Marine Cytotoxin Santacruzamate A Derivatives as Potent HDAC1-3 Inhibitors and Their Synergistic Anti-Leukemia Effects with Venetoclax.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by infiltration of the blood and bone marrow, exhibiting a low remission rate and high recurrence rate. Current research has demonstrated that class I HDAC inhibitors can downregulate anti-apoptotic proteins, leading to apoptosis of AML cells. In the present investigation, we conducted structural modifications of marine cytotoxin Santacruzamate A (SCA), a compound known for its inhibitory activity towards HDACs, resulting in the development of a novel series of potent class I HDACs hydrazide inhibitors. Representative hydrazide-based compound 25c exhibited concentration-dependent induction of apoptosis in AML cells as a single agent. Moreover, 25c exhibited a synergistic anti-AML effect when combined with Venetoclax, a clinical Bcl-2 inhibitor employed in AML therapy. This combination resulted in a more pronounced downregulation of anti-apoptotic proteins Mcl-1 and Bcl-xL, along with a significant upregulation of the pro-apoptotic protein cleaved-caspase3 and the DNA double-strand break biomarker γ-H2AX compared to monotherapy. These results highlighted the potential of 25c as a promising lead compound for AML treatment, particularly when used in combination with Venetoclax.

Baicalin protects against hepatocyte injury caused by aflatoxin B1 via the TP53-related ferroptosis Pathway.

OBJECTIVE: Baicalin has antioxidative, antiviral, and anti-inflammatory properties. However, its ability to alleviate oxidative stress (OS) and DNA damage in liver cells exposed to aflatoxin B1 (AFB1), a highly hepatotoxic compound, remains uncertain. In this study, the protective effects of baicalin on AFB1-induced hepatocyte injury and the mechanisms underlying those effects were investigated. METHODS: Stable cell lines expressing CYP3A4 were established using lentiviral vectors to assess oxidative stress levels by conducting assays to determine the content of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Additionally, DNA damage was evaluated by 8-hydroxy-2-deoxyguanosine (8-OHdG) and comet assays. Transcriptome sequencing, molecular docking, and in vitro experiments were conducted to determine the mechanisms underlying the effects of baicalin on AFB1-induced hepatocyte injury. In vivo, a rat model of hepatocyte injury induced by AFB1 was used to evaluate the effects of baicalin. RESULTS: In vitro, baicalin significantly attenuated AFB1-induced injury caused due to OS, as determined by a decrease in ROS, MDA, and SOD levels. Baicalin also considerably decreased AFB1-induced DNA damage in hepatocytes. This protective effect of baicalin was found to be closely associated with the TP53-mediated ferroptosis pathway. To elaborate, baicalin physically interacts with P53, leading to the suppression of the expression of GPX4 and SLC7A11, which in turn inhibits ferroptosis. In vivo findings showed that baicalin decreased DNA damage and ferroptosis in AFB1-treated rat liver tissues, as determined by a decrease in the expression of γ-H2AX and an increase in GPX4 and SLC7A11 levels. Overexpression of TP53 weakened the protective effects of baicalin. CONCLUSIONS: Baicalin can alleviate AFB1-induced OS and DNA damage in liver cells via the TP53-mediated ferroptosis pathway. In this study, a theoretical foundation was established for the use of baicalin in protecting the liver from the toxic effects of AFB1.

Inhibition of Astrocytic Carbohydrate Sulfotransferase 15 Promotes Nerve Repair After Spinal Cord Injury via Mitigation of CSPG Mediated Axonal Inhibition.

Nerve tissue regeneration is a significant problem. After neural diseases and damage such as spinal cord injury (SCI), the accumulation of chondroitin sulfate proteoglycans (CSPG) comprising axonal inhibitory glycosaminoglycan chains in the microenvironment is a major barrier that obstructs nerve repair. Interfering with the production of glycosaminoglycans, especially the critical inhibitory chains, could be a potential therapeutic strategy for SCI, which is, however, poorly defined. This study identifies Chst15, the chondroitin sulfotransferase controlling the generation of axonal inhibitory chondroitin sulfate-E, as a therapeutic target of SCI. Using a recently reported small molecular Chst15 inhibitor, this study investigates the effects of Chst15 inhibition on astrocyte behaviors and the associated consequences of in vivo disruption of the inhibitory microenvironment. Deposition of CSPGs in the extracellular matrix and migration of astrocytes are both significantly impaired by Chst15 inhibition. Administration of the inhibitor in transected spinal cord tissues of rats effectively promotes motor functional restoration and nerve tissue regeneration by a mechanism related to the attenuation of inhibitory CSPGs, glial scar formation and inflammatory responses. This study highlights the role of Chst15 in the CSPG-mediated inhibition of neural recovery after SCI and proposes an effective neuroregenerative therapeutic strategy that uses Chst15 as a potential target.

A near-infrared fluorescent probe for detecting hydrogen sulfide with high selectivity in cells and ulcerative colitis in mice.

Although hydrogen sulfide (H2S) is a well-known toxic gas, its vital role as a gas transmitter in various physiological and pathological processes of living systems cannot be ignored. Relevant investigations indicate that endogenous H2S is involved in the development of ulcerative colitis pathology and is overexpressed in ulcerative colitis, and hence can be considered as an ulcerative colitis biomarker. Herein, an isophorone-xanthene-based NIR fluorescent probe (IX-H2S) was constructed to image H2S. Owing to its large conjugated structure, the probe exhibits a near-infrared emission wavelength of 770 nm with a large Stokes shift (186 nm). Moreover, IX-H2S has excellent selectivity for the detection of H2S without interference from other analytes including thiols. In addition, the probe has been successfully applied not only in fluorescence imaging of endogenous and exogenous H2S in living cells, but also in imaging of H2S in normal and ulcerative colitis mice. Encouraged by the eminent performance, IX-H2S is expected to be a potent "assistant" for the diagnosis of ulcerative colitis.

Efficacy and safety of salvianolate and enoxaparin in the prevention of perioperative deep venous thrombosis in gastrointestinal surgery.

OBJECTIVE: In this study, the efficacy and safety of salvianolate were compared with enoxaparin in the prevention of perioperative deep vein thrombosis in gastrointestinal surgery. METHODS: From October 2017 to September 2019, 563 patients who underwent gastrointestinal surgery were collected. Based on the inclusion and exclusion criteria, 119 patients were divided into two groups: enoxaparin group (n = 65) and salvianolate group (n = 54). Comparisons were made regarding the outcomes: prothrombin time (PT), prothrombin activity (PTA), international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen (FIB), thrombin time (TT), D-dimer level (D-D), platelet count (PLT), hematokrit (HCT), and incidence of deep vein thrombosis (DVT). RESULTS: The main outcomes showed no significance between enoxaparin group and salvianolate group (p > .05). The incidence of DVT in salvianolate group was 1.85%, significantly lower than that in enoxaparin group (12.3%) (p < .05). No serious adverse reactions occurred in the two groups during treatment. CONCLUSION: Compared with enoxaparin, salvianolate has an advantage in the prevention of perioperative thrombosis in gastrointestinal surgery with a lower incidence of DVT.

Real-time dissection of dynamic uncoating of individual influenza viruses.

Uncoating is an obligatory step in the virus life cycle that serves as an antiviral target. Unfortunately, it is challenging to study viral uncoating due to methodology limitations for detecting this transient and dynamic event. The uncoating of influenza A virus (IAV), which contains an unusual genome of eight segmented RNAs, is particularly poorly understood. Here, by encapsulating quantum dot (QD)-conjugated viral ribonucleoprotein complexes (vRNPs) within infectious IAV virions and applying single-particle imaging, we tracked the uncoating process of individual IAV virions. Approximately 30% of IAV particles were found to undergo uncoating through fusion with late endosomes in the "around-nucleus" region at 30 to 90 minutes postinfection. Inhibition of viral M2 proton channels and cellular endosome acidification prevented IAV uncoating. IAV vRNPs are released separately into the cytosol after virus uncoating. Then, individual vRNPs undergo a three-stage movement to the cell nucleus and display two diffusion patterns when inside the nucleus. These findings reveal IAV uncoating and vRNP trafficking mechanisms, filling a critical gap in knowledge about influenza viral infection.

Ecological strategies of biological and chemical control agents on wildfire disease of tobacco (Nicotiana tabacum L.).

BACKGROUND: To investigate the ecological effects of chemical and biological control methods on tobacco wildfire disease, a plot field experiment was conducted to compare the control efficiency and mechanisms of a chemical pesticide (kasugamycin wettable powder, KWP) and a biological control agent (BCA) through high-throughput sequencing of bacterial 16S rRNA genes. RESULTS: The results showed that the BCA displayed better performance in decreasing the disease index and morbidity of tobacco than the chemical pesticide. By monitoring the endophytic community within tobacco leaves, it was found that the control effects of these two methods might be mediated by different changes in the endophytic bacterial communities and community assembly patterns. The application of either method decreased the taxonomic diversity of the leaf endophytic community. Compared to the BCA, KWP showed a more significant effect on the endophytic community structure, while the endophytic community treated with the BCA was able to return to the original state, which presented much lower disease infection. The disease control efficiency of KWP and BCA treatments might be achieved by increasing the abundance of Sphingomonas and Streptophyta, respectively. Furthermore, an analysis of the ecological processes in community assembly indicated that the BCA strengthened the homogeneous and variable selection, while KWP enhanced ecological drift. CONCLUSIONS: The results suggested different control mechanisms between KWP and BCA treatments, which will help in developing diverse ecological strategies for plant disease control.

Exosomal miRNA profiling before and after surgery revealed potential diagnostic and prognostic markers for lung adenocarcinoma.

Exosome is a crucial manner for cancer cell to cell communication and circulating exosomes sever as promising diagnostic and prognostic markers for various types of diseases. A predominant type of cargo of exosome is small RNAs, especially miRNAs. Here, we profiled plasma exosomal miRNAs of six lung adenocarcinoma patients before and after surgery, as well as six healthy individuals as normal control. Our profiling revealed 38 upregulated and 37 downregulated exosomal miRNAs in the plasma of lung adenocarcinoma patients. Additionally, we found that most upregulated miRNAs were increased in the lung adenocarcinoma samples of TCGA database. We further evaluated the correlation between the upregulated exosomal miRNAs and overall survival with Kaplan-Meier survival analysis using online databases. Our results suggested that exosomal miR-151a-5p, miR-10b-5p, miR-192-5p, miR-106b-3p, and miR-484 are potential prognostic markers for lung adenocarcinoma. Importantly, we validated candidate miRNAs in lung adenocarcinoma patients before and after surgery as well as in healthy controls and found that miR-484 was significantly increased in the plasma of lung adenocarcinoma patients and strikingly decreased post-surgery. Hence, we provided novel information on lung adenocarcinoma-derived exosomal miRNA and potential non-invasive diagnostic and prognostic markers for lung adenocarcinoma.

Small-molecule PROTAC degraders of the Bromodomain and Extra Terminal (BET) proteins - A review.

The PROteolysis TArgeting Chimeric (PROTAC) concept has provided an opportunity for the discovery and development of a completely new type of therapy involving induction of protein degradation. The BET proteins, comprised of BRD2, BRD3, BRD4 and the testis-specific BRDT protein, are epigenetic readers and master transcription coactivators. Extremely potent and efficacious small-molecule PROTAC degraders of the BET proteins, based on available, potent and selective BET inhibitors, have been reported. BET degraders differ from BET inhibitors in their cellular potency, phenotypic effects, pharmacokinetic properties and toxicity profiles. Herein, we provide a review of BET degraders and the differential outcome observed in the cellular and animal models for BET degraders in comparison to BET inhibitors.

Integrated network analysis reveals the importance of microbial interactions for maize growth.

Microbes play a critical role in soil global biogeochemical circulation and microbe-microbe interactions have also evoked enormous interests in recent years. Utilization of green manures can stimulate microbial activity and affect microbial composition and diversity. However, few studies focus on the microbial interactions or detect the key functional members in communities. With the advances of metagenomic technologies, network analysis has been used as a powerful tool to detect robust interactions between microbial members. Here, random matrix theory-based network analysis was used to investigate the microbial networks in response to four different green manure fertilization regimes (Vicia villosa, common vetch, milk vetch, and radish) over two growth cycles from October 2012 to September 2014. The results showed that the topological properties of microbial networks were dramatically altered by green manure fertilization. Microbial network under milk vetch amendment showed substantially more intense complexity and interactions than other fertilization systems, indicating that milk vetch provided a favorable condition for microbial interactions and niche sharing. The shift of microbial interactions could be attributed to the changes in some major soil traits and the interactions might be correlated to plant growth and production. With the stimuli of green manures, positive interactions predominated the network eventually and the network complexity was in consistency with maize productivity, which suggested that the complex soil microbial networks might benefit to plants rather than simple ones, because complex networks would hold strong the ability to cope with environment changes or suppress soil-borne pathogen infection on plants. In addition, network analyses discerned some putative keystone taxa and seven of them had directly positive interactions with maize yield, which suggested their important roles in maintaining environmental functions and in improving plant growth.

Structural Characterization and Analysis of Human Immunodeficiency Virus Encapsulating Quantum Dots.

Virus internal labeling by inorganic nanoparticle is a suitable technique for single virus imaging. However, it is unknown that the effect of the internal inorganic nanoparticle on morphology and structure of viral core in mature enveloped Human immunodeficiency virus 1 (HIV-1). Also, the analysis of intact HIV-1 particles and virus-inorganic nanoparticle hybrids is almost impossible with conventional negative staining because HIV-1 is inherently fragile and unstable. Herein, we carried out morphological and structural analysis of a newly constructed quantum dot (QD)-encapsulated infectious HIV-1 particle by using an optimized procedure for the electron microscopic analysis of negatively stained HIV-1 particles. The virus fixation and staining conditions were optimized to ensure the integrity of HIV-1, allowing the ready access to structural information on the viral envelope and core. Morphological and structural analysis by optimized TEM provide key information about viruses, viral core and nanoparticles, which indicates that the encapsulation of quantum dots had no effect on the morphology or mean size of the viral particle, or on the shape, length, width, or angle of the HIV-1 core.

Oxygenation of Simple Olefins through Selective Allylic C-C Bond Cleavage: A Direct Approach to Cinnamyl Aldehydes.

A novel metal-free allylic C-C σ-bond cleavage of simple olefins to give valuable cinnamyl aldehydes is reported. 1,2-Aryl or alkyl migration through allylic C-C bond cleavage occurs in this transformation, which is assisted by an alkyl azide reagent. This method enables O-atom incorporation into simple unfunctionalized olefins to construct cinnamyl aldehydes. The reaction features simple hydrocarbon substrates, metal-free conditions, and high regio- and stereoselectivity.

A Long Noncoding RNA ZEB1-AS1 Promotes Tumorigenesis and Predicts Poor Prognosis in Glioma.

Emerging studies show that long noncoding RNAs (lncRNAs) have important roles in carcinogenesis. lncRNA ZEB1 antisense 1 (ZEB1-AS1) is a novel lncRNA, whose clinical significance, biological function, and underlying mechanism remains unclear in glioma. Here, we found that ZEB1-AS1 was highly expressed in glioma tissues, being closely related to clinical stage of glioma. Moreover, patients with high ZEB1-AS1 levels had poor prognoses, with the evidence provided by multivariate Cox regression analysis indicating that ZEB1-AS1 expression could serve as an independent prognostic factor in glioma patients. Functionally, silencing of ZEB1-AS1 could significantly inhibit cell proliferation, migration, and invasion, as well as promote apoptosis. Knockdown of ZEB1-AS1 significantly induced the G0/G1 phase arrest and correspondingly decreased the percentage of S phase cells. Further analysis indicated that ZEB1-AS1 could regulate the cell cycle by inhibiting the expression of G1/S transition key regulators, such as Cyclin D1 and CDK2. Furthermore, ZEB1-AS1 functioned as an important regulator of migration and invasion via activating epithelial to mesenchymal transition (EMT) through up-regulating the expression of ZEB1, MMP2, MMP9, N-cadherin, and Integrin-ß1 as well as decreasing E-cadherin levels in the metastatic progression of glioma. Additionally, forced down-regulation of ZEB1-AS1 could dramatically promote apoptosis by increasing the expression level of Bax and reducing Bcl-2 expression in glioma. Taken together, our data suggest that ZEB1-AS1 may serve as a new prognostic biomarker and therapeutic target of glioma.

Splitting a Substrate into Three Parts: Gold-Catalyzed Nitrogenation of Alkynes by C-C and C≡C Bond Cleavage.

A gold-catalyzed nitrogenation of alkynes for the synthesis of carbamides and amino tetrazoles through C-C and C≡C bond cleavages is described. A diverse set of functionalized carbamide and amino tetrazole derivatives were selectively constructed under mild conditions. The chemoselectivity can be easily switched by the selection of the acid additives. The reaction is characterized by its broad substrate scope, direct construction of high value products, easy operation under air, and mild conditions at room temperature. This chemistry provides a way to transform alkynes by splitting the substrate into three parts.

MicroRNA-184 acts as a potential diagnostic and prognostic marker in epithelial ovarian cancer and regulates cell proliferation, apoptosis and inflammation.

MicroRNA-184 (miR-184) is found to be significantly deregulated in human cancers associated with tumorigenesis and progression. In this study, we aimed to investigate the role and mechanism of miR-184 expression in epithelial ovarian cancer (EOC). Relative expression of miR-184 was measured by quantificational real-time polymerase chain reaction assay (qRT-PCR) in 80 EOC patients. Kaplan-Meier curve and the log-rank test were conducted to detect the prognostic value of miR-184. Function assays including cell proliferation, apoptosis and inflammation were further explored in vitro. We found that miR-184 was down-regulated in EOC tissues and cell lines compared with paired non-cancerous tissues and IOSE, respectively. Moreover, miR-184 was expressed at significantly lower levels in late-stage (III/IV) EOC tissues. Cox regression multivariate analysis indicated that miR-184 and FIGO stage were independent prognostic indicators for EOC patients. Patients with high miR-184 level achieved significantly a higher 5-year survival rate compared with low level group (P < 0.001). Functional assays showed that miR-184 over-expression could suppress EOC cell proliferation as well as inflammation and induce apoptosis in vitro. Altogether, our results suggest that miR-184 together with pathologic diagnosis is critical for prognosis determination in EOC patients and help select treatment strategy.

Analysis of Niemann-Pick C1-like 1 (NPC1L1) genetic polymorphisms and haplotypes in Chinese Han population.

Niemann-Pick C1-like 1 (NPC1L1i) protein is the key transporter responsible for dietary cholesterol absorption. Recent studies indicated that several functional polymorphisms of NPC1L1 were associated with coronary heart disease (CHD) and response to ezetimibe therapy. The aim of the present study was to analyze the allele frequency and haplotype distribution of NPC1L1 polymorphisms in Chinese Hans and to compare them with those of other ethnic populations reported before. Blood samples were collected from 424 unrelated Chinese Hans (246 males and 178 females). Ten NPC1L1 polymorphisms (-762T > C, -133A > G, -18C > A, 1721C > T, 1735C > G, 1764T > C, 1767G > A, 27677T > C, 25342A > C and 28650A > G) were genotyped by direct sequencing or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Among the variants, the minor allele frequency of -762T > C and 1735C > G were 35.0% and 37.0%, respectively. Furthermore, these two polymorphisms were highly linked with a D' value of 0.80. The observed frequencies of two major haplotypes were 59.1% for T-762/C1735 and 30.1% for C-762/G1735, respectively. The frequencies of the rest variants were extremely low (1.8% for - 133G, 1.5% for -18A, 0.9% for 1721T and only 0.2% for 27677C allele, respectively) or even not detected (1764T > C, 1767G > A, 25342A > C and 28650A > G) in our study population. Comparison with other ethnic populations revealed a remarkable genetic variability in the incidences of NPC1L1 polymorphisms. The frequencies of NPC1L1 polymorphisms in Chinese Hans are comparable to Japanese population but totally different from Caucasians, African-Americans and Hispanic individuals. This is the first study to report the ethnic difference in the frequencies of NPC1L1 functional polymorphisms in detail. -762T > C and 1735C > G are two prevalent NPC1L1 variants which need further studies to explore their clinical impact on CHD prevalence and response to ezetimibe therapy in Chinese Hans.

A high-throughput inhibition screening of major human cytochrome P450 enzymes using an in vitro cocktail and liquid chromatography-tandem mass spectrometry.

A sensitive and high-throughput inhibition screening liquid chromatography-mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of five probe metabolites (7-hydroxycoumarin, CYP2A6; 4-hydroxytolbutamide, CYP2C9; 4'-hydroxymephenytoin, CYP2C19; α-hydroxymetoprolol, CYP2D6; and 1-hydroxymidazolam, CYP3A4) for in vitro cytochrome P450 activity determination in human liver microsome and recombinant. All the metabolites and the internal standard, tramadol, were separated on a Waters 2695 series liquid chromatograph with a Phenomenex Luna C18 column (150 × 2.0 mm, 5 µm). Quality control samples and a positive control CYP inhibitor were included in the method. The IC50 values determined for typical CYP inhibitors were reproducible and in agreement with the literature. The method was selective and showed good accuracy (99.13-103.37%), and inter-day (RSD < 6.20%) and intra-day (RSD < 6.13%) precision. Also, the incubation extracts of the sample were stable at room temperature (20 °C) for 48 h and for 96 h in the autosampler (4 °C). The presented method is the first HPLC-MS/MS method of this combination for simultaneous detection of the five metabolites 7-hydroxycoumarin, 4-hydroxytolbutamide, 4'-hydroxymephenytoin, α-hydroxymetoprolol and 1-hydroxymidazolam in a single-run process. It is possible that the high-quality and -throughput cocktail provides suitable information in drug discovery and screening for new drug entities.

Correction: Establishment of a prediction model for prehospital return of spontaneous circulation in out-of-hospital patients with cardiac arrest.

[This corrects the article on p. 508 in vol. 15, PMID: 37900904.].

A Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRASG12C Inhibitor.

AMG510, as the first approved inhibitor for KRASG12C mutation, has shown promising efficacy in nonsmall-cell lung cancer and colorectal cancer harboring KRASG12C mutation. However, the moderate response rate and the rapid emergence of acquired resistance limit the therapeutic potential of AMG510, highlighting the need for the development of combination strategies. Here, we observed the suppression of RAS-MAPK signaling induced by AMG510 was prolonged and enhanced by SOS1 knockdown. Thus, we design, synthesize, and characterize a potent and specific SOS1 degrader 23. Compound 23 showed efficient SOS1 degradation in KRAS-driven cancer cells and achieved significant antiproliferative potency. Importantly, the combination of 23 with AMG510 suppressed RAS signaling feedback activation, showing synergistic effects against KRASG12C mutant cells in vitro and in vivo. Our findings demonstrated that KRASG12C inhibition plus SOS1 degradation as a potential therapeutic strategy to improve antitumor response and overcome acquired resistance to KRASG12C inhibitor.

Selective C(sp2)-C(sp) bond cleavage: the nitrogenation of alkynes to amides.

Breakthrough: A novel catalyzed direct highly selective C(sp2)-C(sp) bond functionalization of alkynes to amides has been developed. Nitrogenation is achieved by the highly selective C(sp2)-C(sp) bond cleavage of aryl-substituted alkynes. The oxidant-free and mild conditions and wide substrate scope make this method very practical.