Metabolome profiling and transcriptome analysis filling the early crucial missing steps of piperine biosynthesis in Piper nigrum L.

Black pepper (Piper nigrum L.), the world renown as the King of Spices, is not only a flavorsome spice but also a traditional herb. Piperine, a species-specific piper amide, is responsible for the major bioactivity and pungent flavor of black pepper. However, several key steps for the biosynthesis of piperoyl-CoA (acyl-donor) and piperidine (acyl-acceptor), two direct precursors for piperine, remain unknown. In this study, we used guilt-by-association analysis of the combined metabolome and transcriptome, to identify two feruloyldiketide-CoA synthases responsible for the production of the C5 side chain scaffold feruloyldiketide-CoA intermediate, which is considered the first and important step to branch metabolic fluxes from phenylpropanoid pathway to piperine biosynthesis. In addition, we also identified the first two key enzymes for piperidine biosynthesis derived from lysine in P. nigrum, namely a lysine decarboxylase and a copper amine oxidase. These enzymes catalyze the production of cadaverine and 1-piperideine, the precursors of piperidine. In vivo and in vitro experiments verified the catalytic capability of them. In conclusion, our findings revealed enigmatic key steps of piperine biosynthetic pathway and thus provide a powerful reference for dissecting the biosynthetic logic of other piper amides.

Stearoyl coenzyme A desaturase 1 (SCD1) regulates foot-and-mouth disease virus replication by modulating host cell lipid metabolism and viral protein 2C-mediated replication complex formation.

The life cycle of foot-and-mouth disease virus (FMDV) is tightly regulated by host cell lipid metabolism. In previous studies, we reported downregulated expression of stearoyl coenzyme A desaturase-1 (SCD1), a key enzyme of fatty acid metabolism, in BHK-VEC cells (a virus-negative cell line derived from BKH-21 cells with persistent FMDV infection) on comparing transcriptomic data for BHK-VEC and BHK-21 cells (Y. Yuan et al., Front Cell Infect Microbiol 12:940906, 2022, https://doi.org/10.3389/fcimb.2022.940906; L. Han et al., Vet Microbiol 263:109247, 2021, https://doi.org/10.1016/j.vetmic.2021.109247). In the present study, we identify that SCD1 regulates FMDV replication. SCD1 overexpression or exogenous addition of oleic acid (OA), a product of the enzymatic activity of SCD1, increased FMDV replication in both BHK-21 cells and SCD1-knockdown cells. Overexpression of SCD1 or exogenous addition of OA restored FMDV infection and replication in BHK-VEC cells, and OA also promoted FMDV replication in BHK-21 cells with persistent FMDV infection. SCD1 recruited the nonstructural FMDV protein 2C to a detergent-resistant membrane located in the perinuclear region of cells to form replication complexes. Inhibiting SCD1 enzyme activity resulted in a significantly decreased number of FMDV replication complexes with abnormal morphology. Inhibition of SCD1 activity also effectively decreased the replication of other RNA viruses such as respiratory enteric orphan virus-3-176, poliovirus-1, enterovirus 71, and vesicular stomatitis virus. Our results demonstrate that SCD1, as a key host regulator of RNA virus replication, is a potential target for developing novel drugs against infections by RNA viruses. IMPORTANCE: Many positive-stranded RNA viruses, including foot-and-mouth disease virus (FMDV), alter host membranes and lipid metabolism to create a suitable microenvironment for their survival and replication within host cells. In FMDV-infected cells, the endoplasmic reticulum membrane is remodeled, forming vesicular structures that rely heavily on increased free fatty acids, thereby linking lipid metabolism to the FMDV replication complex. Nonstructural FMDV protein 2C is crucial for this complex, while host cell enzyme stearoyl coenzyme A desaturase 1 (SCD1) is vital for lipid metabolism. We found that FMDV infection alters SCD1 expression in host cells. Inhibiting SCD1 expression or its enzymatic activity markedly decreases FMDV replication, while supplementing oleic acid, a catalytic product of SCD1, regulates FMDV replication. Additionally, SCD1 forms part of the FMDV replication complex and helps recruit 2C to a detergent-resistant membrane. Our study provides insights into the pathogenesis of FMDV and a potential novel drug target against the virus.

Surface Oxygen Vacancies and Corona Polarization of Bi4Ti3O12 Nanosheets for Synergistically Enhanced Sonopiezoelectric Therapy.

Sonopiezoelectric therapy, an ultrasound-activated piezoelectric nanomaterial for tumor treatment, has emerged as a novel alternative modality. However, the limited piezoelectric catalytic efficiency is a serious bottleneck for its practical application. Excellent piezoelectric catalysts with high piezoelectric coefficients, good deformability, large mechanical impact surface area, and abundant catalytically active sites still need to be developed urgently. In this study, the classical ferroelectric material, bismuth titanate (Bi4Ti3O12, BTO), is selected as a sonopiezoelectric sensitizer for tumor therapy. BTO generates electron-hole pairs under ultrasonic irradiation, which can react with the substrates in a sonocatalytic-driven redox reaction. Aiming to further improve the catalytic activity of BTO, modification of surface oxygen vacancies and treatment of corona polarization are envisioned in this study. Notably, modification of the surface oxygen vacancies reduces its bandgap and inhibits electron-hole recombination. Additionally, the corona polarization treatment immobilized the built-in electric field on BTO, further promoting the separation of electrons and holes. Consequently, these modifications greatly improve the sonocatalytic efficiency for in situ generation of cytotoxic ROS and CO, effectively eradicating the tumor.

Sulfur-Vacancy-Engineered Two-Dimensional Cu@SnS2-x Nanosheets Constructed via Heterovalent Substitution for High-Efficiency Piezocatalytic Tumor Therapy.

Ultrasound (US)-mediated piezocatalytic tumor therapy has attracted much attention due to its notable tissue-penetration capabilities, noninvasiveness, and low oxygen dependency. Nevertheless, the efficiency of piezocatalytic therapy is limited due to an inadequate piezoelectric response, low separation of electron-hole (e--h+) pairs, and complex tumor microenvironment (TME). Herein, an ultrathin two-dimensional (2D) sulfur-vacancy-engineered (Sv-engineered) Cu@SnS2-x nanosheet (NS) with an enhanced piezoelectric effect was constructed via the heterovalent substitution strategy of Sn4+ by Cu2+. The introduction of Cu2+ ion not only causes changes in the crystal structure to increase polarization but also generates rich Sv to decrease band gap from 2.16 to 1.62 eV and inhibit e--h+ pairs recombination, collectively leading to the highly efficient generation of reactive oxygen species under US irradiation. Moreover, Cu@SnS2-x shows US-enhanced TME-responsive Fenton-like catalytic activity and glutathione depletion ability, further aggravating the oxidative stress. Both in vitro and in vivo results prove that the Sv-engineered Cu@SnS2-x NSs can significantly kill tumor cells and achieve high-efficiency piezocatalytic tumor therapy in a biocompatible manner. Overall, this study provides a new avenue for sonocatalytic therapy and broadens the application of 2D piezoelectric materials.

The Host Protein CAD Regulates the Replication of FMDV through the Function of Pyrimidines' De Novo Synthesis.

Foot-and-mouth disease virus (FMDV) is a single-stranded picornavirus that causes economically devastating disease in even-hooved animals. There has been little research on the function of host cells during FMDV infection. We aimed to shed light on key host factors associated with FMDV replication during acute infection. We found that HDAC1 overexpression in host cells induced upregulation of FMDV RNA and protein levels. Activation of the AKT-mammalian target of rapamycin (mTOR) signaling pathway using bpV(HOpic) or SC79 also promoted FMDV replication. Furthermore, short hairpin RNA (shRNA)-induced suppression of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), a transcription factor downstream of the AKT-mTOR signaling pathway, resulted in downregulation of FMDV RNA and protein levels. Coimmunoprecipitation assays showed that the ACTase domain of CAD could interact with the FMDV 2C protein, suggesting that the ACTase domain of CAD may be critical in FMDV replication. CAD proteins participate in de novo pyrimidine synthesis. Inhibition of FMDV replication by deletion of the ACTase domain of CAD in host cells could be reversed by supplementation with uracil. These results revealed that the contribution of the CAD ACTase domain to FMDV replication is dependent on de novo pyrimidine synthesis. Our research shows that HDAC1 promotes FMDV replication by regulating de novo pyrimidine synthesis from CAD via the AKT-mTOR signaling pathway. IMPORTANCE Foot-and-mouth disease virus is an animal virus of the Picornaviridae family that seriously harms the development of animal husbandry and foreign trade of related products, and there is still a lack of effective means to control its harm. Replication complexes would generate during FMDV replication to ensure efficient replication cycles. 2C is a common viral protein in the replication complex of Picornaviridae virus, which is thought to be an essential component of membrane rearrangement and viral replication complex formation. The host protein CAD is a key protein in the pyrimidines de novo synthesis. In our research, the interaction of CAD and FMDV 2C was demonstrated in FMDV-infected BHK-21 cells, and it colocalized with 2C in the replication complex. The inhibition of the expression of FMDV 3D protein through interference with CAD and supplementation with exogenous pyrimidines reversed this inhibition, suggesting that FMDV might recruit CAD through the 2C protein to ensure pyrimidine supply during replication. In addition, we also found that FMDV infection decreased the expression of the host protein HDAC1 and ultimately inhibited CAD activity through the AKT-mTOR signaling pathway. These results revealed a unique means of counteracting the virus in BHK-21 cells lacking the interferon (IFN) signaling pathway. In conclusion, our study provides some potential targets for the development of drugs against FMDV.

Link prediction in protein-protein interaction network: A similarity multiplied similarity algorithm with paths of length three.

Protein-protein interactions (PPIs) are crucial for various biological processes, and predicting PPIs is a major challenge. To solve this issue, the most common method is link prediction. Currently, the link prediction methods based on network Paths of Length Three (L3) have been proven to be highly effective. In this paper, we propose a novel link prediction algorithm, named SMS, which is based on L3 and protein similarities. We first design a mixed similarity that combines the topological structure and attribute features of nodes. Then, we compute the predicted value by summing the product of all similarities along the L3. Furthermore, we propose the Max Similarity Multiplied Similarity (maxSMS) algorithm from the perspective of maximum impact. Our computational prediction results show that on six datasets, including S. cerevisiae, H. sapiens, and others, the maxSMS algorithm improves the precision of the top 500, area under the precision-recall curve, and normalized discounted cumulative gain by an average of 26.99%, 53.67%, and 6.7%, respectively, compared to other optimal methods.

Cellulose synthase-like OsCSLD4: a key regulator of agronomic traits, disease resistance, and metabolic indices in rice.

KEY MESSAGE: Cellulose synthase-like OsCSLD4 plays a pivotal role in regulating diverse agronomic traits, enhancing resistance against bacterial leaf blight, and modulating metabolite indices based on the multi-omics analysis in rice. To delve deeper into this complex network between agronomic traits and metabolites in rice, we have compiled a dataset encompassing genome, phenome, and metabolome, including 524 diverse accessions, 11 agronomic traits, and 841 metabolites, enabling us to pinpoint eight hotspots through GWAS. We later discovered four distinct metabolite categories, encompassing 15 metabolites that are concurrently present on the QTL qC12.1, associated with leaf angle of flag and spikelet length, and finally focused the cellulose synthase-like OsCSLD4, which was pinpointed through a rigorous process encompassing sequence variation, haplotype, ATAC, and differential expression across diverse tissues. Compared to the wild type, csld4 exhibited significant reductions in the plant height, flag leaf length, leaf width, spikelet length, 1000-grain weight, grain width, grain thickness, fertility, yield per plant, and bacterial blight resistance. However, there were significant increase in tiller numbers, degree of leaf rolling, flowering period, growth period, grain length, and empty kernel rate. Furthermore, the content of four polyphenol metabolites, excluding metabolite N-feruloyltyramine (mr1268), notably rose, whereas the levels of the other three polyphenol metabolites, smiglaside C (mr1498), 4-coumaric acid (mr1622), and smiglaside A (mr1925) decreased significantly in mutant csld4. The content of amino acid L-tyramine (mr1446) exhibited a notable increase, whereas the alkaloid trigonelline (mr1188) displayed a substantial decrease among the mutants. This study offered a comprehensive multi-omics perspective to analyze the genetic mechanism of OsCSLD4, and breeders can potentially enhance rice's yield, bacterial leaf blight resistance, and metabolite content, leading to more sustainable and profitable rice production.

Dose-response relationships between body-mass index and pressure injuries occurrence in hospitalized patients: A multi-center prospective study.

BACKGROUND: Pressure injuries (PIs) are one of the leading potentially preventable hospital-acquired complications associated with prolonged hospital length, poor quality of life and financial burden. The relationship between body mass index (BMI) and PIs occurrence is controversial. OBJECTIVE: The aim of this study was to further examine relationships between BMI and PIs occurrence in hospitalized patients. DESIGN: A multi-center prospective study. SETTING: 39 hospitals located in northwest China from April 2021 to July 2023. PARTICIPANTS: 175,960 hospitalized patients aged over 18 years were enrolled, and 170,800 patients were included in the final analysis. METHODS: BMI and clinical characteristics were assessed at baseline. PIs assessment were performed by trained nurses, with data recorded for the presence, the location and stage of each PI. For staging PIs, the National Pressure Ulcer Advisory Panel（NPUAP） staging system were used. The multivariate logistic regressions analysis and restricted cubic splines (RCS) models were used to explore associations between BMI and PIs, adjusting for potential confounders. RESULTS: Of 175,960 participants, 5160 were excluded from analyses. The multivariate logistic regression model identified a positive relationship between under-weight BMI and risk of PIs occurrence (OR = 1.60, 95% CI:1.18-2.17). We also found U shaped association between BMI and PIs occurrence (non-linear P < 0.001). BMI less than 23 kg/m2 significantly increased risk of PIs, and there was a tendency to increase risk of PIs at BMI higher than 30 kg/m2. We stratified participants by sex to further investigate their association and found the risk of PIs increases substantially in women at BMI below 17 kg/m2 and in men at BMI below 23 kg/m2. CONCLUSIONS: The present study indicated that there was an approximate U shaped relationship between BMI and PIs occurrence, and this association was potentially different between men and women.

Defect-Repaired g-C3N4 Nanosheets: Elevating the Efficacy of Sonodynamic Cancer Therapy Through Enhanced Charge Carrier Migration.

Sonodynamic therapy (SDT) has garnered growing interest owing to its high tissue penetration depth and minimal side effects. However, the lack of efficient sonosensitizers remains the primary limiting factor for the clinical application of this treatment method. Here, defect-repaired graphene phase carbon nitride (g-C3N4) nanosheets are prepared and utilized for enhanced SDT in anti-tumor treatment. After defect engineering optimization, the bulk defects of g-C3N4 are significantly reduced, resulting in higher crystallinity and exhibiting a polyheptazine imide (PHI) structure. Due to the more extended conjugated structure of PHI, facilitating faster charge transfer on the surface, it exhibits superior SDT performance for inducing apoptosis in tumor cells. This work focuses on introducing a novel carbon nitride nanomaterial as a sonosensitizer and a strategy for optimizing sonosensitizer performance by reducing bulk defects.

Distribution, sources, and risk assessment of polycyclic aromatic hydrocarbons (PAHs) in Kaokaowusu river sediments near a coal industrial zone.

This study systematically analyzed the contents, compositions, and sources of polycyclic aromatic hydrocarbons (PAHs) in river sediments near an important energy and chemical base in northwest China. In addition, their possible adverse effects on the ecology and human health were assessed. The PAH concentrations in this study area ranged from 2641.28 to 16783.72 (ng/g dw). PAHs of medium molecular weight (3-ring and 4-ring) showed the largest proportion, followed by PAHs of higher molecular weight (5-ring and 6-ring). The results of molecular diagnostic ratios and principal component analysis revealed that PAHs in the region have complex sources, with incomplete combustion of local fossil fuels and traffic exhaust factors being the main sources. The total toxic equivalent concentration of PAHs varied from 10.05 to 760.26 ng/g, and according to the sediment quality guidelines, PAHs have high potential ecological risk in the lower reaches of the river. The mean effect range-median quotient for the region was 0.46, and the combined ecological risk was at moderate to high levels (21% probability of toxicity). The lifetime carcinogenic risks for adults and children exposed to PAHs were 2.95 × 10-3 and 1.87 × 10-2, respectively, which are much higher than the limit of 10-4, indicating moderate to high potential cancer risks. Therefore, the local government should consider taking some environmental remediation measures. This study can provide theoretical support for pollution prevention measures and ecological restoration strategies for rivers in resource-rich areas.

The potential role of ferroptosis in the physiopathology of deep tissue injuries.

Deep tissue injuries (DTIs) are a serious type of pressure injuries that mainly occur at the bony prominences and can develop rapidly, making prevention and treatment more difficult. Although consistent research efforts have been made over the years, the cellular and molecular mechanisms contributing to the development of DTIs remain unclear. More recently, ferroptosis, a novel regulatory cell death (RCD) type, has been identified that is morphological, biochemical and genetic criteria distinct from apoptosis, autophagy and other known cell death pathways. Ferroptosis is characterized by iron overload, iron-dependent lipid peroxidation and shrunken mitochondria. We also note that some of the pathological features of DTI are known to be key features of the ferroptosis pathway. Numerous studies have confirmed that ferroptosis may be involved in chronic wounds, including DTIs. Here, we elaborate on the basic pathological features of ferroptosis. We also present the evidence that ferroptosis is involved in the pathology of DTIs and highlight a future perspective on this emerging field, desiring to provide more possibilities for the prevention and treatment of DTIs.

Response of anthocyanin biosynthesis to light by strand-specific transcriptome and miRNA analysis in Capsicum annuum.

BACKGROUND: Anthocyanins have distinct biological functions in plant coloring, plant defense against strong light, UV irradiation, and pathogen infection. Aromatic hydroxyl groups and ortho-dihydroxyl groups in anthocyanins are able to inhibit free-radical chain reactions and hydroxyl radicals. Thus, anthocyanins play an antioxidative role by removing various types of ROS. Pepper is one of the solanaceous vegetables with the largest cultivation area in China. The purple-fruited pepper is rich in anthocyanins, which not only increases the ornamental nature of the pepper fruit but also benefits the human body. In this experiment, light-induced regulatory pathways and related specific regulators of anthocyanin biosynthesis were examined through integrative transcriptomic and metabolomic analysis. RESULTS: Results revealed that delphinium 3-O-glucoside significantly accumulated in light exposed surface of pepper fruit after 48 h as compared to shaded surface. Furthermore, through strand-specific sequencing technology, 1341 differentially expressed genes, 172 differentially expressed lncRNAs, 8 differentially expressed circRNAs, and 28 differentially expressed miRNAs were identified significantly different among both surfaces. The flavonoid synthesis pathway was significantly enriched by KEGG analysis including SHT (XM_016684802.1), AT-like (XM_016704776.1), CCoAOMT (XM_016698340.1, XM_016698341.1), CHI (XM_016697794.1, XM_016697793.1), CHS2 (XM_016718139.1), CHS1B (XM_016710598.1), CYP98A2-like (XM_016688489.1), DFR (XM_016705224.1), F3'5'H (XM_016693437.1), F3H (XM_016705025.1), F3'M (XM_016707872.1), LDOX (XM_016712446.1), TCM (XM_016722116.1) and TCM-like (XM_016722117.1). Most of these significantly enriched flavonoid synthesis pathway genes may be also regulated by lncRNA. Some differentially expressed genes encoding transcription factors were also identified including MYB4-like (XM_016725242.1), MYB113-like (XM_016689220.1), MYB308-like (XM_016696983.1, XM_016702244.1), and EGL1 (XM_016711673.1). Three 'lncRNA-miRNA-mRNA' regulatory networks with sly-miR5303, stu-miR5303g, stu-miR7997a, and stu-miR7997c were constructed, including 28 differentially expressed mRNAs and 6 differentially expressed lncRNAs. CONCLUSION: Possible light regulated anthocyanin biosynthesis and transport genes were identified by transcriptome analysis, and confirmed by qRT-PCR. These results provide important data for further understanding of the anthocyanin metabolism in response to light in pepper.

Plant growth-promoting rhizobacterium Pseudomonas sp. CM11 specifically induces lateral roots.

Plant growth-promoting rhizobacteria are involved in altering secondary root (SR) formation, but hitherto there has been no distinction between the different types of SRs upon induction of soil biota, and the genetic pathways involved. By using plate and soil systems, we studied the effects of the Pseudomonas strains CM11 and WCS417 on plant performance with a focus on root development. Through a combination of cellular, molecular and genetic analyses, we investigated the type of SRs induced upon CM11 and WCS417 root inoculation using genetic pathways associated with specific SR types. CM11 was shown to affect the root architecture differently from WCS417. CM11 inoculation leads to primary root arrest, whereas WCS417 reveals a longer primary root. Both CM11 and WCS417 activate the PLETHORA 3,5,7-controlled lateral root pathway, rather than the WUSCHEL-RELATED HOMEOBOX 11,12-controlled adventitious (lateral) root pathway. In addition, CM11 promotes plant growth in model and various crop species. It improves plant fitness traits, such as bigger shoots, faster bolting and higher yield in terms of seeds. Our results indicate that the root system architecture can be promoted by activation of PLETHORA 3,5,7 dependent primed lateral pre-branch sites upon inoculation with CM11, which creates great potential to gain a better understanding of root plasticity.

SKLB-14b, a novel oral microtubule-destabilizing agent based on hydroxamic acid with potent anti-tumor and anti-multidrug resistance activities.

A hydroxamic acid based microtubule-destabilizing agent (MDA) SKLB-14b was discovered in this study, which was derived from shortening the linker length of the HDAC6 and microtubule dual-target inhibitor SKLB-23bb. SKLB-14b exhibited low nanomolar IC50 values on a wide spectrum of human cancer cell lines including both sensitive and multidrug-resistant cell lines. Surprisingly, its anti-proliferative activity relied on the presence of the hydroxamic acid group but lost inhibitory activity against HDACs. SKLB-14b bound to the colchicine site of tubulin and could inhibit tubulin polymerization. It exhibited good metabolic stability in liver microsomes, no inhibitory effect on CYP450 isoenzymes and high oral bioavailability. In vivo experiments revealed that SKLB-14b was potent in both sensitive (A2780S, HCT116) and resistant (A2780/T) xenograft mice models. Furthermore, in the patient-derived tumor xenograft (PDX) models of osimertinib resistant non-small cell lung cancer (NSCLC), 50 mg/kg of SKLB-14b administered every twodays inhibited tumor growth by 70.6% without obvious toxicity, better than the 59.7% inhibition rate of paclitaxel. Mechanistically, we found that SKLB-14b exerted anti-tumor and anti-multidrug resistance effects in vitro and in vivo through cell cycle arrest and pro-apoptotic activities, as well as vascular disrupting activities. Therefore, we discovered that SKLB-14b, as a novel MDA based on hydroxamic acid, could serve as a potential drug candidate for cancer therapy which deserves further investigation.

Synthesis and biological evaluation of 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives as novel dual FLT3/CDK4 inhibitors.

FMS-like tyrosine kinase-3 (FLT3) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been proven to play a significant role in tumor therapy. Herein, based on the previously reported JAK2/FLT3 inhibitor 18e, we described the synthesis, structure-activity relationship and biological evaluation of a series of unique 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives that inhibited FLT3 and CDK4 kinases. The optimized compound 23k exhibited low nanomolar range activities with IC50 values of 11 and 7 nM for FLT3 and CDK4, respectively. In the MV4-11 xenograft tumor model, the tumor growth inhibition rate of 23k dosed at 200 mg/kg was 67%, suggesting that 23k possessed an antitumor therapeutic effect.

Establishment of an in vitro safety assessment model for lipid-lowering drugs using same-origin human pluripotent stem cell-derived cardiomyocytes and endothelial cells.

Cardiovascular safety assessment is vital for drug development, yet human cardiovascular cell models are lacking. In vitro mass-generated human pluripotent stem cell (hPSC)-derived cardiovascular cells are a suitable cell model for preclinical cardiovascular safety evaluations. In this study, we established a preclinical toxicology model using same-origin hPSC-differentiated cardiomyocytes (hPSC-CMs) and endothelial cells (hPSC-ECs). For validation of this cell model, alirocumab, a human antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), was selected as an emerging safe lipid-lowering drug; atorvastatin, a common statin (the most effective type of lipid-lowering drug), was used as a drug with reported side effects at high concentrations, while doxorubicin was chosen as a positive cardiotoxic drug. The cytotoxicity of these drugs was assessed using CCK8, ATP, and lactate dehydrogenase release assays at 24, 48, and 72 h. The influences of these drugs on cardiomyocyte electrophysiology were detected using the patch-clamp technique, while their effects on endothelial function were determined by tube formation and Dil-acetylated low-density lipoprotein (Dil-Ac-LDL) uptake assays. We showed that alirocumab did not affect the cell viability or cardiomyocyte electrophysiology in agreement with the clinical results. Atorvastatin (5-50 µM) dose-dependently decreased cardiovascular cell viability over time, and at a high concentration (50 µM, ~100 times the normal peak serum concentration in clinic), it affected the action potentials of hPSC-CMs and damaged tube formation and Dil-Ac-LDL uptake of hPSC-ECs. The results demonstrate that the established same-origin hPSC-derived cardiovascular cell model can be used to evaluate lipid-lowering drug safety in cardiovascular cells and allow highly accurate preclinical assessment of potential drugs.

Integrated Transcriptomic and Metabolomic Analyses of Cold-Tolerant and Cold-Sensitive Pepper Species Reveal Key Genes and Essential Metabolic Pathways Involved in Response to Cold Stress.

Cold stress, triggered by particularly low temperatures, is one of the most severe forms of abiotic stress in pepper plants and a major constraint to the global pepper industry, threatening crop production and food security. To acclimatize to extreme conditions, the plant undergoes numerous modifications, including genetic and metabolic modulations. A thorough study of both the genetic and metabolic alterations of plants in response to cold stress is vital to understanding and developing the cold stress resistance mechanism. This study implemented transcriptome and metabolome analyses to evaluate the cold stress response in cold-tolerant and cold-sensitive pepper species. The weighted gene co-expression network revealed three significant modules related to cold stress tolerance in Capsicum pubescens. We identified 17 commonly enriched genes among both species at different time points in 10 different comparisons, including the AP2 transcription factor, LRR receptor-like serine, hypersensitivity-related 4-like protein, and uncharacterized novel.295 and novel.6172 genes. A pathway enrichment analysis indicated that these DEGs were mainly associated with the MAPK signaling pathway, hormone signaling pathway, and primary and secondary metabolism. Additionally, 21 significantly differentially accumulated metabolites (DAMs) were identified in both species after 6 h of cold stress. A transcriptome and metabolome integrated analysis revealed that 54 genes correlated with metabolites enriched in five different pathways. Most genes and metabolites involved in carbohydrate metabolism, the TCA cycle, and flavonoid biosynthesis pathways were upregulated in cold-tolerant plants under cold stress. Together, the results of this study provide a comprehensive gene regulatory and metabolic network in response to cold stress and identified some key genes and metabolic pathways involved in pepper cold tolerance. This study lays a foundation for the functional characterization and development of pepper cultivars with improved cold tolerance.

Conferring BiVO4 Nanorods with Oxygen Vacancies to Realize Enhanced Sonodynamic Cancer Therapy.

Owing to the high depth of tissue penetration, non-invasiveness, and controllability, ultrasound (US)-mediated sonodynamic therapy (SDT) has shown broad application prospects for tumor treatment. However, the electron-hole separation inefficiency of sonosensitizers and the tumor hypoxia remain two major challenges limiting the effect of SDT. Here, ultrafine photoetched bismuth vanadate (BiVO4 ) nanorods modified with DSPE-PEG2000 (PEBVO@PEG NRs) were fabricated to achieve in situ self-supply of oxygen (O2 ) and reactive oxygen species (ROS) for hypoxic tumor therapy. The photoetching approach could enhance the charge separation by inducing enriched oxygen vacancies on the surface of BiVO4 , thereby improving the generation efficiency of ROS and O2 . The PEBVO@PEG overcome the main obstacles of traditional sonosensitizers in the SDT process and show promising sonodynamic therapeutic effects, thus providing new strategies for improving the performance of sonosensitizer and hypoxic tumor elimination.

From natural products to HDAC inhibitors: An overview of drug discovery and design strategy.

Histone deacetylases (HDACs) play a key role in the homeostasis of protein acetylation in histones and have recently emerged as a therapeutic target for numerous diseases. The inhibition of HDACs may block angiogenesis, arrest cell growth, and lead to differentiation and apoptosis in tumour cells. Thus, HDAC inhibitors (HDACi) have received increasing attention and many of which are developed from natural sources. In the past few decades, naturally occurring HDACi have been identified to have potent anticancer activities, some of which have demonstrated promising therapeutic effects on haematological malignancies. In this review, we summarized the discovery and modification of HDAC inhibitors from natural sources, novel drug design that uses natural products as parent nuclei, and dual target design strategies that combine HDAC with non-HDAC targets.

Degree of polymerization mapping Raman feature extraction of oil-paper insulation aging based on quadratic mutual information.

To assess the aging of oil-paper insulation, an accelerated aging experiment is executed. Raman spectroscopy, a nondestructive detection method with access to component identification and fault diagnosis, is used to analyze the aging of oil-paper insulation. Raman feature of oil-paper insulation aging with a close relationship with the degree of polymerization is obtained based on the concept of quadratic mutual information. By analyzing the relationship between the extracted feature and the degree of polymerization of samples at different aging degrees, the feasibility of reflecting the aging degree of oil-paper insulation is determined. By load analysis, the chemical correlation between the extracted feature and oil-paper insulation aging is clarified. For eight test samples, the prediction error of degree of polymerization based on Raman features is less than 50. These results show that the features extracted in this paper are helpful to realizing the Raman spectrum diagnosis of oil-paper insulation aging.