cytotoxic effects.

Supramolecular cyclodextrin-based reservoir as nasal delivery vehicle for rivastigmine to brain.

The purpose of this study involved the synthesis of supramolecular reservoir (i.e. cyclodextrin metal-organic framework, MOF) using cyclodextrins as building blocks, followed by cross-linking to obtain crosslinked CD framework (CDF) using CD-MOF as template and functionalized with borneol (BO) to enhance rivastigmine (RIV) permeation and facilitate brain targeting via intranasal administration.

Selective Inhibition of P2Y and P2Y Receptor Signal Pathways in Platelet Aggregation in Transgenic Cell Lines and Rats by Potassium 2-(1-Hydroxypentyl)-Benzoate, Puerarin and Salvianolic Acid B.

Aim: Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB), puerarin and salvianolic acid B are three natural products or derivatives that can inhibit platelet aggregation. However, the mechanisms of dl-PHPB, puerarin and salvianolic acid B to inhibit platelet aggregation are still not clear.

Method: Here, 2-methylthioadenosine diphosphate (2-MeSADP) was used as an inducer to confirm the effects of three drugs on platelet aggregation and illustrate the corresponding mechanisms.