"Cave Effect" Induces Self-Assembled Bimetallic Hollow Structure for Three-in-One Lateral Flow Immunoassay.

Bimetallic hollow structures have attracted much attention due to their unique properties, but they still face the problems of nonuniform alloys and excessive etching leading to structural collapse. Here, uniform bimetallic hollow nanospheres are constructed by pore engineering and then highly loaded with hemin (Hemin@MOF). Interestingly, in the presence of polydopamine (PDA), the competitive coordination between anionic polymer (γ-PGA) and dimethylimidazole does not lead to the collapse of the external framework but self-assembly into a hollow structure. By constructing the Hemin@MOF immune platform and using E. coli O157:H7 as the detection object, we find that the visual detection limits can reach 10, 3, and 3 CFU/mL in colorimetric, photothermal, and catalytic modes, which is 4 orders of magnitude lower than the traditional gold standard. This study provides a new idea for the morphological modification of the metal-organic skeleton and multifunctional immunochromatography detection.

Unveil the mechanism for EHMT -- A novel triterpenoid inhibits proliferation and induces apoptosis in colon cancer through ROS-mediated JNK signaling pathway.

Colon cancer ranks among the most prevalent malignancies worldwide, trailing only lung and breast cancer in incidence. Despite the availability of numerous therapeutic strategies, the burden of new cases and fatalities remains high in countries undergoing socioeconomic transitions. Natural products offer promising avenues for developing more effective and less toxic anticancer agents, expanding the clinical arsenal. In this investigation, we isolated a triterpenoid, (21 S,23 R,24 R)-21,23-epoxy-24-hydroxy-21-methoxytirucalla-7,25-dien-3-one (EHMT), from the fruits of Melia azedarach L., which exhibited significant inhibitory activity against colon cancer cells while sparing normal cells. EHMT effectively curtailed colony formation and induced apoptosis and cell cycle arrest in the HCT116 cell line. Furthermore, EHMT prompted the generation of reactive oxygen species (ROS) and the depolarization of mitochondrial membrane potential. Notably, EHMT treatment triggered ROS-mediated cell apoptosis via activation of the JNK signaling pathway in HCT116 cells. Additionally, our findings extended to Caenorhabditis elegans, where EHMT induced ROS accumulation and apoptosis. Collectively, these findings position EHMT as a promising candidate for the development of anticancer agents in the treatment of colon cancer, offering new hope in the battle against this formidable disease.

Tunable Fano resonance with an ultra-wide free spectral range from a photonic integrated circuit.

In this paper, a reconfigurable photonic integrated circuit that can produce various resonances is proposed and demonstrated. Particularly, it can generate a high performance Fano resonance with an ultra-wide free-spectral range. Moreover, the extinction ratio, slope rate, and center wavelength of the Fano resonance are tunable using integrated phase shifters. This work paves the way towards a variety of new applications, including low threshold lasers, low power consumption modulators, and high sensitivity sensors.

Formic Acid-Regulated Defect Engineering in Zr-Based Metal-Organic Frameworks toward Fluorescence Sensor for Sensitive Detection of Chlortetracycline.

The elaborate defect-engineering of luminescent metal-organic frameworks (MOFs) allows them with enhanced sensing performance. A modulator-induced defect formation strategy is adopted in this paper, and the impact of the open-metal sites on sensing process is rationalized. It is demonstrated that the defect level can be tuned to a remarkable extent by controlling the amount of modulator. When a particular defect concentration is reached, the UiO-66-xFA can be acted as highly sensitive ratiometric fluorescence probes for chlortetracycline (CTE) determination with an ultralow detection limit of 9.9 nm. Furthermore, by virtue of the obvious variation in fluorescence chromaticity of probes from blue to yellow, a sensory hydrogels-based smartphone platform is proposed for visible quantitation of CTE by identifying the RGB values. A delicate device integrated with UV lamp and dark cavity has been developed for avoiding inconsistencies of ambient light and visual errors. Finally, the sensor obtains satisfactory results in the detection of actual seafood samples, with no significant differences from those of liquid chromatography-mass spectrometry. This approach anticipates a novel route to sensitize optical sensors through the design and synthesis of moderate defects in luminescent MOFs.

Total saponins from Panax japonicus attenuate acute alcoholic liver oxidative stress and hepatosteatosis by p62-related Nrf2 pathway and AMPK-ACC/PPARα axis in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax japonicus (T. Nees) C.A. Mey. (PJ) has been used as a tonic traditional Chinese medicine (TCM) for years. Based on its meridian tropism in liver, spleen, and lung, PJ was popularly used to enhance the function of these organs. It is originally recorded with detoxicant effect on binge drink in Ben Cao Gang Mu Shi Yi, a persuasive Chinese materia medica. And binge dink has a close relationship with alcoholic liver disease (ALD). Hence, it's meaningful to investigate whether PJ exerts liver protection against binge drink toxicity. AIM OF THE STUDY: This investigation was carried out not only to emphasize the right recognition of total saponins from PJ (SPJ), but also to study on its sober-up effectiveness and defensive mechanism against acute alcoholic liver injury in vivo and in vitro. MATERIALS AND METHODS: SPJ constituents were verified by HPLC-UV analysis. In vivo, acute alcoholic liver oxidative stress and hepatosteatosis were established by continuous ethanol gavage to C57BL/6 mice for 3 days. SPJ was pre-administered for 7 days to investigate its protective efficacy. Loss of righting reflex (LORR) assay was employed to assess anti-inebriation effect of SPJ. Transaminases levels and hematoxylin and eosin (H&E) staining were measured to indicate the alcoholic liver injury. Antioxidant enzymes were measured to evaluate the oxidative stress degree in liver. Measurement of hepatic lipid accumulation was based on Oil Red O staining. Levels of inflammatory cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA). In vitro, HepG2 cells were treated with ethanol for 24 h, and SPJ was pre-administered for 2 h. 2,7-dichlorofluorescein diacetate (DCFH-DA) was used as a probe to indicate reactive oxygen species (ROS) generation. Nrf2 activation was verified by the favor of specific inhibitor, ML385. The nuclear translocation of Nrf2 was indicated with immunofluorescence analysis. Proteins expressions of related pathways were determined by Western blotting. RESULTS: Oleanane-type saponins are the most abundant constituents of SPJ. In this acute model, SPJ released inebriation of mice in a dose dependent manner. It decreased levels of serum ALT and AST, and hepatic TG. Besides, SPJ inhibited CYP2E1 expression and reduced MDA level in liver, with upregulations of antioxidant enzymes GSH, SOD and CAT. p62-related Nrf2 pathway was activated by SPJ with downstream upregulations of GCLC and NQO1 in liver. AMPK-ACC/PPARα axis was upregulated by SPJ to alleviate hepatic lipidosis. Hepatic IL-6 and TNF-α levels were downregulated by SPJ, which indicated a regressive lipid peroxidation in liver. In HepG2 cells, SPJ reduced ethanol-exposed ROS generation. Activated p62-related Nrf2 pathway was verified to contribute to the alleviation of alcohol-induced oxidative stress in hepatic cells. CONCLUSION: This attenuation of hepatic oxidative stress and steatosis suggested the therapeutic value of SPJ for ALD.

Translation and mRNA Stability Control.

Messenger RNA (mRNA) stability and translational efficiency are two crucial aspects of the post-transcriptional process that profoundly impact protein production in a cell. While it is widely known that ribosomes produce proteins, studies during the past decade have surprisingly revealed that ribosomes also control mRNA stability in a codon-dependent manner, a process referred to as codon optimality. Therefore, codons, the three-nucleotide words read by the ribosome, have a potent effect on mRNA stability and provide cis-regulatory information that extends beyond the amino acids they encode. While the codon optimality molecular mechanism is still unclear, the translation elongation rate appears to trigger mRNA decay. Thus, transfer RNAs emerge as potential master gene regulators affecting mRNA stability. Furthermore, while few factors related to codon optimality have been identified in yeast, the orthologous genes in vertebrates do not necessary share the same functions. Here, we discuss codon optimality findings and gene regulation layers related to codon composition in different eukaryotic species.

Inhibition of bladder cancer growth with homoharringtonine by inactivating integrin α5/ß1-FAK/Src axis: A novel strategy for drug application.

The application of immune checkpoint inhibitors and FGFR protein tyrosine kinase inhibitors have made a tremendous breakthrough in bladder cancer therapy. However, inadequate drug responses and drug resistance interfere with successful treatment outcomes. For a new drug to enter the market, there is a long development cycle with high costs and low success rates. Repurposing previously Food and Drug Administration (FDA)-approved medications and using novel drug discovery strategies may be an optimal approach. Homoharringtonine (HHT) has been used for hematologic malignancies for over 40 years in China and was approved by the FDA approximately 10 years ago. Many studies have demonstrated that HHT effectively inhibits the development of several types of solid tumors, although the underlying mechanisms of action are unclear. In this study, we investigated the mechanisms underlying HHT activity against bladder cancer growth. We first compared HTT with the drugs currently used clinically for bladder cancer treatment. HHT showed stronger inhibitory activity than cisplatin, carboplatin, and doxorubicin. Our in vitro and in vivo data demonstrated that HHT inhibited proliferation, colony formation, migration, and cell adhesion of bladder cancer cells and induced apoptosis and cell cycle arrest in the nanomolar concentration range. Furthermore, we revealed that HHT treatment could downregulate the MAPK/Erk and PI3k/Akt signaling pathways by inactivating the integrin α5/ß1-FAK/Src axis. HHT-induced activity reduced cell-ECM interactions and cell migration, thus suppressing tumor metastasis progression. Altogether, HHT shows enormous potential as an anticancer agent and may be applied as a combination treatment strategy for bladder cancer.

Arginine limitation drives a directed codon-dependent DNA sequence evolution response in colorectal cancer cells.

Utilization of specific codons varies between organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons. Moreover, arginine limitation-a feature of tumor microenvironments-is sufficient to induce arginine codon-switching mutations in human colon cancer cells. Such DNA codon switching events encode mutant proteins with arginine residue substitutions. Mechanistically, arginine limitation caused rapid reduction of arginine transfer RNAs and the stalling of ribosomes over arginine codons. Such selective pressure against arginine codon translation induced an adaptive proteomic shift toward low-arginine codon-containing genes, including specific amino acid transporters, and caused mutational evolution away from arginine codons-reducing translational bottlenecks that occurred during arginine starvation. Thus, environmental availability of a specific amino acid can influence DNA sequence evolution away from its cognate codons and generate altered proteins.

A novel combination treatment of antiADAM17 antibody and erlotinib to overcome acquired drug resistance in non-small cell lung cancer through the FOXO3a/FOXM1 axis.

After the identification of specific epidermal growth factor receptor (EGFR)-activating mutations as one of the most common oncogenic driver mutations in non-small cell lung cancer (NSCLC), several EGFR-tyrosine kinase inhibitors (EGFR-TKIs) with different clinical efficacies have been approved by various health authorities in the last two decades in targeting NSCLC harboring specific EGFR-activating mutations. However, most patients whose tumor initially responded to the first-generation EGFR-TKI developed acquired resistance. In this study, we developed a novel combination strategy, "antiADAM17 antibody A9(B8) + EGFR-TKIs", to enhance the efficacy of EGFR-TKIs. The addition of A9(B8) was shown to restore the effectiveness of erlotinib and overcome acquired resistance. We found that when A9(B8) antibody was treated with erlotinib or gefitinib, the combination treatment synergistically increased apoptosis in an NSCLC cell line and inhibited tumor growth in vivo. Interestingly, the addition of A9(B8) could only reduce the survival of the erlotinib-resistant NSCLC cell line and inhibit the growth of erlotinib-resistant tumors in vivo but not gefitinib-resistant cells. Furthermore, we revealed that A9(B8) overcame erlotinib resistance through the FOXO3a/FOXM1 axis and arrested the cell cycle at the G1/S phase, resulting in the apoptosis of cancer cells. Hence, this study establishes a novel, promising strategy for overcoming acquired resistance to erlotinib through the FOXO3a/FOXM1 axis by arresting the cell cycle at the G1/S phase.

iCodon customizes gene expression based on the codon composition.

Messenger RNA (mRNA) stability substantially impacts steady-state gene expression levels in a cell. mRNA stability is strongly affected by codon composition in a translation-dependent manner across species, through a mechanism termed codon optimality. We have developed iCodon ( www.iCodon.org ), an algorithm for customizing mRNA expression through the introduction of synonymous codon substitutions into the coding sequence. iCodon is optimized for four vertebrate transcriptomes: mouse, human, frog, and fish. Users can predict the mRNA stability of any coding sequence based on its codon composition and subsequently generate more stable (optimized) or unstable (deoptimized) variants encoding for the same protein. Further, we show that codon optimality predictions correlate with both mRNA stability using a massive reporter library and expression levels using fluorescent reporters and analysis of endogenous gene expression in zebrafish embryos and/or human cells. Therefore, iCodon will benefit basic biological research, as well as a wide range of applications for biotechnology and biomedicine.

Biflavonoids from the twigs and leaves of Cephalotaxus oliveri Mast. and their α-glucosidase inhibitory activity.

Three new biflavonoids, umcephabiovins C - E (1 - 3), along with fourteen known compounds were isolated from the twigs and leaves of Cephalotaxus oliveri. Their structures and configurations were elucidated by UV, IR, NMR, ECD, and HR-ESI-MS spectra. Compounds 1 - 3 exhibited significant α-glucosidase inhibitory activity with IC50 values of 7.05 ± 2.66, 24.45 ± 4.73, and 1.84 ± 1.14 µM, respectively. Compound 11 showed moderate cytotoxicity against the BaF3/T315I cell line.

A novel bioengineered fragment peptide of Vasostatin-1 exerts smooth muscle pharmacological activities and anti-angiogenic effects via blocking VEGFR signalling pathway.

Chromogranin A (CgA) is a hydrophilic glycoprotein released by post-ganglionic sympathetic neurons. CgA consists of a single peptide chain containing numerous paired basic residues, which are typical cleavage sites in prohormones to generate bioactive peptides. It is recognized as a diagnostic and prognostic serum marker for neuroendocrine tumours. Vasostatin-1 is one of the most conserved regions of CgA and has diverse inhibitory biological activities. In this study, a novel peptide fragment that contains three typical functional structures of Vasostatin-1 was synthesized. This unique bioengineered Vasostatin-1 Derived Peptide (named V1DP) includes a highly conserved domain between vertebrate species in its N-terminal region, comprising a disulphide bridge formed by two cysteine residues at amino acid positions 17 and 38, respectively. Besides, V1DP contains two significant tripeptide recognition sequences: the amino acid triplets, RGD and KGD. Our data demonstrated that V1DP could induce a dose-dependent relaxation of rat arterial smooth muscle and also increase the contraction activity of rat uterus smooth muscle. More importantly, we found that V1DP inhibits cancer cell proliferation, modulate the HUVEC cell migration, and exhibit anti-angiogenesis effect both in vitro and in vivo. We further investigated the actual mechanism of V1DP, and our results confirmed that V1DP involves inhibiting the vascular endothelial growth factor receptor (VEGFR) signalling. We docked V1DP to the apo structures of VEGFR2 and examined the stability of the peptide in the protein pockets. Our simulation and free energy calculations results indicated that V1DP can bind to the catalytic domain and regulatory domain pockets, depending on whether the conformational state of the protein is JM-in or JM-out. Taken together, our data suggested that V1DP plays a role as the regulator of endothelial cell function and smooth muscle pharmacological homeostasis. V1DP is a water-soluble and biologically stable peptide and could further develop as an anti-angiogenic drug for cancer treatment.

Translation of small downstream ORFs enhances translation of canonical main open reading frames.

In addition to canonical open reading frames (ORFs), thousands of translated small ORFs (containing less than 100 codons) have been identified in untranslated mRNA regions (UTRs) across eukaryotes. Small ORFs in 5' UTRs (upstream (u)ORFs) often repress translation of the canonical ORF within the same mRNA. However, the function of translated small ORFs in the 3' UTRs (downstream (d)ORFs) is unknown. Contrary to uORFs, we find that translation of dORFs enhances translation of their corresponding canonical ORFs. This translation stimulatory effect of dORFs depends on the number of dORFs, but not the length or peptide they encode. We propose that dORFs represent a new, strong, and universal translation regulatory mechanism in vertebrates.

Putting the Brakes on Tumorigenesis with Natural Products of Plant Origin: Insights into the Molecular Mechanisms of Actions and Immune Targets for Bladder Cancer Treatment.

Bladder cancer is the 10th most commonly diagnosed cancer worldwide. Although the incidence in men is 4 times higher than that in women, the diagnoses are worse for women. Over the past 30 years, the treatment for bladder cancer has not achieved a significant positive effect, and the outlook for mortality rates due to muscle-invasive bladder cancer and metastatic disease is not optimistic. Phytochemicals found in plants and their derivatives present promising possibilities for cancer therapy with improved treatment effects and reduced toxicity. In this study, we summarize the promising natural products of plant origin with anti-bladder cancer potential, and their anticancer mechanisms-especially apoptotic induction-are discussed. With the developments in immunotherapy, small-molecule targeted immunotherapy has been promoted as a satisfactory approach, and the discovery of novel small molecules against immune targets for bladder cancer treatment from products of plant origin represents a promising avenue of research. It is our hope that this could pave the way for new ideas in the fields of oncology, immunology, phytochemistry, and cell biology, utilizing natural products of plant origin as promising drugs for bladder cancer treatment.

Translation affects mRNA stability in a codon-dependent manner in human cells.

mRNA translation decodes nucleotide into amino acid sequences. However, translation has also been shown to affect mRNA stability depending on codon composition in model organisms, although universality of this mechanism remains unclear. Here, using three independent approaches to measure exogenous and endogenous mRNA decay, we define which codons are associated with stable or unstable mRNAs in human cells. We demonstrate that the regulatory information affecting mRNA stability is encoded in codons and not in nucleotides. Stabilizing codons tend to be associated with higher tRNA levels and higher charged/total tRNA ratios. While mRNAs enriched in destabilizing codons tend to possess shorter poly(A)-tails, the poly(A)-tail is not required for the codon-mediated mRNA stability. This mechanism depends on translation; however, the number of ribosome loads into a mRNA modulates the codon-mediated effects on gene expression. This work provides definitive evidence that translation strongly affects mRNA stability in a codon-dependent manner in human cells.

A Novel Strategy for Quantitative Analysis of Major Ginsenosides in Panacis Japonici Rhizoma with a Standardized Reference Fraction.

Panacis Japonici Rhizoma (Zhu-Jie-Shen in Chinese), the root of P. japonicus C.A. Mey., is commonly used in traditional Chinese Medicine. Saponins are the major bioactive compounds in this herb. The similarity of polarity and structure of the natural products in herb caused the difficulty of purification and resulted in the shortage and high cost of the reference compounds, which has greatly hindered efforts toward quantification in quality control. A novel strategy using a standardized reference fraction for qualification of the major saponins in Panacis Japonici Rhizoma was proposed to easily and effectively control the quality of PJR. The strategy is feasible and reliable, and the methodology of the developed approach is also validated. The standardized reference fraction was used for quantification, which might solve the shortage of the pure reference compounds in the quality control of herbal medicines.

Paired related homeobox 1 transactivates dopamine D2 receptor to maintain propagation and tumorigenicity of glioma-initiating cells.

Glioblastoma multiforme (GBM) is a highly invasive brain tumor with limited therapeutic means and poor prognosis. Recent studies indicate that glioma-initiating cells/glioma stem cells (GICs/GSCs) may be responsible for tumor initiation, infiltration, and recurrence. GICs could aberrantly employ molecular machinery balancing self-renewal and differentiation of embryonic neural precursors. Here, we find that paired related homeobox 1 (PRRX1), a homeodomain transcription factor that was previously reported to control skeletal development, is expressed in cortical neural progenitors and is required for their self-renewal and proper differentiation. Further, PRRX1 is overrepresented in glioma samples and labels GICs. Glioma cells and GICs depleted with PRRX1 could not propagate in vitro or form tumors in the xenograft mouse model. The GIC self-renewal function regulated by PRRX1 is mediated by dopamine D2 receptor (DRD2). PRRX1 directly binds to the DRD2 promoter and transactivates its expression in GICs. Blockage of the DRD2 signaling hampers GIC self-renewal, whereas its overexpression restores the propagating and tumorigenic potential of PRRX1-depleted GICs. Finally, PRRX1 potentiates GICs via DRD2-mediated extracellular signal-related kinase (ERK) and AKT activation. Thus, our study suggests that therapeutic targeting the PRRX1-DRD2-ERK/AKT axis in GICs is a promising strategy for treating GBMs.

Chikusetsusaponin IVa methyl ester induces G1 cell cycle arrest, triggers apoptosis and inhibits migration and invasion in ovarian cancer cells.

BACKGROUND: Panacis Japonici Rhizoma (PJR) is one of the most famous Chinese medical herbs that is known for exhibiting potential anti-cancer effects. PURPOSE: This study aims to isolate and investigate the anti-cancer potential of saponins from PJR in ovarian cancer cells. METHODS: The compounds were separated by comprehensive chromatographic methods. By comparison of the 1H- and 13C NMR data, as well as the HR-ESI-MS data, with the corresponding references, the structures of compounds were determined. MTT assay was performed to evaluate cell viability, along with flow cytometry for cell cycle analysis. JC-1 staining, Annexin V-PI double staining as well as Hoechst 33; 342 staining were used for detecting cell apoptosis. Western blot analysis was conducted to determine the relative protein level. Transwell assays were performed to investigate the effect of the saponin on cell migration and invasion and zymography experiments were used to detect the enzymatic activities. RESULTS: Eleven saponins were isolated from PJR and their anti-proliferative effects were evaluated in human ovarian cancer cells. Chikusetsusaponin IVa methyl ester (1) exhibited the highest anti-proliferative potential among these isolates with the IC50 values at less than 10 µM in both ovarian cancer A2780 and HEY cell lines. Compound 1 induced G1 cell cycle arrest accompanied with an S phase decrease, and down-regulated the expression of cyclin D1, CDK2, and CDK6. Further study showed that compound 1 effectively decreased the cell mitochondrial membrane potential, increased the annexin V positive cells and nuclear chromatin condensation, as well as enhanced the expression of cleaved PARP, Bax and cleaved-caspase 3 while decreasing that of Bcl-2. Moreover, compound 1 suppressed the migration and invasion of HEY and A2780 cells, down-regulated the expression of Cdc42, Rac, RohA, MMP2 and MMP9, and decreased the enzymatic activities of MMP2 and MMP9. CONCLUSION: These results provide a comprehensive evaluation of compound 1 as a potential agent for the treatment of ovarian cancer.