Comprehensive Similarity Algorithm and Molecular Dynamics Simulation-Assisted Terahertz Spectroscopy for Intelligent Matching Identification of Quorum Signal Molecules (N-Acyl-Homoserine Lactones).

To investigate the mechanism of aquatic pathogens in quorum sensing (QS) and decode the signal transmission of aquatic Gram-negative pathogens, this paper proposes a novel method for the intelligent matching identification of eight quorum signaling molecules (N-acyl-homoserine lactones, AHLs) with similar molecular structures, using terahertz (THz) spectroscopy combined with molecular dynamics simulation and spectral similarity calculation. The THz fingerprint absorption spectral peaks of the eight AHLs were identified, attributed, and resolved using the density functional theory (DFT) for molecular dynamics simulation. To reduce the computational complexity of matching recognition, spectra with high peak matching values with the target were preliminarily selected, based on the peak position features of AHL samples. A comprehensive similarity calculation (CSC) method using a weighted improved Jaccard similarity algorithm (IJS) and discrete Fréchet distance algorithm (DFD) is proposed to calculate the similarity between the selected spectra and the targets, as well as to return the matching result with the highest accuracy. The results show that all AHL molecular types can be correctly identified, and the average quantization accuracy of CSC is 98.48%. This study provides a theoretical and data-supported foundation for the identification of AHLs, based on THz spectroscopy, and offers a new method for the high-throughput and automatic identification of AHLs.

Analysis of Net Primary Productivity Variation and Quantitative Assessment of Driving Forces-A Case Study of the Yangtze River Basin.

Net primary productivity (NPP) can indirectly reflect vegetation's capacity for CO2 fixation, but its spatiotemporal dynamics are subject to alterations to some extent due to the influences of climate change and human activities. In this study, NPP is used as an indicator to investigate vegetarian carbon ability changes in the vital ecosystems of the Yangtze River Basin (YRB) in China. We also explored the NPP responses to climate change and human activities. We conducted a comprehensive analysis of the temporal dynamics and spatial variations in NPP within the YRB ecosystems from 2003 to 2020. Furthermore, we employed residual analysis to quantitatively assess the contributions of climate factors and human activities to NPP changes. The research findings are as follows: (1) Over the 18-year period, the average NPP within the basin amounted to 543.95 gC/m2, displaying a noticeable fluctuating upward trend with a growth rate of approximately 3.1 gC/m2; (2) The areas exhibiting an increasing trend in NPP account for 82.55% of the total study area. Regions with relatively high stability in the basin covered 62.36% of the total area, while areas with low stability accounted for 2.22%, mainly situated in the Hengduan Mountains of the western Sichuan Plateau; (3) NPP improvement was jointly driven by human activities and climate change, with human activities contributing more significantly to NPP growth. Specifically, the contributions were 65.39% in total, with human activities contributing 59.28% and climate change contributing 40.01%. This study provides an objective assessment of the contributions of human activities and climate change to vegetation productivity, offering crucial insights for future ecosystem development and environmental planning.

Three-dimensional molecular architecture of mouse organogenesis.

Mammalian embryos exhibit sophisticated cellular patterning that is intricately orchestrated at both molecular and cellular level. It has recently become apparent that cells within the animal body display significant heterogeneity, both in terms of their cellular properties and spatial distributions. However, current spatial transcriptomic profiling either lacks three-dimensional representation or is limited in its ability to capture the complexity of embryonic tissues and organs. Here, we present a spatial transcriptomic atlas of all major organs at embryonic day 13.5 in the mouse embryo, and provide a three-dimensional rendering of molecular regulation for embryonic patterning with stacked sections. By integrating the spatial atlas with corresponding single-cell transcriptomic data, we offer a detailed molecular annotation of the dynamic nature of organ development, spatial cellular interactions, embryonic axes, and divergence of cell fates that underlie mammalian development, which would pave the way for precise organ engineering and stem cell-based regenerative medicine.

Gut microbial fatty acid isomerization modulates intraepithelial T cells.

The human gut microbiome constantly converts natural products derived from the host and diet into numerous bioactive metabolites1-3. Dietary fats are essential micronutrients that undergo lipolysis to release free fatty acids (FAs) for absorption in the small intestine4. Gut commensal bacteria modify some unsaturated FAs-for example, linoleic acid (LA)-into various intestinal FA isomers that regulate host metabolism and have anticarcinogenic properties5. However, little is known about how this diet-microorganism FA isomerization network affects the mucosal immune system of the host. Here we report that both dietary factors and microbial factors influence the level of gut LA isomers (conjugated LAs (CLAs)) and that CLAs in turn modulate a distinct population of CD4+ intraepithelial lymphocytes (IELs) that express CD8αα in the small intestine. Genetic abolition of FA isomerization pathways in individual gut symbionts significantly decreases the number of CD4+CD8αα+ IELs in gnotobiotic mice. Restoration of CLAs increases CD4+CD8αα+ IEL levels in the presence of the transcription factor hepatocyte nuclear factor 4γ (HNF4γ). Mechanistically, HNF4γ facilitates CD4+CD8αα+ IEL development by modulating interleukin-18 signalling. In mice, specific deletion of HNF4γ in T cells leads to early mortality from infection by intestinal pathogens. Our data reveal a new role for bacterial FA metabolic pathways in the control of host intraepithelial immunological homeostasis by modulating the relative number of CD4+ T cells that were CD4+CD8αα+.

Simultaneous profiling of spatial gene expression and chromatin accessibility during mouse brain development.

The brain is a complex tissue whose function relies on coordinated anatomical and molecular features. However, the molecular annotation of the spatial organization of the brain is currently insufficient. Here, we describe microfluidic indexing-based spatial assay for transposase-accessible chromatin and RNA-sequencing (MISAR-seq), a method for spatially resolved joint profiling of chromatin accessibility and gene expression. By applying MISAR-seq to the developing mouse brain, we study tissue organization and spatiotemporal regulatory logics during mouse brain development.

Terahertz Spectroscopy and Imaging Techniques for Herbal Medicinal Plants Detection: A Comprehensive Review.

Herbal medicine (HM), derived from various therapeutic plants, has garnered considerable attention for its remarkable effectiveness in treating diseases. However, numerous issues including improved varieties selection, hazardous residue detection, and concoction management affect herb quality throughout the manufacturing process. Therefore, a practical, rapid, nondestructive detection technology is necessary. Terahertz (THz) spectroscopy, with low energy, penetration, and fingerprint features, becomes preferable method for herb quality appraisal. There are three parts in our review. THz techniques, data processing, and modeling methods were introduced in Part I. Three primary applications (authenticity, composition and active ingredients, and origin detection) of THz in medicinal plants quality detection in industrial processing and marketing were detailed in Part II. A thorough investigation and outlook on the well-known applications and advancements of this field were presented in Part III. This review aims to bring new enlightenment to the in-depth THz application research in herbal medicinal plants.

A novel ratiometric fluorescent probe for sensitive detection of jasmonic acid in crops.

Herein, a novel ratiometric fluorescent probe was proposed for sensitive detection of jasmonic acid (JA) based on NCQDs@Co-MOFs@MIPs. The prepared NCQDs, with uniquely dual-emissive performance, are insensitive to JA due to electrostatic repulsion. Interestingly, the introduction of Co-MOFs not only avoided the self-aggregation of NCQDs, but changed the surface charge of NCQDs and triggered the response of NCQDs to JA. More importantly, the imprinted recognition sites from MIPs provided "key-lock" structures to specifically capture JA molecules, greatly improving the selectivity of the probe to JA. Under the synergistic actions of Co-MOFs and MIPs, JA can interact with NCQDs through photo-induced electron transfer (PET), resulting in the changes on emission intensity of the probe at Em = 367 nm and 442 nm. Based on the observations, the quantification of JA was realized in the range of 1-800 ng/mL with the limit of detection (LOD) of 0.35 ng/mL. In addition, the probe was used for detecting JA in rice with satisfactory analysis results, indicating the probe holds great potential for monitoring JA levels in crops. Overall, this strategy provides new insights into the construction of practical probes for sensitive detection of plant hormones in crops.

Cell-specific imputation of drug connectivity mapping with incomplete data.

Drug repositioning allows expedited discovery of new applications for existing compounds, but re-screening vast compound libraries is often prohibitively expensive. "Connectivity mapping" is a process that links drugs to diseases by identifying compounds whose impact on expression in a collection of cells reverses the disease's impact on expression in disease-relevant tissues. The LINCS project has expanded the universe of compounds and cells for which data are available, but even with this effort, many clinically useful combinations are missing. To evaluate the possibility of repurposing drugs despite missing data, we compared collaborative filtering using either neighborhood-based or SVD imputation methods to two naive approaches via cross-validation. Methods were evaluated for their ability to predict drug connectivity despite missing data. Predictions improved when cell type was taken into account. Neighborhood collaborative filtering was the most successful method, with the best improvements in non-immortalized primary cells. We also explored which classes of compounds are most and least reliant on cell type for accurate imputation. We conclude that even for cells in which drug responses have not been fully characterized, it is possible to identify unassayed drugs that reverse in those cells the expression signatures observed in disease.

Elevated THBS3 predicts poor overall survival for clear cell renal cell carcinoma and identifies LncRNA/RBP/THBS3 mRNA networks.

This study was used to assess THBS3's overall survival (OS) prognostic values in clear cell renal cell carcinoma (ccRCC) as well as to determine the LncRNA/RNA binding protein (RBP)/THBS3 interactions. Clinical data and RNA sequencing data were gathered from the TCGA dataset. Significant pathways associated with THBS3 were identified by gene set enrichment analysis (GSEA). Cox regression analyses, both univariate and multivariate, were applied to assess factors with independent prognostic abilities. We also discussed THBS3's relationship to immunity. We discovered that THBS3 expression was increased in ccRCC samples, as well as shorter OS in the TCGA dataset (P<0.05). External verification results in GSE6344, ICGC, ArrayExpress, UALCAN datasets, and qRT-PCR remained consistent (all P<0.05). Cox regression analyses, both univariate and multivariate, identified THBS3 as a factor with independent prognostic ability (both P<0.001). THBS3 expression as well as several clinicopathological variables were included in the nomogram OS prognosis prediction method as well. GSEA identified four THBS3-related signal pathways and THBS3 was revealed to be significantly associated with MSI, TMB, neoantigen, and immunity (all P<0.05). We also identified several LncRNA/RBP/THBS3 mRNA networks as potentially THBS3-related mechanisms. For THBS3-related drug sensitivities, THBS3 was negatively associated with Actinomycin D, Cobimetinib, Eribulin mesilate, Geldanamycin analog, and Vinblastine, while it was positively related to Erlotinib drug sensitivity. In addition to being an independent prognostic factor for ccRCC, THBS3 had a close connection to immunity, with identifying LncRNA/RBPs/THBS3 mRNA networks. Verifications of our findings in vivo and in vitro should be done in the future.

Nanoporous Graphene Oxide-Based Quartz Crystal Microbalance Gas Sensor with Dual-Signal Responses for Trimethylamine Detection.

This paper presents a straightforward method to develop a nanoporous graphene oxide (NGO)-functionalized quartz crystal microbalance (QCM) gas sensor for the detection of trimethylamine (TMA), aiming to form a reliable monitoring mechanism strategy for low-concentration TMA that can still cause serious odor nuisance. The synthesized NGO material was characterized by transmission electron microscopy, X-ray photoelectron spectroscopy, and Fourier transform infrared spectroscopy to verify its structure and morphology. Compared with the bare and GO-based QCM sensors, the NGO-based QCM sensor exhibited ultra-high sensitivity (65.23 Hz/µL), excellent linearity (R2 = 0.98), high response/recovery capability (3 s/20 s) and excellent repeatability (RSD = 0.02, n = 3) toward TMA with frequency shift and resistance. Furthermore, the selectivity of the proposed NGO-based sensor to TMA was verified by analysis of the dual-signal responses. It is also proved that increasing the conductivity did not improve the resistance signal. This work confirms that the proposed NGO-based sensor with dual signals provides a new avenue for TMA sensing, and the sensor is expected to become a potential candidate for gas detection.

Transcriptome Analysis Reveals Genes and Pathways Associated with Salt Tolerance during Seed Germination in Suaeda liaotungensis.

Seed germination is susceptible to external environmental factors, especially salt stress. Suaeda liaotungensis is a halophyte with strong salt tolerance, and the germination rate of brown seeds under 1000 mM NaCl treatment still reached 28.9%. To explore the mechanism of salt stress response during brown seed germination in Suaeda liaotungensis, we conducted transcriptomic analysis on the dry seeds (SlD), germinated seeds under the control condition (SlG_C), and salt treatment (SlG_N). Transcriptome analysis revealed that 13314 and 755 differentially expressed genes (DEGs) from SlD vs. SlG_C and SlG_C vs. SlG_N were detected, respectively. Most DEGs were enriched in pathways related to transcription regulation and hormone signal transduction, ROS metabolism, cell wall organization or biogenesis, and carbohydrate metabolic process in two contrasting groups. Compared with the control condition, POD and CAT activity, H2O2, soluble sugar, and proline contents were increased during germinated seeds under salt stress. Furthermore, functional analysis demonstrated that overexpression of SlNAC2 significantly enhanced salt tolerance during the germination stage in Arabidopsis. These results not only revealed the tolerant mechanism of brown seed germination in response to salinity stress but also promoted the exploration and application of salt-tolerant gene resources of Suaeda liaotungensis.

High-Precision Automatic Identification of Fentanyl-Related Drugs by Terahertz Spectroscopy with Molecular Dynamics Simulation and Spectral Similarity Mapping.

Fentanyl is a potent opioid analgesic with high bioavailability. It is the leading cause of drug addiction and overdose death. To better control the abuse of fentanyl and its derivatives, it is crucial to develop rapid and sensitive detection methods. However, fentanyl-related substrates undergo similar molecular structures resulting in similar properties, which are difficult to be identified by conventional spectroscopic methods. In this work, a method for the automatic identification of 8 fentanyl-related substances with similar spectral characteristics was developed using terahertz (THz) spectroscopy coupled with density functional theory (DFT) and spectral similarity mapping (SSM). To characterize the THz fingerprints of these fentanyl-related samples more accurately, the method of baseline estimation and denoising with sparsity was performed before revealing the unique molecular dynamics of each substance by DFT. The SSM method was proposed to identify these fentanyl analogs based on weighted spectral cosine-cross similarity and fingerprint discrete Fréchet distance, generating a matching list by stepwise searching the entire spectral database. The top matched list returned the identification results of the target fentanyl analogs with accuracies of 94.48~99.33%. Results from this work provide algorithms' increased reliability, which serves as an artificial intelligence-based tool for high-precision fentanyl analysis in real-world samples.

Ultra-sensitive detection of hydrogen peroxide and levofloxacin using a dual-functional fluorescent probe.

Herein, a flower-shaped fluorescent probe was proposed for hydrogen peroxide (H2O2) and levofloxacin (LVF) sensing based on MoOx QDs@Co/Zn-MOFs with porous structure. Both MoOx QDs and Co/Zn-MOFs exhibited peroxidase-like properties, and the combination of them greatly aroused the synergistic catalytic capabilities between them. In o-Phenylenediamine (OPD)-H2O2 system, MoOx QDs@Co/Zn-MOFs efficiently catalyzed H2O2 to produce •OH and then oxidized OPD to its oxidation product (OxOPD). The OxOPD could not only emit blue fluorescence, but also inhibit the fluorescent intensity of MoOx QDs through fluorescence resonance energy transfer (FRET). Moreover, when introducing LVF into the system, the fluorescent intensities of MoOx QDs increased along with the aggregation of themselves while that of OxOPD remained unchanged, which was explained by the joint behavior of FRET and photo-induced electron transfer (PET) instead of the conventional aggregation-induced emission enhancement (AIEE). With these observation, the proposed probe was employed for H2O2 and LVF determination in biological samples with the limit of detection (LOD) of 32.60 pmol/L and 0.85 µmol/L, respectively, suggesting the method holds great promises for trace H2O2 and LVF monitoring in eco-environment.

Intergenerational effects of preconception opioids on glucose homeostasis and hepatic transcription in adult male rats.

Adolescence represents a period of significant neurodevelopment during which adverse experiences can lead to prolonged effects on disease vulnerability, including effects that can impact future offspring. Adolescence is a common period for the initiation of drug use, including the use of opioids. Beyond effects on central reward, opioids also impact glucose metabolism, which can impact the risk of diabetes. Moreover, recent animal models suggest that the effects of adolescent opioids can effect glucose metabolism in future offspring. Indeed, we demonstrated that the adult male offspring of females exposed to morphine for 10 days during adolescence (referred to as MORF1 males) are predisposed to the adverse effects of an obesogenic diet. As adults, MORF1 males fed a high fat moderate sucrose diet (FSD) for just 6 weeks had increased fasting glucose and insulin levels when compared to age-matched offspring of females exposed to saline during adolescence (SALF1 males). Clinically, a similar profile of impaired fasting glucose has been associated with hepatic insulin resistance and an increased risk of non-alcoholic fatty liver disease. Thus, in the current study, we used RNA sequencing to determine whether adult MORF1 males demonstrate significant alterations in the hepatic transcriptome suggestive of alterations in metabolism. Age-matched SALF1 and MORF1 males were fed either FSD or control diet (CD) for 8 weeks. Similar to our previous observations, FSD-maintained MORF1 males gained more weight and displayed both fasting hyperglycemia and hyperinsulinemia when compared to FSD-maintained SALF1 males, with no significant effect on glucagon. No differences in bodyweight or fasting-induce glucose were observed in control diet (CD)-maintained F1 males, although there was a trend for CD MORF1 males to display elevated levels of fasting insulin. Unexpectedly, transcriptional analyses revealed profound differences in the hepatic transcriptome of CD-maintained MORF1 and SALF1 (1686 differentially expressed genes) with no significant differences between FSD-maintained MORF1 and SALF1 males. As changes in the hepatic transcriptome were not revealed under 8 weeks FSD conditions, we extended the feeding paradigm and conducted a glucose tolerance test to determine whether impaired fasting glucose observed in FSD MORF1 males was due to peripheral insulin resistance. Impaired glucose tolerance was observed in both CD and FSD MORF1 males, and to a more limited extent in FSD SALF1 males. These findings implicate intergenerational effects of adolescent morphine exposure on the risk of developing insulin resistance and associated comorbidities, even in the absence of an obesogenic diet.

Nucleolar protein NOP2 could serve as a potential prognostic predictor for clear cell renal cell carcinoma.

As an indispensable part for cancer precision medicine, biomarkers and signatures for predicting cancer prognosis and therapeutic benefits were urgently required. The purpose of this study was to investigate the prognostic roles of NOP2 in renal clear cell carcinoma (ccRCC) for overall survival (OS) and its relationships with immunity. NOP2-related gene expression matrix associated with clinical information was obtained from the Cancer Genome Atlas (TCGA) ccRCC dataset and NOP2-related pathways were identified by gene set enrichment analysis (GSEA). Associations among the NOP2 expression and MSI, TMB, TNB, and immunity were also explored. Both the NOP2 mRNA and protein/phosphoprotein had a higher expression in ccRCC tumor tissues than in normal kidney tissues (both P < 0.001) and elevated NOP2 expression was associated with poor OS (P < 0.001). Logistic regression analysis revealed the NOP2 expression was significantly linked to stage, age, grade, N stage, T stage, and M stage (all P < 0.05). Univariate/multivariate Cox hazard regression analysis results indicated that NOP2 was an independent prognostic factor for OS in ccRCC and GSEA revealed five NOP2-related signaling pathways. Nomogram based on NOP2 and eight clinical characteristic parameters (grade, age, stage, gender, T stage, race, M stage, N stage) was constructed and carefully evaluated. Furthermore, NOP2 gene expression was also found to be significantly related to MSI, TMB, and immunity. Our findings revealed that NOP2 might be a potential prognostic factor for OS in ccRCC and it was significantly associated with immunity, MSI, and TMB.

Terahertz dual-band metamaterial absorber for trace indole-3-acetic acid and tricyclazole molecular detection based on spectral response analysis.

A terahertz (THz) metamaterial absorber based on a split ring resonator (SRR) structure was used to realize the highly accurate detection of trace pesticides, including indole-3-acetic acid (IAA) and tricyclazole. The density functional theory (DFT) was used to analysis the THz fingerprint peaks of IAA and tricyclazole. According to the dual-band (0.918 and 1.575 THz) near-perfect absorption characteristics of the absorber in the transverse magnetic (TM) polarization state, the univariate regressions were used to analyze the responses of peak amplitude and frequency to pesticide concentrations. For IAA, the sensing response based on the peak amplitude at 1.575 THz was the best with a coefficient of determination (R2) of 0.9627. As for tricyclazole, the best sensing response was based on the peak frequency at 1.575 THz with a R2 of 0.8742. Moreover, the detection accuracy of IAA (R2 = 0.9752) and tricyclazole (R2 = 0.9177) were significantly improved through effective variable selection and multivariate fusion. The results indicated that the limit of detection (LOD) of two pesticides both reached 10 ng/L. This study provided a good experimental basis for trace hazardous substances detection, presenting a new prospect for food quality and safety control in the future.

Novel insights into the role of BRD4 in fine particulate matter induced airway hyperresponsiveness.

Epidemiological research has identified that exposure to fine particulate matter (PM2.5) can increase airway hyperresponsiveness (AHR) which is considered a typical characteristic of asthma. Although the effect of PM2.5 on AHR has been elucidated to a certain degree, its exact mechanism remains unclear. Bromodomain-containing protein 4 (BRD4) is recognized as a member of the bromodomain and extraterminal (BET) family, with the ability to maintain higher-order chromatin configuration and regulate gene expression programs. The primary objective of our study was to examine the role of BRD4 in AHR triggered by PM2.5, and to elucidate its possible molecular mechanism. A mouse model with AHR was established using a nose-only PM2.5 exposure system. We observed that PM2.5 enhanced AHR in the experimental group compared to the control group, and this alteration was accompanied by increased lung inflammation and BRD4 expression in bronchi-lung tissue. However, the BRD4 inhibitor (ZL0420) could alleviate the aforementioned alterations in the mouse model with PM2.5 exposure. To explore the exact molecular mechanism, we further examined the role of BRD4 in human airway smooth muscle cells (hASMCs) after exposure to PM2.5 DMSO extracts. We found that PM2.5 DMSO extracts, which promoted the contraction and migration of hASMCs, was accompanied by an increase in the levels of BRD4, kallikrein 14 (KLK14), bradykinin 2 receptor (B2R), matrix metalloproteinases2(MMP-2), matrix metalloproteinases9(MMP-9), vimentin and bradykinin (BK) secretion, while ZL0420 and BRD4 gene silencing could reverse this response. In summary, these results demonstrate that BRD4 is an important player in AHR triggered by PM2.5, and BRD4 inhibition can ameliorate AHR induced by PM2.5. In addition, PM2.5 DMSO extracts can promote the contraction and migration of hASMCs by increasing BRD4 expression.

Trace Identification and Visualization of Multiple Benzimidazole Pesticide Residues on Toona sinensis Leaves Using Terahertz Imaging Combined with Deep Learning.

Molecular spectroscopy has been widely used to identify pesticides. The main limitation of this approach is the difficulty of identifying pesticides with similar molecular structures. When these pesticide residues are in trace and mixed states in plants, it poses great challenges for practical identification. This study proposed a state-of-the-art method for the rapid identification of trace (10 mg·L-1) and multiple similar benzimidazole pesticide residues on the surface of Toona sinensis leaves, mainly including benzoyl (BNL), carbendazim (BCM), thiabendazole (TBZ), and their mixtures. The new method combines high-throughput terahertz (THz) imaging technology with a deep learning framework. To further improve the model reliability beyond the THz fingerprint peaks (BNL: 0.70, 1.07, 2.20 THz; BCM: 1.16, 1.35, 2.32 THz; TBZ: 0.92, 1.24, 1.66, 1.95, 2.58 THz), we extracted the absorption spectra in frequencies of 0.2-2.2 THz from images as the input to the deep convolution neural network (DCNN). Compared with fuzzy Sammon clustering and four back-propagation neural network (BPNN) models (TrainCGB, TrainCGF, TrainCGP, and TrainRP), DCNN achieved the highest prediction accuracies of 100%, 94.51%, 96.26%, 94.64%, 98.81%, 94.90%, 96.17%, and 96.99% for the control check group, BNL, BCM, TBZ, BNL + BCM, BNL + TBZ, BCM + TBZ, and BNL + BCM + TBZ, respectively. Taking advantage of THz imaging and DCNN, the image visualization of pesticide distribution and residue types on leaves was realized simultaneously. The results demonstrated that THz imaging and deep learning can be potentially adopted for rapid-sensing detection of trace multi-residues on leaf surfaces, which is of great significance for agriculture and food safety.

Abiraterone Acetate Induces CREB1 Phosphorylation and Enhances the Function of the CBP-p300 Complex, Leading to Resistance in Prostate Cancer Cells.

PURPOSE: Abiraterone acetate (AA), an inhibitor of cytochrome P450 17alpha-hydroxylase/17, 20 lyase, is an FDA-approved drug for advanced prostate cancer. However, not all patients respond to AA, and AA resistance ultimately develops in patients who initially respond. We aimed to identify AA resistance mechanisms in prostate cancer cells. EXPERIMENTAL DESIGN: We established several AA-resistant cell lines and performed a comprehensive study on mechanisms involved in AA resistance development. RNA sequencing and phospho-kinase array screenings were performed to discover that the cAMP-response element CRE binding protein 1 (CREB1) was a critical molecule in AA resistance development. RESULTS: The drug-resistant cell lines are phenotypically stable without drug selection, and exhibit permanent global gene expression changes. The phosphorylated CREB1 (pCREB1) is increased in AA-resistant cell lines and is critical in controlling global gene expression. Upregulation of pCREB1 desensitized prostate cancer cells to AA, while blocking CREB1 phosphorylation resensitized AA-resistant cells to AA. AA treatment increases intracellular cyclic AMP (cAMP) levels, induces kinases activity, and leads to the phosphorylation of CREB1, which may subsequently augment the essential role of the CBP/p300 complex in AA-resistant cells because AA-resistant cells exhibit a relatively higher sensitivity to CBP/p300 inhibitors. Further pharmacokinetics studies demonstrated that AA significantly synergizes with CBP/p300 inhibitors in limiting the growth of prostate cancer cells. CONCLUSIONS: Our studies suggest that AA treatment upregulates pCREB1, which enhances CBP/p300 activity, leading to global gene expression alterations, subsequently resulting in drug resistance development. Combining AA with therapies targeting resistance mechanisms may provide a more effective treatment strategy.

A history of opioid exposure in females increases the risk of metabolic disorders in their future male offspring.

Worldwide consumption of opioids remains at historic levels. Preclinical studies report intergenerational effects on the endogenous opioid system of future progeny following preconception morphine exposure. Given the role of endogenous opioids in energy homeostasis, such effects could impact metabolism in the next generation. Thus, we examined diet-induced modifications in F1 male progeny of morphine-exposed female rats (MORF1). When fed a high fat-sugar diet (FSD) for 6 weeks, MORF1 males display features of emerging metabolic syndrome; they consume more food, gain more weight, and develop fasting-induced hyperglycemia and hyperinsulinemia. In the hypothalamus, proteins involved in energy homeostasis are modified and RNA sequencing revealed down-regulation of genes associated with neuronal plasticity, coupled with up-regulation of genes associated with immune, inflammatory, and metabolic processes that are specific to FSD-maintained MORF1 males. Thus, limited preconception morphine exposure in female rats increases the risk of metabolic syndrome/type 2 diabetes in the next generation.