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.

Design, synthesis, and structure-activity relationship studies of triazolo-pyrimidine derivatives as WRN inhibitors for the treatment of MSI tumors.

Werner syndrome RecQ helicase (WRN), a member of the RecQ helicase family, has recently been identified as a synthetic lethal target in microsatellite instability (MSI) tumors. The triazolo-pyrimidine compound HRO761 is the first WRN inhibitor to enter clinical trials, but research on this scaffold remains limited. Here, we designed a series of derivatives to systematically study the structure-activity relationship (SAR) of triazolo-pyrimidine scaffolds, leading to the discovery of compound S35.

Anti-inflammatory and antinociceptive effects, toxicity, and phytochemical analysis of Wall.

Preliminary pharmacological studies revealed that the EtOAc fraction (BGEA) might be the main active fraction with anti-inflammatory and antinociceptive effects in Wall. Further assays on BGEA at doses of 200, 400, and 800 mg/kg using four animal models showed that it could inhibit the xylene-induced ear edema, carrageenan-induced paw edema, and acetic acid-induced writhing and prolong the latency time in the hot-plate test. ELISA analysis revealed that the anti-inflammatory activity of BGEA might be associated with the decrease of TNF-, IL-1, and IL-6 levels and the increase of the IL-10 level.

Analysis of Risk Factors of Postoperative Lower Extremity Deep Venous Thrombosis in Patients With Cervical Cancer.

Deep venous thrombosis (DVT) has a significant negative impact on surgical and tumor patient's safety and quality of life. There was no specific report on the incidence and risk factors of postoperative lower extremity DVT in cervical cancer patients. Analysis of the risk factors of postoperative DVT in patients with cervical cancer is of great clinical significance for prevention and treatment.

Age-induced Changes in Ginsenoside Accumulation and Primary Metabolic Characteristics of Panax Ginseng in Transplantation Mode.

Background: Ginseng ( Mayer) is an important natural medicine. However, a long culture period and challenging quality control requirements limit its further use. Although artificial cultivation can yield a sustainable medicinal supply, research on the association between the transplantation and chaining of metabolic networks, especially the regulation of ginsenoside biosynthetic pathways, is limited.

The Role of Iron Overload in Diabetic Cognitive Impairment: A Review.

It is well documented that diabetes mellitus (DM) is strongly associated with cognitive decline and structural damage to the brain. Cognitive deficits appear early in DM and continue to worsen as the disease progresses, possibly due to different underlying mechanisms. Normal iron metabolism is necessary to maintain normal physiological functions of the brain, but iron deposition is one of the causes of some neurodegenerative diseases.

Clinical efficacy analysis of laparoscopic uterine artery pre-ligation combined with hysteroscopic curettage in the treatment of type II cesarean scar pregnancy.

Objective: To explore and evaluate the clinical therapeutic effect of laparoscopic uterine artery pre-ligation combined with hysteroscopic curettage in the treatment of type II cesarean scar pregnancy.

Methods: This study analyzed the clinical data of patients with cesarean scar pregnancy (CSP) in the Maternal and Child Health Hospital of Hubei Province from 2018 to 2022. A total of 134 patients with type II cesarean section were enrolled, out of which 78 patients were included in the final analysis.

Mechanistic Studies on the Stereoselectivity of FFAR1 Modulators.

Free fatty acid receptor 1 (FFAR1) is a potential therapeutic target for the treatment of type 2 diabetes (T2D). It has been validated that agonists targeting FFAR1 can achieve the initial therapeutic endpoints of T2D, and the epimer agonists (,) AM-8596 can activate FFAR1 differently, with one acting as a partial agonist and the other as a full agonist. Up to now, the origin of the stereoselectivity of FFAR1 agonists remains elusive.

In silico prediction of potential drug-induced nephrotoxicity with machine learning methods.

In recent years, drug-induced nephrotoxicity has been one of the main reasons for the failure of drug development. Early prediction of the nephrotoxicity for drug candidates is critical to the success of clinical trials. Therefore, it is very important to construct an effective model that can predict the potential nephrotoxicity of compounds.

Development of a gliclazide ionic liquid and its mesoporous silica particles: an effective formulation strategy to improve oral absorption properties.

Ionic liquid (IL) technology provides a useful platform to enhance the oral absorption of therapeutic agents. In the present work, gliclazide (GLI), a second-generation sulfonylurea drug was transformed into an IL with tetrabutylphosphonium. The physicochemical properties of this IL were systematically characterized by DSC, TGA, FT-IR, NMR, and HPLC.

The Role of Autophagy in Tumor Immune Infiltration in Colorectal Cancer.

Objective: This study is aimed at exploring the association between autophagy and tumor immune infiltration (TII) in colorectal cancer (CRC).

Methods And Materials: We downloaded the transcriptome profiling and clinical data for CRC from The Cancer Genome Atlas (TCGA) database and obtained the normal colon transcriptome profiling data from Genotype-Tissue Expression Project (GTEx) database. The list of autophagy-related signatures was obtained from the Human Autophagy Database.

Discovery of New Estrogen-Related Receptor α Agonists via a Combination Strategy Based on Shape Screening and Ensemble Docking.

Estrogen-related receptor α (ERRα), a member of nuclear receptors (NRs), plays a role in the regulation of cellular energy metabolism and is reported to be a novel potential target for type 2 diabetes therapy. To date, only a few agonists of ERRα have been identified to improve insulin sensitivity and decrease blood glucose levels. Herein, the discovery of novel potent agonists of ERRα determined using a combined virtual screening approach is described.

In Silico Prediction of Potential Drug Combinations for Type 2 Diabetes Mellitus by an Integrated Network and Transcriptome Analysis.

Type 2 diabetes mellitus (T2DM) is a heterogeneous disorder, so achieving the desired therapeutic efficacy through monotherapy is tricky. Drug combinations play a vital role in treating multiple complex diseases by providing increased efficacy and reduced toxicity. Here, we adopted a computational framework to discover potential drugs and drug pairs for T2DM.

Alternative Splicing Events in Tumor Immune Infiltration in Colorectal Cancer.

Despite extensive research, the exact mechanisms involved in colorectal cancer (CRC) etiology and pathogenesis remain unclear. This study aimed to examine the correlation between tumor-associated alternative splicing (AS) events and tumor immune infiltration (TII) in CRC. We analyzed transcriptome profiling and clinical CRC data from The Cancer Genome Atlas (TCGA) database and lists of AS-related and immune-related signatures from the SpliceSeq and Innate databases, respectively to develop and validate a risk model of differential AS events and subsequently a TII risk model.

Insights into the Molecular Mechanisms of Liuwei Dihuang Decoction via Network Pharmacology.

The traditional Chinese medicines (TCMs) have been used to treat diseases over a long history, but it is still a great challenge to uncover the underlying mechanisms for their therapeutic effects due to the complexity of their ingredients. Based on a novel network pharmacology-based approach, we explored in this study the potential therapeutic targets of Liuwei Dihuang (LWDH) decoction in its neuroendocrine immunomodulation (NIM) function. We not only collected the known targets of the compounds in LWDH but also predicted the targets for these compounds using the balanced substructure-drug-target network-based inference (bSDTNBI), which is a target prediction method based on network inferring developed by our laboratory.

Computational Insights into Molecular Activation and Positive Cooperative Mechanisms of FFAR1 Modulators.

Free fatty acid receptor 1 (FFAR1), a member of class A in G-protein-coupled receptors (GPCRs), is a promising antidiabetic target. The crystal structure of FFAR1 revealed that one agonist (MK-8666) binds to the extracellular vestibule of this receptor, while another (AP8) occupies the surface pocket between transmembrane (TM) helices TM4 and TM5. In this study, we performed 1 μs unbiased molecular dynamics (MD) simulation on each of five systems, to uncover why two ligands in completely different sites both serve as agonists and how they exert a positive synergistic effect together.

Insights into the interaction mechanisms of estrogen-related receptor alpha (ERRα) with ligands via molecular dynamics simulations.

Estrogen-related receptor alpha (ERRα), a member of nuclear receptors (NRs), participates in energy metabolism. Recent experiments identified that several agonists to increase the activity of ERRα, which have a therapeutic effect in improving insulin sensitivity and lowering blood glucose levels. However, the detailed molecular mechanism about how the ligands affect the structure of ERRα remains elusive.

Computational insights into the interaction mechanisms of estrogen-related receptor alpha with endogenous ligand cholesterol.

Estrogen-related receptor alpha (ERRα) has attracted increasing concerns. ERRα, orphan nuclear receptor, plays important roles in energy metabolism. Therefore, small molecule agonists of ERRα could be a potential therapeutic strategy in the treatment of metabolic diseases such as diabetes.

Isorhamnetin protects endothelial cells model CRL1730 from oxidative injury by hydrogen peroxide.

To explore the protective effect and mechanism of isorhamnetin against oxidative injury caused by HO to endothelial cell strain CRL1730 of human umbilical vein. HO and endothelial cell strain CRL1730 were used, as a model of injured endothelial cell. Three levels of crude drugs areorhamnetin, 22.

Single-Word Recognition Need Not Depend on Single-Word Features: Narrative Coherence Counteracts Effects of Single-Word Features that Lexical Decision Emphasizes.

Research on reading comprehension of connected text emphasizes reliance on single-word features that organize a stable, mental lexicon of words and that speed or slow the recognition of each new word. However, the time needed to recognize a word might not actually be as fixed as previous research indicates, and the stability of the mental lexicon may change with task demands. The present study explores the effects of narrative coherence in self-paced story reading to single-word feature effects in lexical decision.

Non-visually-guided distance perception depends on matching torso fluctuations between training and test.

Blindwalking to replicate an instructed distance requires various sensory signals. Recent evidence in movement science across many organisms suggests that multifractal organization of connective tissue supports the use of these signals. Multifractal structure is a multiplicity of power laws defining distribution of proportion across many time scales that helps predict judgments of the objects' length.

[Protection and mechanism of total flavone of Hippophae rhamnoides on vascular endothelial cells].

Objective: To observe the protection of total flavones of Hippophae Rhamnoides (TFH) on vascular endothelial cells (VECs).

Methods: Human umbilical VECs (ECV304) were used. The vascular endothelial injured cell model was prepared using hydrogen dioxide (H2O2).