Investigation of the drug-drug interaction and incompatibility mechanism between Aconitum carmichaelii Debx and Pinellia ternata (Thunb.) Breit.

ETHNOPHARMACOLOGICAL RELEVANCE: The combination of Aconitum carmichaelii Debx (Chuanwu, CW) and Pinellia ternata (Thunb.) Breit (Banxia, BX) forms an herbal pair within the eighteen incompatible medicaments (EIM), indicating that BX and CW are incompatible. However, the scientific understanding of this incompatibility mechanism, especially the corresponding drug-drug interaction (DDI), remains complex and unclear. AIM OF THE STUDY: This study aims to explain the DDI and potential incompatibility mechanism between CW and BX based on pharmacokinetics and cocktail approach. MATERIALS AND METHODS: Ultraperformance liquid chromatography-tandem mass spectrometry methods were established for pharmacokinetics and cocktail studies. To explore the DDI between BX and CW, in the pharmacokinetics study, 10 compounds were determined in rat plasma after administering CW and BX-CW herbal pair extracts. In the cocktail assay, the pharmacokinetic parameters of five probe substrates were utilized to assess the influence of BX on cytochrome P450 (CYP) isoenzyme (dapsone for CYP3A4, phenacetin for CYP1A2, dextromethorphan for CYP2D6, tolbutamide for CYP2C9, and omeprazole for CYP2C19). Finally, the DDI and incompatibility mechanism of CW and BX were integrated to explain the rationality of EIM theory. RESULTS: BX not only enhances the absorption of aconitine and benzoylaconine but also accelerates the metabolism of mesaconitine, benzoylmesaconine, songorine, and fuziline. Moreover, BX affects the activity of CYP enzymes, which regulate the metabolism of toxic compounds. CONCLUSIONS: BX altered the activity of CYP enzymes, consequently affecting the metabolism of toxic compounds from CW. This incompatibility mechanism may be related to the increased absorption of these toxic compounds in vivo.

Stability mechanism of Monascus pigment-soy protein isolate-maltodextrin complex.

BACKGROUND: Monascus pigment (MP) is a natural food coloring with vital physiological functions but prone to degradation and color fading under light conditions. RESULTS: This study investigated the effect of complex formation of soybean protein isolate (SPI), maltodextrin (MD), and MP on the photostability of MP. Light stability was assessed through retention rate and color difference. Fluorescence spectroscopy (FS), circular dichroism (CD), Fourier-transform infrared (FTIR) spectroscopy, and X-ray diffraction (XRD) explored MP, SPI, and MD interactions, clarifying the MP-SPI-MD complex mechanism on the light stability of MP. Microstructure and differential scanning calorimetry (DSC) analyzed the morphology and thermal properties. The retention rate of MP increased to approximately 80%, and minimal color difference was observed when adding SPI and MD simultaneously. FS revealed hydrophobic interaction between MP and SPI. FTIR analysis showed intensity changes and peak shifts in amide I band and amide II band, which proved the hydrophobic interaction. CD showed a decrease in α-helix content and an increase in ß-sheet content after complex formation, indicating strengthened hydrogen bonding interactions. Scanning electron microscopy (SEM) analysis demonstrated that MP was attached to the surface and interior of complexes. XRD showed MP as crystalline, while SPI and MD were amorphous, complexes exhibited weakened or absent peaks, suggesting MP encapsulation. The results of DSC were consistent with XRD. CONCLUSION: SPI and MD enveloped MP through hydrogen bonding and hydrophobic interaction, ultimately enhancing its light stability and providing insights for pigment-protein-polysaccharide interactions and improving pigment stability in the food industry. © 2024 Society of Chemical Industry.

Gender associations between phthalate exposure and biomarkers of oxidative stress: A prospective cohort study.

Previous epidemiologic research has shown that phthalate exposure in pregnant women is related to adverse birth outcomes in a sex-specific manner. However, the biological mechanism of phthalate exposure that causes these birth outcomes remains poorly defined. In this research, we investigated the association between phthalate exposure and placental oxidative stress in a large population-based cohort study, aiming to initially explore the relationship between phthalate exposure and gene expression in placental oxidative stress in a sex-specific manner. Quantitative PCR was performed to measure the expression of placental inflammatory mRNAs (HO-1, HIF1α, and GRP78) in 2469 placentae. The multiple linear regression models were used to investigate the associations between mRNA and urinary phthalate monoesters. Phthalate metabolites monomethyl phthalate (MMP) and mono-n-butyl phthalate (MBP) were positively correlated with higher HIF1α expression in placentae of male fetuses (p < .05). Mono-benzyl phthalate (MBzP) increased the expression of HO-1, HIF1α, and GRP78 in placentae of male fetuses, and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) up-regulated the expression of HIF1α and GRP78. Additionally, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively correlated with HO-1, HIF1α, and GRP78 in placentae of female fetuses. Maternal phthalate exposure was associated with oxidative stress variations in placental tissues. The associations were closer in the placentas of male fetuses than in that of female ones. The placenta oxidative stress is worth further investigation as a potential mediator of maternal exposure-induced disease risk in children.

Single-embryo transcriptomic atlas of oxygen response reveals the critical role of HIF-1α in prompting embryonic zygotic genome activation.

Adaptive response to physiological oxygen levels (physO2; 5% O2) enables embryonic survival in a low-oxygen developmental environment. However, the mechanism underlying the role of physO2 in supporting preimplantation development, remains elusive. Here, we systematically studied oxygen responses of hallmark events in preimplantation development. Focusing on impeded transcriptional upregulation under atmospheric oxygen levels (atmosO2; 20% O2) during the 2-cell stage, we functionally identified a novel role of HIF-1α in promoting major zygotic genome activation by serving as an oxygen-sensitive transcription factor. Moreover, during blastocyst formation, atmosO2 impeded H3K4me3 and H3K27me3 deposition by deregulating histone-lysine methyltransferases, thus impairing X-chromosome inactivation in blastocysts. In addition, we found atmosO2 impedes metabolic shift to glycolysis before blastocyst formation, thus resulting a low-level histone lactylation deposition. Notably, we also reported an increased sex-dimorphic oxygen response of embryos upon preimplantation development. Together, focusing on genetic and epigenetic events that are essential for embryonic survival and development, the present study advances current knowledge of embryonic adaptive responses to physO2, and provides novel insight into mechanism underlying irreversibly impaired developmental potential due to a short-term atmosO2 exposure.

Causal effects of glycemic traits and endometriosis: a bidirectional and multivariate mendelian randomization study.

BACKGROUND: Observational studies have suggested an association between endometriosis and glycemic traits, but causality remains unclear. We used bidirectional and multivariate Mendelian randomization (MR) to examine the causal effect of glycemic traits on endometriosis and vice versa. METHODS: We obtained genome-wide association studies summary data of endometriosis and glycemic traits in our study. Inverse variance weighted (IVW), Weighted median, MR-Egger and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) were applied in bidirectional two-sample MR analyses. MVMR was implemented to estimate the causal effect for fasting insulin (FI), fasting glucose (FG), and glycosylated hemoglobin A1c (HbA1c) on endometriosis. To test the validity of our findings, a number of sensitivity analyses were conducted. RESULTS: The risk of endometriosis was significantly increased by genetically predicted T1DM (OR = 1.02, 95% CI 1.00-1.04, p = 0.0171, q = 0.0556) and GDM (OR = 1.01, 95% CI 1.01-1.02, p = 1.34 × 10- 8, q = 1.74 × 10- 7). Endometriosis had a suggestive association with HbA1c (Beta = 0.04, 95% CI 0.00-0.08, p = 0.0481, q = 0.1251). Using multivariate Mendelian randomization (MVMR), a significant causal effect of FI on genetically predicted endometriosis was found (OR = 2.18, 95% CI 1.16-4.09, p = 0.0154, q = 0.0547). Moreover, no causal associations between endometriosis and other glycemic traits were detected. CONCLUSION: Our findings supported the significant causal associations of T1DM, GDM and FI with endometriosis, respectively. Additionally, a suggestive association was found of endometriosis on HbA1c. Importantly, our study may shed light on etiology studies and clinical management of endometriosis.

Comparative Analysis of the Chloroplast Genomes of Eight Species of the Genus Lirianthe Spach with Its Generic Delimitation Implications.

Based on Sima and Lu's system of the family Magnoliaceae, the genus Lirianthe Spach s. l. includes approximately 25 species, each with exceptional landscaping and horticultural or medical worth. Many of these plants are considered rare and are protected due to their endangered status. The limited knowledge of species within this genus and the absence of research on its chloroplast genome have greatly impeded studies on the relationship between its evolution and systematics. In this study, the chloroplast genomes of eight species from the genus Lirianthe were sequenced and analyzed, and their phylogenetic relationships with other genera of the family Magnoliaceae were also elucidated. The results showed that the chloroplast genome sizes of the eight Lirianthe species ranged from 159,548 to 159,833 bp. The genomes consisted of a large single-copy region, a small single-copy region, and a pair of inverted repeat sequences. The GC content was very similar across species. Gene annotation revealed that the chloroplast genomes contained 85 protein-coding genes, 37 tRNA genes, and 8 rRNA genes, totaling 130 genes. Codon usage analysis indicated that codon usage was highly conserved among the eight Lirianthe species. Repeat sequence analysis identified 42-49 microsatellite sequences, 16-18 tandem repeats, and 50 dispersed repeats, with microsatellite sequences being predominantly single-nucleotide repeats. DNA polymorphism analysis revealed 10 highly variable regions located in the large single-copy and small single-copy regions, among which rpl32-trnL, petA-psbJ, and trnH-psbA were the recommended candidate DNA barcodes for the genus Lirianthe species. The inverted repeat boundary regions show little variation between species and are generally conserved. The result of phylogenetic analysis confirmed that the genus Lirianthe s. l. is a monophyletic taxon and the most affinal to the genera, Talauma and Dugandiodendron, in Sima and Lu's system and revealed that the genus Lirianthe s. s. is paraphyletic and the genus Talauma s. l. polyphyletic in Xia's system, while Magnolia subsection Gwillimia is paraphyletic and subsection Blumiana polyphyletic in Figlar and Nooteboom's system. Morphological studies found noticeable differences between Lirianthe species in aspects including leaf indumentum, stipule scars, floral orientation, tepal number, tepal texture, and fruit dehiscence. In summary, this study elucidated the chloroplast genome evolution within Lirianthe and laid a foundation for further systematic and taxonomic research on this genus.

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Long-term occupation of coal gangue dumping sites (CGDS) may destroy ecological environment of nearby area. However, how the CGDS affects the distribution pattern of soil seed banks and vegetation in the nearby area is not clear. In this study, we investigated soil seed bank and vegetation at different distances from the second CGDS of Yangchangwan in Ningdong mining area, Lingwu, Ningxia. The results showed that soil seed bank was mainly distributed in 0-10 cm layer and decreased with increasing soil depth. Species richness of soil seed bank and vegetation first increased and then tended to be stable with increasing distance to the CGDS. The influence range of CGDS on soil seed banks was 300-500 m and was 100-300 m on aboveground vegetation. The CGDS did not affect the vertical distribution pattern of soil seed bank, but significantly affected the horizontal distribution pattern of soil seed banks and aboveground vegetation. The key area of vegetation restoration around the CGDS was between 100 m and 300 m.

Circ-Bptf Ameliorates Learning and Memory Impairments via the miR-138-5p/p62 Axis in APP/PS1 Mice.

Alzheimer's disease (AD) is a common age-associated progressive neurodegenerative disorder that is implicated in the aberrant regulation of numerous circular RNAs (circRNAs). Here, we reported that circ-Bptf, a conserved circRNA derived from the Bptf gene, showed an age-dependent decrease in the hippocampus of APP/PS1 mice. Overexpression of circ-Bptf significantly reversed dendritic spine loss and learning and memory impairment in APP/PS1 mice. Moreover, we found that circ-Bptf was predominantly localized to the cytoplasm and upregulated p62 expression by binding to miR-138-5p. Furthermore, the miR-138-5p mimics reversed the decreased expression of p62 induced by the silencing of circ-Bptf. Together, our findings suggested that circ-Bptf ameliorated learning and memory impairments via the miR-138-5p/p62 axis in APP/PS1 mice. It may act as a potential player in AD pathogenesis and therapy.

Reciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer.

Squamous cell carcinomas (SCCs) are common and aggressive malignancies. Immune check point blockade (ICB) therapy using PD-1/PD-L1 antibodies has been approved in several types of advanced SCCs. However, low response rate and treatment resistance are common. Improving the efficacy of ICB therapy requires better understanding of the mechanism of immune evasion. Here, we identify that the SCC-master transcription factor TP63 suppresses interferon-γ (IFNγ) signaling. TP63 inhibition leads to increased CD8+ T cell infiltration and heighten tumor killing in in vivo syngeneic mouse model and ex vivo co-culture system, respectively. Moreover, expression of TP63 is negatively correlated with CD8+ T cell infiltration and activation in patients with SCC. Silencing of TP63 enhances the anti-tumor efficacy of PD-1 blockade by promoting CD8+ T cell infiltration and functionality. Mechanistically, TP63 and STAT1 mutually suppress each other to regulate the IFNγ signaling by co-occupying and co-regulating their own promoters and enhancers. Together, our findings elucidate a tumor-extrinsic function of TP63 in promoting immune evasion of SCC cells. Over-expression of TP63 may serve as a biomarker predicting the outcome of SCC patients treated with ICB therapy, and targeting TP63/STAT/IFNγ axis may enhance the efficacy of ICB therapy for this deadly cancer.

A dual computational and experimental strategy to enhance TSLP antibody affinity for improved asthma treatment.

Thymic stromal lymphopoietin is a key cytokine involved in the pathogenesis of asthma and other allergic diseases. Targeting TSLP and its signaling pathways is increasingly recognized as an effective strategy for asthma treatment. This study focused on enhancing the affinity of the T6 antibody, which specifically targets TSLP, by integrating computational and experimental methods. The initial affinity of the T6 antibody for TSLP was lower than the benchmark antibody AMG157. To improve this, we utilized alanine scanning, molecular docking, and computational tools including mCSM-PPI2 and GEO-PPI to identify critical amino acid residues for site-directed mutagenesis. Subsequent mutations and experimental validations resulted in an antibody with significantly enhanced blocking capacity against TSLP. Our findings demonstrate the potential of computer-assisted techniques in expediting antibody affinity maturation, thereby reducing both the time and cost of experiments. The integration of computational methods with experimental approaches holds great promise for the development of targeted therapeutic antibodies for TSLP-related diseases.

Spatial Visual Imagery (SVI)-Based Electroencephalograph Discrimination for Natural CAD Manipulation.

With the increasing demand for natural interactions, people have realized that an intuitive Computer-Aided Design (CAD) interaction mode can reduce the complexity of CAD operation and improve the design experience. Although interaction modes like gaze and gesture are compatible with some complex CAD manipulations, they still require people to express their design intentions physically. The brain contains design intentions implicitly and controls the corresponding body parts that execute the task. Therefore, building an end-to-end channel between the brain and computer as an auxiliary mode for CAD manipulation will allow people to send design intentions mentally and make their interaction more intuitive. This work focuses on the 1-D translation scene and studies a spatial visual imagery (SVI) paradigm to provide theoretical support for building an electroencephalograph (EEG)-based brain-computer interface (BCI) for CAD manipulation. Based on the analysis of three spatial EEG features related to SVI (e.g., common spatial patterns, cross-correlation, and coherence), a multi-feature fusion-based discrimination model was built for SVI. The average accuracy of the intent discrimination of 10 subjects was 86%, and the highest accuracy was 93%. The method proposed was verified to be feasible for discriminating the intentions of CAD object translation with good classification performance. This work further proves the potential of BCI in natural CAD manipulation.

Electronic structure and magnetothermal properties of two-dimensional ScCl.

Two-dimensional ferromagnetic materials with intrinsic half-metallic properties have strong application advantages in nanoscale spintronics. Herein, density functional theory calculations show that monolayer ScCl is a ferromagnetic metallic material when undoped (n = 0), and the transition from metal to half-metal occurs with the continuous doping of holes. On the contrary, as the concentration of doped electrons increases, the system will exhibit metallic characteristics, which is particularly evident from a variation in spin polarizability. Furthermore, we have discussed how doped carriers affect the shape of the Fermi surface and the Fermi velocity of electrons. Most importantly, Monte Carlo simulations show that the ScCl monolayer is particularly regulated by carrier concentration (n) and magnetic field (h). Additionally, trends in energy and magnetic exchange coupling in different magnetic configurations (AFM phase and FM phase) with different doping concentrations are presented. When n < -0.16, the material is not only a half-metallic material that easily flips the magnetic axis, but also proves to be a candidate ferromagnetic material that works stably at room temperature in terms of dynamic stability. In addition, the origin of magnetocrystalline anisotropy is analyzed, and the contribution of different orbitals to spin-orbit coupling is presented. Moreover, we note that when magnetic field is small (h < 1 T), the change in size has a significant effect on ferromagnetic phase transition. However, when the system size is large (size >15 nm), TC is less sensitive to magnetic field. In addition, hole doping and size effect will greatly affect the hC of the system, but when the hole doping exceeds the critical value (n = -0.16), its influence on the hysteresis loop is no longer obvious. These interesting magnetic phenomena and easily adjustable physical properties show us that monolayer ScCl will be a promising functional material.

Natural compound library screening to identify berberine as a treatment for rheumatoid arthritis.

OBJECTIVE: Fibroblast-like synoviocytes (FLS) play a critical role on the exacerbation and deterioration of rheumatoid arthritis (RA). Aberrant activation of FLS pyroptosis signaling is responsible for the hyperplasia of synovium and destruction of cartilage of RA. This study investigated the screened traditional Chinese medicine berberine (BBR), an active alkaloid extracted from the Coptis chinensis plant, that regulates the pyroptosis of FLS and secretion of inflammatory factors in rheumatoid arthritis. METHODS: First, BBR was screened using a high-throughput drug screening strategy, and its inhibitory effect on RA-FLS was verified by in vivo and in vitro experiments. Second, BBR was intraperitoneally administrated into the collagen-induced arthritis rat model, and the clinical scores, arthritis index, and joint HE staining were evaluated. Third, synovial tissues of CIA mice were collected, and the expression of NLRP3, cleaved-caspase-1, GSDMD-N, Mst1, and YAP was detected by Western blot. RESULTS: The administration of BBR dramatically alleviated the severity of collagen-induced arthritis rat model with a decreased clinical score and inflammation reduction. In addition, BBR intervention significantly attenuates several pro-inflammatory cytokines (interleukin-1ß, interleukin-6, interleukin-17, and interleukin-18). Moreover, BBR can reduce the pyroptosis response (caspase-1, NLR family pyrin domain containing 3, and gasdermin D) of the RA-FLS in vitro, activating the Hippo signaling pathway (Mammalian sterile 20-like kinase 1, yes-associated protein, and transcriptional enhanced associate domains) so as to inhibit the pro-inflammatory effect of RA-FLS. CONCLUSION: These results support the role of BBR in RA and may have therapeutic implications by directly repressing the activation, migration of RA-FLS, which contributing to the attenuation of the progress of CIA. Therefore, targeting PU.1 might be a potential therapeutic approach for RA. Besides, BBR inhibited RA-FLS pyroptosis by downregulating of NLRP3 inflammasomes (NLRP3, caspase-1) and eased the pro-inflammatory activities via activating the Hippo signaling pathway, thereby improving the symptom of CIA.

Tenascin-C as a potential biomarker and therapeutic target for esophageal squamous cell carcinoma.

PURPOSE: To establish a prognostic model of esophageal squamous cell carcinoma (ESCC) patients based on tenascin-C (TNC) expression level and clinicopathological characteristics, and to explore the therapeutic potential of TNC inhibition. METHODS: The expression of TNC was detected using immunohistochemistry (IHC) in 326 ESCC specimens and 50 normal esophageal tissues. Prognostic factors were determined by Cox regression analyses and were incorporated to establish the nomogram. The effects of TNC knockdown on ESCC cells were assessed in vitro and in vivo. Transcriptome sequencing (RNA-seq) and gene set enrichment analysis (GSEA) were performed to reveal signaling pathways regulated by TNC knockdown. The therapeutic significance of TNC knockdown combined with small-molecule inhibitors on cell proliferation was examined. RESULTS: TNC protein was highly expressed in 48.77 % of ESCC tissues compared to only 2 % in normal esophageal epithelia (p < 0.001). The established nomogram model, based on TNC expression, pT stage, and lymph node metastasis, showed good performance on prognosis evaluation. More importantly, the reduction of TNC expression inhibited tumor cell proliferation and xenograft growth, and mainly down-regulated signaling pathways involved in tumor growth, hypoxia signaling transduction, metabolism, infection, etc. Knockdown of TNC enhanced the inhibitory effect of inhibitors targeting ErbB, PI3K-Akt, Ras and MAPK signaling pathways. CONCLUSION: The established nomogram may be a promising model for survival prediction in ESCC. Reducing TNC expression enhanced the sensitivity of ESCC cells to inhibitors of Epidermal Growth Factor Receptor (EGFR) and downstream signaling pathways, providing a novel combination therapy strategy.

Nuclear-cytoplasmic translocation of SQSTM1/p62 protein enhances ESCC cell migration and invasion by stabilizing EPLIN expression.

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignant disease with a poor prognosis. We previously found that p62 presented a marked nuclear-cytoplasmic translocation in ESCC cells as compared that in normal esophageal epithelial cells, but its effects on ESCC cells remain unclear. This study aims to clarify the impacts of different cellular localization of p62 on the function of ESCC cells and the underlying molecular mechanisms. We here demonstrated that cytoplasmic p62 enhances the migration and invasion abilities of esophageal cancer cells, whereas nuclear p62 has no effect. We further explored the interaction protein of p62 by using GST pull-down experiment and identified EPLIN as a potential protein interacting with p62. In addition, reducing EPLIN expression significantly inhibited the migration and invasion of ESCC cells, which were rescued when EPLIN expression was restored after the p62 knockdown. At a molecular level, p62 in cytoplasm positively regulated the expression of EPLIN via enhancing its protein stability. Data from the TCGA and GEO database displayed a significant up-regulation of EPLIN mRNA expression in ESCC tissues compared with corresponding paired esophageal epithelial samples. Our findings present evidence that the nuclear-cytoplasmic translocation of p62 protein contributes to an aggressive malignancy phenotype, providing candidate molecular biomarkers and potential molecular targets for the diagnosis and treatment of ESCC.

Geniposide improves depression-like behavior in prenatal stress male offspring through restoring HPA axis- and glucocorticoid receptor-associated dysfunction.

AIMS: Prenatal stress (PS) has an important impact on the brain development of offspring, which can lead to attention deficits, anxiety and depression in offspring. Geniposide (GE) is a kind of iridoid glycoside extracted from Gardenia jasminoides Ellis. It has various pharmacological effects and has been proved that have antidepressant effects. The aim of this study was to investigate the effect of GE on depression-like behavior in PS-induced male offspring mice and explore the possible molecular mechanisms. METHODS: We used a prenatal restraint stress model, focusing on male PS-induced offspring mice to study the effects of GE. KEY FINDINGS: The results showed that GE administration for 4 weeks significantly improved the depression-like behavior in PS offspring mice, which was manifested by markedly increasing the sucrose preference of PS offspring and the activity in the open field test, and reducing the immobility time in the forced swimming test. In addition, GE significantly reduced the levels of hypothalamic-pituitary-adrenal (HPA) axis-related hormones and exceedingly increased the protein expression of MAP2 and GAP43 in PS offspring. Furthermore, GE increased Glucocorticoid receptors (GR) nuclear translocation in the hippocampus of PS offspring, and enhanced the expression of synaptic plasticity-related proteins. CONCLUSION: The results of this study showed that GE exerts antidepressant effects in male PS offspring mice by regulating the HPA axis, GR function and proteins related to synaptic plasticity.

Characterization of Four Complete Mitogenomes of Monolepta Species and Their Related Phylogenetic Implications.

Monolepta is one of the diverse genera in the subfamily Galerucinae, including 708 species and 6 sub-species worldwide. To explore the information on the mitogenome characteristics and phylogeny of the section "Monoleptites", especially the genus Monolepta, we obtained the newly completed mitochondrial genomes (mitogenomes) of four Monolepta species using high-throughput sequencing technology. The lengths of these four new mitochondrial genomes are 16,672 bp, 16,965 bp, 16,012 bp, and 15,866 bp in size, respectively. All four mitochondrial genomes include 22 transfer RNA genes (tRNAs), 13 protein-coding genes (PCGs), 2 ribosomal RNA genes (rRNAs), and one control region, which is consistent with other Coleoptera. The results of the nonsynonymous with synonymous substitution rates showed that ND6 had the highest evolution rate, while COI displayed the lowest evolution rate. The substitution saturation of three datasets (13 PCGs_codon1, 13 PCGs_codon2, 13 PCGs_codon3) showed that there was no saturation across all datasets. Phylogenetic analyses based on three datasets (ND1, 15 genes of mitogenomes, and 13 PCGs_AA) were carried out using maximum likelihood (ML) and Bayesian inference (BI) methods. The results showed that mitogenomes had a greater capacity to resolve the main clades than the ND1 gene at the suprageneric and species levels. The section "Monoleptites" was proven to be a monophyletic group, while Monolepta was a non-monophyletic group. Based on ND1 data, the newly sequenced species whose antennal segment 2 was shorter than 3 were split into several clades, while, based on the mitogenomic dataset, the four newly sequenced species had close relationships with Paleosepharia. The species whose antennal segment 2 was as long as 3 were split into two clades, which indicated that the characteristic of "antennal segment 2 as long as 3" of the true "Monolepta" evolved multiple times in several subgroups. Therefore, to explore the relationships among the true Monolepta, the most important thing is to perform a thorough revision of Monolepta and related genera in the future.

Folic acid-coupled bovine serum albumin-modified magnetic nanocomposites from quantum-sized Fe3O4 and layered double hydroxide for actively targeted delivery of 5-fluorouracil.

The development of multifunctional magnetic nanocomposites as a drug delivery system for cancer therapy is highly desirable in current nanomedicine. Herein, folic acid-bovine serum albumin conjugate (FA-BSA) was modified on nanocomposites by combining quantum-sized Fe3O4 and layered double hydroxide (LDH) to obtain a novel FA-BSA/Fe3O4@LDH for the delivery of the anticancer drug 5-Fluorouracil (5-Fu). The prepared nanocomposites showed good dispersibility, colloidal stability, magnetic property and erythrocyte compatibility. FA-BSA/Fe3O4@LDH/5-Fu showed pH responsiveness, with both the amount and duration of release of FA-BSA/Fe3O4@LDH/5-Fu being significantly higher in pH 5.0 release medium than in pH 7.4 release medium. The cellular experiments implied that no significant cytotoxicity of FA-BSA/Fe3O4@LDH, particularly due to the presence of FA-BSA, which further enhanced the biocompatibility of the nanocomposite. Furthermore, FA-BSA/Fe3O4@LDH/5-Fu could specifically target the 2D HepG2 cells model and 3D hepatoma cell microspheres model in vitro, and efficient internalization through folate receptor-mediated endocytosis, showing excellent anti-cancer cell activity in a concentration-dependent manner. Therefore, the constructed FA-BSA/Fe3O4@LDH was able to provide a potential novel multifunctional nanocomposite for magnetic-targeting drug delivery and pH-responsive release of drugs to enhance the efficiency of cancer therapy.

Ectopic Expression of a Truncated Isoform of Hair Keratin 81 in Breast Cancer Alters Biophysical Characteristics to Promote Metastatic Propensity.

Keratins are an integral part of cell structure and function. Here, it is shown that ectopic expression of a truncated isoform of keratin 81 (tKRT81) in breast cancer is upregulated in metastatic lesions compared to primary tumors and patient-derived circulating tumor cells, and is associated with more aggressive subtypes. tKRT81 physically interacts with keratin 18 (KRT18) and leads to changes in the cytosolic keratin intermediate filament network and desmosomal plaque formation. These structural changes are associated with a softer, more elastically deformable cancer cell with enhanced adhesion and clustering ability leading to greater in vivo lung metastatic burden. This work describes a novel biomechanical mechanism by which tKRT81 promotes metastasis, highlighting the importance of the biophysical characteristics of tumor cells.

Nitrogenous compounds from Aesculus wilsonii seeds.

Eight nitrogenous compounds including five undescribed ones, aeswilnitrousol A (1), aeswilnitrousosides BD (2-4), and 6-(2-hydroxy-3-methylbutylamino)-8-oxoadenine (5) were isolated from the seeds of Aesculus wilsonii. Their structures and absolute configurations were established based on spectroscopic determination, calculated electronic circular dichroism (ECD) analysis, as well as chemical reaction methods. Among the three known compounds, 7 and 8 were obtained from the Aesculus genus for the first time, and 6 was gained from this plant initially. The 13C NMR data of 7 and 8 were reported for the first time. Moreover, the inhibitory effect of all the isolates against LPS-induced nitric oxide production in RAW264.7 macrophages was evaluated. As a result, compounds 2 and 8 exhibited anti-inflammatory activity in a concentration-dependent manner at 10, 25, and 50 µM.