Targeting cholesterol metabolism in Cancer: From molecular mechanisms to therapeutic implications.

Cholesterol is an essential component of cell membranes and helps to maintain their structure and function. Abnormal cholesterol metabolism has been linked to the development and progression of tumors. Changes in cholesterol metabolism triggered by internal or external stimuli can promote tumor growth. During metastasis, tumor cells require large amounts of cholesterol to support their growth and colonization of new organs. Recent research has shown that cholesterol metabolism is reprogrammed during tumor development, and this can also affect the anti-tumor activity of immune cells in the surrounding environment. However, identifying the specific targets in cholesterol metabolism that regulate cancer progression and the tumor microenvironment is still a challenge. Additionally, exploring the potential of combining statin drugs with other therapies for different types of cancer could be a worthwhile avenue for future drug development. In this review, we focus on the molecular mechanisms of cholesterol and its derivatives in cell metabolism and the tumor microenvironment, and discuss specific targets and relevant therapeutic agents that inhibit aspects of cholesterol homeostasis.

Soy protein isolate-based active films functionalized with Zanthoxylum bungeanum by-products: Effects on barrier, mechanical, antioxidant and cherry tomato preservation performance.

In this work, soy protein isolate (SPI)-based films enriched with naturally sourced Zanthoxylum bungeanum leaf extract (ZBLE) were prepared. Different ZBLE contents (0, 1, 3, 5, and 7 % w/w SPI) were incorporated into the SPI matrix to investigate the effect of ZBLE on various properties of the obtained films. ZBLE exhibited excellent compatibility with SPI in terms of tensile strength, water barrier properties, UV-light resistance capability, and antioxidant activities. The films with 5 % ZBLE addition presented the most comprehensive performance. The release of total phenolic compounds in two different aqueous food simulants was analyzed. Furthermore, the films were employed to preserve fresh cherry tomatoes at 25 ± 1 °C for 18 days. The changes in the physicochemical properties (mass loss rate, decay rate, and vitamin C content) of cherry tomatoes revealed that the addition of ZBLE to films significantly extended the storage time. Therefore, the SPI/ZBLE composite film has the potential as an eco-friendly active packaging material for food preservation.

Data-independent acquisition-based global phosphoproteomics reveal the diverse roles of casein kinase 1 in plant development.

Casein kinase 1 (CK1) is serine/threonine protein kinase highly conserved among eukaryotes, and regulates multiple developmental and signaling events through phosphorylation of target proteins. Arabidopsis early flowering 1 (EL1)-like (AELs) are plant-specific CK1s with varied functions, but identification and validation of their substrates is a major bottleneck in elucidating their physiological roles. Here, we conducted a quantitative phosphoproteomic analysis in data-independent acquisition mode to systematically identify CK1 substrates. We extracted proteins from seedlings overexpressing individual AEL genes (AEL1/2/3/4-OE) or lacking AEL function (all ael single mutants and two triple mutants) to identify the high-confidence phosphopeptides with significantly altered abundance compared to wild-type Col-0. Among these, we selected 3985 phosphopeptides with higher abundance in AEL-OE lines or lower abundance in ael mutants compared with Col-0 as AEL-upregulated phosphopeptides, and defined 1032 phosphoproteins. Eight CK1s substrate motifs were enriched among AEL-upregulated phosphopeptides and verified, which allowed us to predict additional candidate substrates and functions of CK1s. We functionally characterized a newly identified substrate C3H17, a CCCH-type zinc finger transcription factor, through biochemical and genetic analyses, revealing a role for AEL-promoted C3H17 protein stability and transactivation activity in regulating embryogenesis. As CK1s are highly conserved across eukaryotes, we searched the rice, mouse, and human protein databases using newly identified CK1 substrate motifs, yielding many more candidate substrates than currently known, largely expanding our understanding of the common and distinct functions exerted by CK1s in Arabidopsis and humans, facilitating future mechanistic studies of CK1-mediated phosphorylation in different species.

Dual-binding domain electrochemiluminescence biosensing platform with self-checking function for sensitive detection of synthetic cathinone in e-cigarettes.

Current single signal electrochemiluminescence (ECL) sensors are susceptible to false positive or false negative phenomena due to experimental conditions. Therefore, sensors with "self-checking" function are attracting democratic attention. In quick succession, a highly sensitive single-cathode dual ECL signal aptasensor with self-checking function to improve the shortcomings mentioned above was designed. This aptasensor used In-based metal-organic framework (MIL-68) as load and stabilizer to effectively attenuate the aggregation-induced quenching (ACQ) effect of porphyrin derivatives (Sn-TCPP) while improve ECL stability. The introduction of cooperative-binding split-aptamers" (CBSAs) aptamers increased the specificity of the aptasensor and its unique double-binding domains detection accelerated the detection efficiency. When analyzing 3,4-methylenedioxypyrovalerone (MDPV), we could calculate two concentrations based on the strength of ECL 1 and ECL 2. If the concentrations are the same, the result would be obtained; if not, it should be retested. Depending on the above operation, the results achieve self-check. It was found that the designed aptasensor could quantify the concentration of MDPV between 1.0 × 10-12 g/L and 1.0 × 10-6 g/L with the limit of detection (LOD) of 1.4 × 10-13 g/L and 2.0 × 10-13 g/L, respectively (3 σ/slope). This study not only improves the detection technology of MDPV, but also explores the dual-signal detection of porphyrin for the first time and enriches the definition of self-checking sensor.

The efficacy and adverse events of delafloxacin in the treatment of acute bacterial infections: A systematic review and meta-analysis of randomized controlled trials.

Background: This study aims to assess the clinical efficacy and adverse events of delafloxacin for the treatment of acute bacterial infections in adult patients through meta-analysis. Methods: The PubMed, Embase, Cochrane library, Web of Science, and Clinical trails databases were searched up to 26 March 2022. Only randomized controlled trials (RCTs) that evaluated delafloxacin and comparator antibiotics for treating acute bacterial infections in adult patients were included. The clinical cure rate and microbiological eradication rate at the posttreatment evaluation, while the secondary outcomes included the risk of adverse events (AEs). Results: In total, six randomized controlled trials (RCTs) involving 3,019 patients with acute bacterial infection were included. There were no significant differences in the clinical cure rate between delafloxacin and comparators (OR = 1.06%, 95% CI = 0.89-1.26, I2 = 0%). Overall, the results showed that delafloxacin had a microbiological eradication rate (documented and presumed) similar to the comparators (OR = 1.33%, 95% CI = 0.94-1.88, I2 = 0%) in the pooled analysis of the six studies. Any treatment-emergent adverse events (TEAEs) did not show significant differences between delafloxacin and the comparators (OR = 0.93%, 95% CI = 0.80-1.08, I2 = 75%). Serious adverse events (SAEs) did not differ between the delafloxacin and comparators (OR = 0.94%, 95% CI = 0.67-1.32, I2 = 0%). The results of gastrointestinal disorders were (OR = 1.26%, 95% CI = 1.01-1.56, I2 = 89%), and nausea, vomiting, and diarrhea were (OR = 0.77%, 95% CI = 0.45-1.34, I2 = 79%), (OR = 1.00%, 95% CI = 0.74-1.36, I2 = 72%), and (OR = 2.10%, 95% CI = 1.70-2.96, I2 = 0%), respectively. The results showed that there was no significant difference in the incidence of nausea and vomiting between delafloxacin and the comparator, but the incidence of diarrhea was higher. The analysis of neurological disorders indicated that the incidence of nervous system disorders was lower in the delafloxacin group (OR = 0.71%, 95% CI = 0.50-1.01, I2 = 52%). Conclusion: The clinical efficacy, microbiological eradication rate and the incidence of AEs of delafloxacin in the treatment of acute bacterial infections were similar to those of the comparators, as an alternative therapeutic agent.

Unravelling the roles of Autophagy in OSCC: A renewed perspective from mechanisms to potential applications.

Oral squamous cell carcinoma (OSCC) is associated with a low survival rate and a high disability rate, making it a serious health burden, particularly in Southeast Asian countries. Therefore, improvements in the diagnosis, treatment, and prognosis prediction of OSCC are highly warranted. Autophagy has a significant impact on cancer development. Studies on autophagy in various human cancers have made outstanding contributions; however, the relationship between autophagy and OSCC remains to be explored. This review highlights the roles of autophagy in OSCC and discusses the relationship between autophagy and Epithelial-mesenchymal transition. Considering the lack of OSCC biomarkers, we focus on the studies involving OSCC-related bioinformatics analysis and molecular targets. Based on some classical targets, we summarize several key autophagy-related biomarkers with a considerable potential for clinical application, which may become the hotspot of OSCC research. In conclusion, we elaborate on the interrelationship between autophagy and OSCC and highlight the shortcomings of current studies to provide insights into the potential clinical strategies.

Taccalonolides: Structure, semi-synthesis, and biological activity.

Microtubules are the fundamental part of the cell cytoskeleton intimately involving in cell proliferation and are superb targets in clinical cancer therapy today. Microtubule stabilizers have become one of the effectively main agents in the last decades for the treatment of diverse cancers. Taccalonolides, the highly oxygenated pentacyclic steroids isolated from the genus of Tacca, are considered a class of novel microtubule-stabilizing agents. Taccalonolides not only possess a similar microtubule-stabilizing activity as the famous drug paclitaxel but also reverse the multi-drug resistance of paclitaxel and epothilone in cellular and animal models. Taccalonolides have captured numerous attention in the field of medicinal chemistry due to their variety of structures, unique mechanism of action, and low toxicity. This review focuses on the structural diversity, semi-synthesis, modification, and pharmacological activities of taccalonolides, providing bright thoughts for the discovery of microtubule-stabilizing drugs.

Molecular-docking-guided design, palladium-catalyzed synthesis and anticancer activity of paclitaxel-benzoxazoles hybrids.

A series of new paclitaxel-benzoxazoles hybrids were designed based on both the molecular docking mode of beta-tubulin with paclitaxel derivatives (7a and 7g), and the activity-structure relationship of C-13 side chain in paclitaxel. Palladium-catalyzed direct Csp2-H arylation of benzoxazoles with different aryl-bromides was used as the key synthetic strategy for the aryl-benzoxazoles moieties in the hybrids. Twenty-six newly synthesized hybrids were screened for their antiproliferative activity against human cancer cell lines such as human breast cancer cells (MDA-MB-231) and liver hepatocellular cells (HepG2) by the MTT assay and results were compared with paclitaxel. Interestingly, most hybrids (7a-7e, 7i, 7k, 7l, 7A, 7B, 7D and 7E) showed significantly active against both cell lines at concentration of 50 µM, which indicated that the hybrid strategy is effective to get structural simplified paclitaxel analogues with high anti-tumor activity.

Targeting Autophagy with Natural Compounds in Cancer: A Renewed Perspective from Molecular Mechanisms to Targeted Therapy.

Natural products are well-characterized to have pharmacological or biological activities that can be of therapeutic benefits for cancer therapy, which also provide an important source of inspiration for discovery of potential novel small-molecule drugs. In the past three decades, accumulating evidence has revealed that natural products can modulate a series of key autophagic signaling pathways and display therapeutic effects in different types of human cancers. In this review, we focus on summarizing some representative natural active compounds, mainly including curcumin, resveratrol, paclitaxel, Bufalin, and Ursolic acid that may ultimately trigger cancer cell death through the regulation of some key autophagic signaling pathways, such as RAS-RAF-MEK-ERK, PI3K-AKT-mTOR, AMPK, ULK1, Beclin-1, Atg5 and p53. Taken together, these inspiring findings would shed light on exploiting more natural compounds as candidate small-molecule drugs, by targeting the crucial pathways of autophagy for the future cancer therapy.

Targeting cancer epigenetic pathways with small-molecule compounds: Therapeutic efficacy and combination therapies.

Epigenetics mainly refers to covalent modifications to DNA or histones without affecting genomes, which ultimately lead to phenotypic changes in cells or organisms. Given the abundance of regulatory targets in epigenetic pathways and their pivotal roles in tumorigenesis and drug resistance, the development of epigenetic drugs holds a great promise for the current cancer therapy. However, lack of potent, selective, and clinically tractable small-molecule compounds makes the strategy to target cancer epigenetic pathways still challenging. Therefore, this review focuses on epigenetic pathways, small molecule inhibitors targeting DNA methyltransferase (DNMT) and small molecule inhibitors targeting histone modification (the main regulatory targets are histone acetyltransferases (HAT), histone deacetylases (HDACs) and histone methyltransferases (HMTS)), as well as the combination strategies of the existing epigenetic therapeutic drugs and more new therapies to improve the efficacy, which will shed light on a new clue on discovery of more small-molecule drugs targeting cancer epigenetic pathways as promising strategies in the future.

Unveiling the Electronic Interaction in ZnO/PtO/Pt Nanoarrays for Catalytic Detection of Triethylamine with Ultrahigh Sensitivity.

The detection of harmful volatile organic compounds is of great significance to environmental quality and human health. However, it still remains a challenge to achieve high detection sensitivity at a relatively low temperature. Herein, an ultrasensitive catalytic sensor for the detection of triethylamine (TEA) based on ZnO/PtO/Pt nanoarray thin films was realized. Sensor measurements reveal that the PtO/Pt sensitizer dramatically reduces the working temperature from 195 °C of a pristine ZnO sensor to 125 °C of ZnO/PtO/Pt sensors. The ZnO/PtO/Pt sensors exhibit an extremely high response of 3513 to 50 ppm TEA, which is three orders of magnitude higher than that of pristine ZnO. Meanwhile, an ultralow limit of detection of 8.3 ppb is achieved. The outstanding performances are superior to those in most previous reports on TEA detection. Mechanistic investigations reveal that the outstanding performances are ascribed to the strong electronic interaction between PtO and ZnO and the catalytic spillover effect of Pt.

Oxygen Vacancies Enabled Porous SnO2 Thin Films for Highly Sensitive Detection of Triethylamine at Room Temperature.

Detection of volatile organic compounds (VOCs) at room temperature (RT) currently remains a challenge for metal oxide semiconductor (MOS) gas sensors. Herein, for the first time, we report on the utilization of porous SnO2 thin films for RT detection of VOCs by defect engineering of oxygen vacancies. The oxygen vacancies in the three-dimensional-ordered SnO2 thin films, prepared by a colloidal template method, can be readily manipulated by thermal annealing at different temperatures. It is found that oxygen vacancies play an important role in the RT sensing performances, which successfully enables the sensor to respond to triethylamine (TEA) with an ultrahigh response, for example, 150.5-10 ppm TEA in a highly selective manner. In addition, the sensor based on oxygen vacancy-rich SnO2 thin films delivers a fast response and recovery speed (53 and 120 s), which can be further shortened to 10 and 36 s by elevating the working temperature to 120 °C. Notably, a low detection limit of 110 ppb has been obtained at RT. The overall performances surpass most previous reports on TEA detection at RT. The outstanding sensing properties can be attributed to the porous structure with abundant oxygen vacancies, which can improve the adsorption of molecules. The oxygen vacancy engineering strategy and the on-chip fabrication of porous MOS thin film sensing layers deliver great potential for creating high-performance RT sensors.

Correction to: In vitro anti-proliferative effects of Zuojinwan on eight kinds of human cancer cell lines.

In the original publication, the AO/EB fluorescent staining result of A549 cells treated with high dose of ZJW for 24 h was repeatedly pasted to those treated with high dose of ZJW for 48 h in Figure 4 due to negligence. In the corrected Fig. 4, we have provided the correct AO/EB result of A549 cells treated with high dose of ZJW for 48 h, which showed no influence to the results.

Correction to: Protective effects of dioscin against alcohol­induced liver injury.

During the course of writing and revision of this paper, the band of GAPDH.

Lewis acid-mediated skeleton transformation of Euphorbia diterpenes: From lathyrane to euphoractane and myrsinane.

Natural euphoractane and myrsinane diterpene skeletons, together with an unnatural 5/7/7/4 fused-ring diterpene skeleton were furnished via BF3·Et2O-mediated transformation of lathyrane-type diterpene, Euphorbia factor L1. The skeleton transformation process was mainly involved in the cascade oxirane-opening (cyclopropane-opening)/oxe-Micheal addition reaction. The structures of three diterpenes were confirmed by comprehensive spectra analysis and single crystals X-ray diffraction. Current results proved the biogenesis pathway between lathyrane with euphoractane and myrsinane by chemical transformation for the first time.