Galeaspid anatomy and the origin of vertebrate paired appendages.

Paired fins are a major innovation1,2 that evolved in the jawed vertebrate lineage after divergence from living jawless vertebrates3. Extinct jawless armoured stem gnathostomes show a diversity of paired body-wall extensions, ranging from skeletal processes to simple flaps4. By contrast, osteostracans (a sister group to jawed vertebrates) are interpreted to have the first true paired appendages in a pectoral position, with pelvic appendages evolving later in association with jaws5. Here we show, on the basis of articulated remains of Tujiaaspis vividus from the Silurian period of China, that galeaspids (a sister group to both osteostracans and jawed vertebrates) possessed three unpaired dorsal fins, an approximately symmetrical hypochordal tail and a pair of continuous, branchial-to-caudal ventrolateral fins. The ventrolateral fins are similar to paired fin flaps in other stem gnathostomes, and specifically to the ventrolateral ridges of cephalaspid osteostracans that also possess differentiated pectoral fins. The ventrolateral fins are compatible with aspects of the fin-fold hypothesis for the origin of vertebrate paired appendages6-10. Galeaspids have a precursor condition to osteostracans and jawed vertebrates in which paired fins arose initially as continuous pectoral-pelvic lateral fins that our computed fluid-dynamics experiments show passively generated lift. Only later in the stem lineage to osteostracans and jawed vertebrates did pectoral fins differentiate anteriorly. This later differentiation was followed by restriction of the remaining field of fin competence to a pelvic position, facilitating active propulsion and steering.

Intravesical delivery of KDM6A-mRNA via mucoadhesive nanoparticles inhibits the metastasis of bladder cancer.

Lysine-specific demethylase 6A (KDM6A), also named UTX, is frequently mutated in bladder cancer (BCa). Although known as a tumor suppressor, KDM6A's therapeutic potential in the metastasis of BCa remains elusive. It also remains difficult to fulfill the effective up-regulation of KDM6A levels in bladder tumor tissues in situ to verify its potential in treating BCa metastasis. Here, we report a mucoadhesive messenger RNA (mRNA) nanoparticle (NP) strategy for the intravesical delivery of KDM6A-mRNA in mice bearing orthotopic Kdm6a-null BCa and show evidence of KDM6A's therapeutic potential in inhibiting the metastasis of BCa. Through this mucoadhesive mRNA NP strategy, the exposure of KDM6A-mRNA to the in situ BCa tumors can be greatly prolonged for effective expression, and the penetration can be also enhanced by adhering to the bladder for sustained delivery. This mRNA NP strategy is also demonstrated to be effective for combination cancer therapy with other clinically approved drugs (e.g., elemene), which could further enhance therapeutic outcomes. Our findings not only report intravesical delivery of mRNA via a mucoadhesive mRNA NP strategy but also provide the proof-of-concept for the usefulness of these mRNA NPs as tools in both mechanistic understanding and translational study of bladder-related diseases.

Alternative splicing-related long noncoding RNA ANRIL facilitates hepatocellular carcinoma by targeting the miR-199a-5p/SRSF1 axis and impacting Anillin.

Hepatocellular carcinoma (HCC) is characterized by aberrant alternative splicing (AS), which plays an important part in the pathological process of this disease. However, available reports about genes and mechanisms involved in AS process are limited. Our previous research has identified ANRIL as a long noncoding RNA related to the AS process of HCC. Here, we investigated the exact effect and the mechanism of ANRIL on HCC progress. The ANRIL expression profile was validated using the real-time quantitative polymerase chain reaction assay. The western blot analysis and IHC assay were conducted on candidate targets, including SRSF1 and Anillin. The clinicopathological features of 97 patients were collected and analyzed. Loss-of and gain-of-function experiments were conducted. The dual-luciferase reporter assay was applied to verify the interaction between ANRIL, miR-199a-5p, and SRSF1. Anomalous upregulation of ANRIL in HCC was observed, correlating with worse clinicopathological features of HCC. HCC cell proliferation, mobility, tumorigenesis, and metastasis were impaired by depleting ANRIL. We found that ANRIL acts as a sponger of miRNA-199a-5p, resulting in an elevated level of its target protein SRSF1. The phenotypes induced by ANRIL/miR-199a-5p/SRSF1 alteration are associated with Anillin, a validated HCC promoter. ANRIL is an AS-related lncRNA promoting HCC progress by modulating the miR-199a-5p/SRSF1 axis. The downstream effector of this axis in the development of HCC is Anillin.

Attenuation of binuclear hepatocytes in the paracancerous liver tissue is associated with short-term recurrence of hepatocellular carcinoma post-radical surgery.

Short-term recurrence of hepatocellular carcinoma (HCC) after radical resection leads to dismal outcomes. To screen high-recurrence risk patients to provide adjuvant treatment is necessary. Herein, based on our previous research, we further focused on the changes in the abundance of binuclear hepatocytes (ABH) in the paracancerous liver tissue to discuss the relationship between the attenuation of binuclear hepatocytes and postoperative short-term recurrence, by combining with the assessment of the value of a reported independent early recurrence risk factor in HCC, protein induced by vitamin K absence or antagonist-II (PIVKA-II). A cohort of 142 paracancerous liver tissues from HCC patients who received radical resection was collected. Binuclear hepatocytes were reduced in the paracancerous liver tissues, compared with the liver tissues from normal donors. ABH was negatively correlated with clinical features such as tumor size, TNM stages, tumor microsatellite formation, venous invasion, and Alpha-fetoprotein (AFP) level, as well as the expression of E2F7 and Anillin, which are two critical regulators concerning the hepatocyte polyploidization. According to the short-term recurrence information, ABH value was laminated, and univariate and multivariate logistic regression was performed to analyze the relationship between paracancerous ABH and short-term tumor relapse. Simultaneously, the predictive effectiveness of the ABH value was compared with the preoperative PIVKA-II value. As observed, the paracancerous ABH value below 1.5% was found to be an independent risk factor for recurrence. In conclusion, the paracancerous ABH is a credible indicator of short-term recurrence of HCC patients after radical resection, and regular assessment of ABH might help to prevent short-term HCC recurrence.

Integrated Anchored Stapling and Hierarchical Dynamics: MSICDA-Driven CREBBP Bromodomain Inhibition.

Despite recent success in the computational approaches of cyclic peptide design, current studies face challenges in modeling noncanonical amino acids and nonstandard cyclizations due to limited data. To address this challenge, we developed an integrated framework for the tailored design of stapled peptides (SPs) targeting the bromodomain of CREBBP (CREBBP-BrD). We introduce a powerful combination of anchored stapling and hierarchical molecular dynamics to design and optimize SPs by employing the MultiScale integrative conformational dynamics assessment (MSICDA) strategy, which involves an initial virtual screening of over 1.5 million SPs, followed by comprehensive simulations amounting to 154.54 µs across 5418 of instances. The MSICDA method provides a detailed and holistic stability view of peptide-protein interactions, systematically isolated optimized peptides and identified two leading candidates, DA#430 and DA#99409, characterized by their enhanced stability, optimized binding, and high affinity toward the CREBBP-BrD. In cell-free assays, DA#430 and DA#99409 exhibited 2- to 12-fold greater potency than inhibitor SGC-CBP30. Cell studies revealed higher peptide selectivity for cancerous versus normal cells over small molecules. DA#430 combined with (+)-JQ-1 showed promising synergistic effects. Our approach enables the identification of peptides with optimized binding, high affinity, and enhanced stability, leading to more precise and effective cyclic peptide design, thereby establishing MSICDA as a generalizable and transformative tool for uncovering novel targeted drug development in various therapeutic areas.

Neratinib for HER2-positive breast cancer with an overlooked option.

Positive human epidermal growth factor receptor 2 (HER2) expression is associated with an increased risk of metastases especially those to the brain in patients with advanced breast cancer (BC). Neratinib as a tyrosine kinase inhibitor can prevent the transduction of HER1, HER2 and HER4 signaling pathways thus playing an anticancer effect. Moreover, neratinib has a certain efficacy to reverse drug resistance in patients with BC with previous HER2 monoclonal antibody or targeted drug resistance. Neratinib, as monotherapy and in combination with other therapies, has been tested in the neoadjuvant, adjuvant, and metastatic settings. Neratinib with high anticancer activity is indicated for the prolonged adjuvant treatment of HER2-positive early BC, or in combination with other drugs including trastuzumab, capecitabine, and paclitaxel for the treatment of advanced HER2-positive BC especially cancers with central nervous system (CNS) metastasis to reduce the risk of BC recurrence. This article reviewed the pharmacological profiles, efficacy, safety, tolerability, and current clinical trials pertaining to neratinib, with a particular focus on the use of neratinib in patients with metastatic breast cancer (MBC) involving the CNS. We further discussed the use of neratinib for HER2-negative and HER2-mutant breast cancers, and mechanisms of resistance to neratinib. The current evidence suggests that neratinib has promising efficacy in patients with BC which is at least non-inferior compared to previous therapeutic regimens. The most common AE was diarrhea, and the incidence, severity and duration of neratinib-related grade 3 diarrhea can be reduced with loperamide. Of note, neratinib has the potential to effectively control and prevent brain metastasis in patients with advanced BC, providing a therapeutic strategy for HER2-positive BC.

Improving the regeneration rate of deep lethal mutant protoplasts by fusion to promote efficient L-lysine fermentation.

BACKGROUND: L-lysine is widely used for feed and special diet products. The transformation of fermentation strains plays a decisive role in the development of these industries. Based on the mutation breeding theory and metabolic engineering methods, this study aimed to improve the regeneration rate of high-lethality protoplasts by combining multiple mutagenesis and homologous cell fusion techniques to efficiently concentrate multiple dominant mutations and optimize the L-lysine production strain Escherichia coli QDW. RESULTS: In order to obtain the best protoplasts, the optimal enzymolysis time was selected as 4 h. The optimal lysozyme concentration was estimated at 0.8 mg/mL, because the protoplast formation rate and regeneration rate reached 90% and 30%, respectively, and their product reached the maximum. In this study, it was necessary that UV mutagenesis be excessive to obtain an expanded mutation library. For high lethality protoplasts, under the premise of minimal influence on its recovery, the optimal time for UV mutagenesis of protoplasts was 7 min, and the optimal time for thermal inactivation of protoplasts at 85 ℃ was 30 min. After homologous fusion, four fusion strains of E. coli were obtained, and their stability was analyzed by flow cytometry. The L-lysine yield of QDW-UH3 increased by 7.2% compared with that of QDW in a fermentation experiment, which promoted the expression of key enzymes in L-lysine synthesis, indicating that the combination of ultraviolet mutagenic breeding and protoplast fusion technology improved the acid-production level of the fusion strain. CONCLUSION: This method provides a novel approach for the targeted construction of microbial cell factories.

Characterization of cross-reactive monoclonal antibodies against SARS-CoV-1 and SARS-CoV-2: Implication for rational design and development of pan-sarbecovirus vaccines and neutralizing antibodies.

Emergence of various circulating SARS-CoV-2 variants of concern (VOCs) promotes the identification of pan-sarbecovirus vaccines and broadly neutralizing antibodies (bNAbs). Here, to characterize monoclonal antibodies cross-reactive against both SARS-CoV-1 and SARS-CoV-2 and to search the criterion for bNAbs against all emerging SARS-CoV-2, we isolated several SARS-CoV-1-cross-reactive monoclonal antibodies (mAbs) from a wildtype SARS-CoV-2 convalescent donor. These antibodies showed broad binding capacity and cross-neutralizing potency against various SARS-CoV-2 VOCs, including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta), but failed to efficiently neutralize Omicron variant and its sublineages. Structural analysis revealed how Omicron sublineages, but not other VOCs, efficiently evade an antibody family cross-reactive against SARS-CoV-1 through their escape mutations. Further evaluation of a series of SARS-CoV-1/2-cross-reactive bNAbs showed a negative correlation between the neutralizing activities against SARS-CoV-1 and SARS-CoV-2 Omicron variant. Together, these results suggest the necessity of using cross-neutralization against SARS-CoV-1 and SARS-CoV-2 Omicron as criteria for rational design and development of potent pan-sarbecovirus vaccines and bNAbs.

Reconfigurable Peptide Analogs of Apolipoprotein A-I Reveal Tunable Features of Nanodisc Assembly.

Nanodisc (ND)-forming membrane scaffold proteins or peptides developed from apolipoprotein A-I (apoA-I) have led to considerable promise in structural biology and therapeutic applications. However, the rationale and regularity characteristics in peptide sequence design remain inconclusive. Here, we proposed a consensus-based normalization approach through the reversed engineering of apoA-IΔ1-45 to design reconfigurable apoA-I peptide analogs (APAs) for tunable ND assembly. We present extensive morphological validations and computational simulation analyses on divergent APA-NDs that are generated by our method. Fifteen divergent APAs were generated accordingly to study the assembly machinery of NDs. We show that APA designs exhibit multifactorial influence in terms of varying APA tandem repeats, sequence composition, and lipid-to-APA ratio to form tunable diameters of NDs. There is a strong positive correlation between DMPC-to-APA ratios and ND diameters. Longer APA with more tandem repeats tends to yield higher particle size homogeneity. Our results also suggest proline is a dispensable residue for the APA-ND formation. Interestingly, proline-rich substitution not only provides an inward-bending effect in forming smaller NDs but also induces the cumulative chain flexibility that enables larger ND formation at higher lipid ratios. Additionally, proline-tryptophan residues in APAs play a dominant role in forming larger NDs. Molecular simulation shows that enriched basic and acidic residues in APAs evoke abundant hydrogen-bond and salt bridge networks to reinforce the structural stability of APA-NDs. Together, our findings provide a rational basis for understanding APA design. The proposed model could be extended to other apolipoproteins for desired ND engineering.

Ferroptosis: From regulation of lipid peroxidation to the treatment of diseases.

Ferroptosis is a regulated cell death mainly manifested by iron-dependent lipid peroxide accumulation. The leading cause of ferroptosis is the imbalance of intracellular oxidative systems (e.g., LOXs, POR, ROS) and antioxidant systems (e.g., GSH/GPx4, CoQ10/FSP1, BH4/GCH1), which is regulated by a complex network. In the past decade, this metabolic network has been continuously refined, and the links with various pathophysiological processes have been gradually established. Apoptosis has been regarded as the only form of regulated cell death for a long time, and the application of chemotherapeutic drugs to induce apoptosis of cancer cells is the mainstream method. However, studies have reported that cancer cells' key features are resistance to apoptosis and chemotherapeutics. For high proliferation, cancer cells often have very active lipid metabolism and iron metabolism, which pave the way for ferroptosis. Interestingly, researchers found that drug-resistant or highly aggressive cancer cells are more prone to ferroptosis. Therefore, ferroptosis may be a potential strategy to eliminate cancer cells. In addition, links between ferroptosis and other diseases, such as neurological disorders and ischemia-reperfusion injury, have also been found. Understanding these diseases from the perspective of ferroptosis may provide new insights into clinical treatment. Herein, the metabolic processes in ferroptosis are reviewed, and the potential mechanisms and targets of ferroptosis in different diseases are summarized.

Recent insights into function, structure and modification of cytochrome P450 153 a family.

Cytochrome P450 153 A (CYP153A) is a versatile enzyme that can catalyze a wide range of oxidation reactions on various substrates. This review provides a comprehensive overview of the current state of knowledge on CYP153A, including its classification, structure, function, and potential applications in biotechnology and pharmaceuticals. The CYP153A family encompasses many enzymes with different functions on a variety of substrates. We also discuss the structural features that are responsible for the different substrate specificities. Additionally, the enzyme has been engineered to increase its catalytic activity and modifications have been made to enhance its properties further. Despite its potential, challenges and limitations associated with studying and exploiting CYP153A remain, such as low expression levels and substrate inhibition. Nonetheless, ongoing research is exploring new ways to harness the enzyme's capabilities, particularly in synthetic biology, biocatalysis, and drug discovery, making it an exciting target for future research.

In situ sprayed NIR-responsive, analgesic black phosphorus-based gel for diabetic ulcer treatment.

The treatment of diabetic ulcer (DU) remains a major clinical challenge due to the complex wound-healing milieu that features chronic wounds, impaired angiogenesis, persistent pain, bacterial infection, and exacerbated inflammation. A strategy that effectively targets all these issues has proven elusive. Herein, we use a smart black phosphorus (BP)-based gel with the characteristics of rapid formation and near-infrared light (NIR) responsiveness to address these problems. The in situ sprayed BP-based gel could act as 1) a temporary, biomimetic "skin" to temporarily shield the tissue from the external environment and accelerate chronic wound healing by promoting the proliferation of endothelial cells, vascularization, and angiogenesis and 2) a drug "reservoir" to store therapeutic BP and pain-relieving lidocaine hydrochloride (Lid). Within several minutes of NIR laser irradiation, the BP-based gel generates local heat to accelerate microcirculatory blood flow, mediate the release of loaded Lid for "on-demand" pain relief, eliminate bacteria, and reduce inflammation. Therefore, our study not only introduces a concept of in situ sprayed, NIR-responsive pain relief gel targeting the challenging wound-healing milieu in diabetes but also provides a proof-of-concept application of BP-based materials in DU treatment.

Transcriptome analysis reveals that yeast extract inhibits synthesis of prodigiosin by Serratia marcescens SDSPY-136.

Prodigiosin (2-methyl-3-pentyl-6-methoxyprodiginine) is a valuable medicinal and edible natural pigment derived from Serratia marcescens. How prodigiosin synthesis is suppressed by environmental factors has not been investigated. Previous studies described a low level of prodigiosin production in the presence of yeast extracts. However, we have observed that S. marcescens SDSPY-136 did not synthesize prodigiosin in yeast extract culture. In this study, transcriptome sequencing of yeast extract cultures was used to estimate the metabolic control of the synthetic prodigiosin pathway in S. marcescens. Key phosphorylation enzymes in the glycolysis pathway, 6-phosphofructokinase, and glyceraldehyde 3-phosphate dehydrogenase, were downregulated by yeast extract and other carbon metabolism pathway genes were enhanced. Genes related to ribosomes, amino acid metabolism, and aminoacyl-tRNA biosynthesis were also highly up-regulated. The presence of metal ions in yeast extracts and the accumulation of fermentation metabolites alter the two-component signaling system, which regulated metabolism to various degrees. The results of metal ion testing suggested that prodigiosin inhibition could be caused by metal ions, such as zinc ion. The findings indicate that yeast extract may affect metabolism through multiple pathways in S. marcescens. This research sheds light on the mechanism of prodigiosin regulatory inhibition.

E2F7 enhances hepatocellular carcinoma growth by preserving the SP1/SOX4/Anillin axis via repressing miRNA-383-5p transcription.

E2F family participates in most human malignancies by activating the transcription of the cell cycle-related genes. Whereas, as a specifical atypical member of this family, E2F7 was described as a repressor against its downstream genes and exerted oscillatory and controversial functions in cancers. Our previous study identified a molecular interaction promoting hepatocellular carcinoma (HCC) growth induced by SOX4 and Anillin. Meanwhile, we preliminarily identified SP1 as the upstream activator of SOX4. Intriguingly, we observed that the repressive E2F7 presents a remarkable high expression in HCC, and is positively correlated and involved in the same pathway with the potentially SP1/SOX4/Anillin axis. However, their exact interaction or mechanism controlling tumor progress between these genes has not been illustrated. Thus, we focused on this point in this study and attempted to improve the potential regulating axis in HCC cell proliferation and tumor growth for promoting tumor prevention and control. The expression profile of E2F7 in HCC tissues and tumor cells was detected along with the related candidate genes, through real-time quantitative polymerase chain reaction assay, the Western blot analysis, and the immunohistochemistry assay, combined with bioinformatics analysis of the HCC information from the the Cancer Genome Altas and Gene Expression Omnibus data sets. The correlation between E2F7 and HCC patients' clinicopathologic features was explored. Gain-of and loss-of-function assays were conducted both in vitro and in vivo along with the rescue experiment, for revealing the relative genes' functions in HCC progress. The ChIP and the dual-luciferase reporter assays were performed to verify the transcriptional regulating profile between E2F7 and SP1/SOX4/Anillin axis. E2F7 was upregulated in HCC and significantly correlated with SP1/SOX4/Anillin axis. High E2F7 expression is associated with dismal clinicopathologic features and poor survival of the patients. E2F7 depletion potently impaired SP1/SOX4/Anillin expression and significantly inhibited HCC growth. Furthermore, intensive exploration demonstrated that E2F7 preserves high SP1 levels by abrogating miR-383-5p in a transcriptional way. Atypical E2F7 is an important repressive transcription factor commonly upregulated in the HCC environment. E2F7 facilitates HCC growth by repressing miR-383-5p transcription and sequentially promoting SP1/SOX4/Anillin axis. Our findings provide us with probable targets for HCC prevention and therapeutic treatment.

Nano-Bio Interactions in Cancer: From Therapeutics Delivery to Early Detection.

Understanding the interactions between nanomaterials and biological systems plays a pivotal role in enhancing the efficacy of nanomedicine and advancing the disease diagnosis. The nanoparticle-protein corona, an active biomolecular layer, is formed around nanoparticles (NPs) upon mixing with biological fluid. The surface layer which consists of rapidly exchanged biomolecules is called the "soft" corona. The inner layer which is more stable and tightly packed is called the "hard" corona. It has been suggested that the NP-protein corona has a decisive effect on the in vivo fate of nanomedicine upon intravenously administration into the mouse. Furthermore, the features of the NP-protein corona make it a powerful platform to enrich low-abundance proteins from serum/plasma for downstream mass-spectrometry (MS)-based proteomics for biomarker discovery and disease diagnosis.Herein, we summarize our recent work on the development of nanomedicine and disease detection from the level of nano-bio interactions between nanoparticles and biological systems. Nanomedicine has made substantial progress over the past two decades. However, the significant enhancement of overall patient survival by nanomedicine remains a challenge due to the lack of a deep understanding of nano-bio interactions in the clinical setting. The pharmacokinetic effect of the protein corona on PEGylated NPs during blood circulation indicated that the adsorbed apolipoproteins could prolong the circulation time of NPs. This mechanistic understanding of the protein corona (active biomolecule) formed around polymeric NPs offered insights into enhancing the efficacy of nanomedicine from the biological interactions point of view. Moreover, we discuss the basic rationale for developing bioresponsive cancer nanomedicine by exploiting the pathophysiological environment around the tumor, typically the pH, reactive oxygen species (ROS), and redox-responsive supramolecular motifs based on synthetic amphiphilic polymers. The protein corona in vivo determines the biological fate of NPs, whereas it opens a new avenue to enrich low abundant proteins in a biospecimen ex vivo to render them "visible" for downstream analytical workflows, such as MS-based proteomics. Blood serum/plasma, due to easy accessibility and great potential to uncover and monitor physiological and pathological changes in health and disease, has remained a major source of detecting protein biomarker candidates. Inspired by the features of the NP-protein corona, a Proteograph platform, which integrates multi-NP-protein coronas with MS for large-scale efficient and deep proteome profiling has been developed. Finally, we conclude this Account with a better understanding of nano-bio interactions to accelerate the nanomedicine translation and how MS-based proteomics can boost our understanding of the corona composition and facilitate the identification of disease biomarkers.

Discoidin domain receptor 1 promotes lung adenocarcinoma migration via the AKT/snail signaling axis.

BACKGROUND: Discoidin domain receptor 1 (DDR1), a member of receptor tyrosine kinase, has been implicated in tumor progression. However, the function and underlying mechanism of DDR1 in lung adenocarcinoma (LUAD) progression is unclear. Thus, we explored the molecular regulatory mechanism of DDR1 in the migration of LUAD. METHODS: Transwell assays, wound healing assays and xenograft tumor assays were performed to study the function of DDR1 in the progression of LUAD. Immunoblotting and quantitative real-time polymerase chain reaction (RT-qPCR) were used to detect the expression levels of genes. Co-immunoprecipitation (co-IP) assays were performed to detect the interaction between DDR1 and AKT. Immunofluorescence and immunohistochemistry assays were used to determine the expression level of proteins in cells and tissues, respectively. RESULTS: DDR1 expression was significantly higher in LUAD tissues than in normal lung tissues, and the level of DDR1 was inversely correlated with prognosis in patients. We found that DDR1 promoted the migration and invasion of LUAD cells in vitro. Furthermore, ectopic expression of DDR1 in LUAD cells altered EMT-related markers expression. Importantly, the DDR1 protein interacted with AKT and phosphorylated AKT. The AKT inhibitor MK2206 interrupted Snail upregulation in DDR1-overexpressing LUAD cells. Finally, our study revealed that depletion of DDR1 attenuated LUAD cell migration in a tumor xenograft mouse model. CONCLUSION: Our findings uncovered that a high abundance of DDR1 increased the migration and invasion capability of LUAD cells via the AKT/Snail signaling axis and indicated that DDR1 could be a potential target for treating LUAD.

Dual Hypoxia-Targeting RNAi Nanomedicine for Precision Cancer Therapy.

As a hallmark of solid tumors, hypoxia promotes tumor growth, metastasis, and therapeutic resistance by regulating the expression of hypoxia-related genes. Hypoxia also represents a tumor-specific stimulus that has been exploited for the development of bioreductive prodrugs and advanced drug delivery systems. Cell division cycle 20 (CDC20) functions as an oncogene in tumorigenesis, and we demonstrated the significant upregulation of CDC20 mRNA in the tumor vs paratumor tissues of breast cancer patients and its positive correlation with tumor hypoxia. Herein, a hypoxia-responsive nanoparticle (HRNP) was developed by self-assembly of the 2-nitroimidazole-modified polypeptide and cationic lipid-like compound for delivery of siRNA to specifically target CDC20, a hypoxia-related protumorigenic gene, in breast cancer therapy. The delivery of siCDC20 by HRNPs sufficiently silenced the expression of CDC20 and exhibited potent antitumor efficacy. We expect that this strategy of targeting hypoxia-correlated protumorigenic genes by hypoxia-responsive RNAi nanoparticles may provide a promising approach in cancer therapy.

ROS-Mediated Selective Killing Effect of Black Phosphorus: Mechanistic Understanding and Its Guidance for Safe Biomedical Applications.

Black phosphorus (BP)-based nanomaterials have distinguished advantages and potential applications in various biomedical fields. However, their biological effects in physiological systems remain largely unexplored. Here, we systematically revealed a reactive oxygen species (ROS)-mediated mechanism for the selective killing of cancer cells by BP-based nanosheets. The treatment with BP-based materials can induce higher levels of ROS in cancer cells than in normal cells, leading to significant changes in the cytoskeleton, cell cycle arrest, DNA damage, and apoptosis in tumor cell lines. We revealed that the decreased superoxide dismutase activity by lipid peroxides could be an essential mechanism of the selectively higher ROS generation induced by BP-based nanosheets in cancer cells. In addition, the selective killing effect only occurred within a certain dosage range (named "SK range" in this study). Once exceeding the SK range, BP-based materials could also induce a high ROS production in normal tissues, leading to detectable DNA damage and pathological characteristics in normal organs and raising safety concerns. These findings not only shed light on a new mechanism for the selective killing of cancer cells by BP-based materials but also provide deep insights into the safe use of BP-based therapies.

Structural Transformative Antioxidants for Dual-Responsive Anti-Inflammatory Delivery and Photoacoustic Inflammation Imaging.

We have synthesized a PEGylated, phenylboronic acid modified L-DOPA pro-antioxidant (pPAD) that can self-assemble into nanoparticles (pPADN) for the loading of a model glucocorticoid dexamethasone (Dex) through 1,3-diol/phenylboronic acid chemistry and hydrophobic interactions for more effective treatment of inflammation. Upon exposure to ROS, pPADN convert into the active form of L-DOPA, and a cascade of oxidative reactions transform it into antioxidative melanin-like materials. Concomitantly, the structural transformation of pPADN triggers the specific release of Dex, along with the acidic pH of inflammatory tissue. In a rat model of osteoarthritis, Dex-loaded pPADN markedly mitigate synovial inflammation, suppress joint destruction and cartilage matrix degradation, with negligible in vivo toxicity. Moreover, in situ structural transformation makes pPADN suitable for noninvasive monitoring of therapeutic effects as a photoacoustic imaging contrast agent.

Pseudogene AKR1B10P1 enhances tumorigenicity and regulates epithelial-mesenchymal transition in hepatocellular carcinoma via stabilizing SOX4.

Pseudogenes exert potential functions in tumorigenicity and tumour process in human beings. In our previous research on oncogene AKR1B10 in hepatocellular carcinoma (HCC), its pseudogene, AKR1B10P1, was preliminarily noticed being anomalistic transcribed, whereas whether AKR1B10P1 plays any specific function in HCC is poorly understood. By using shRNA transfection and lentiviral infection, we regulated the expression of ARK1B10P1 transcript and the relative targets in two ways. As we discovered, pathological transcription of AKR1B10P1 in HCC cells significantly promotes cell growth and motility either in vitro or in vivo. AKR1B10P1 was correlated with relatively dismal features of HCC. The epithelial-mesenchymal transition (EMT) was enhanced by up-regulating AKR1B10P1. And, a potential sequence of AKR1B10P1 transcript was discovered directly interacting with miR-138. SOX4, a pivotal promotor of EMT, was validated as the down-streaming target of miR-138. Mechanistically, degradation of SOX4 mRNA induced by miR-138 was effectively abrogated by AKR1B10P1. In conclusion, pseudogene AKR1B10P1 exerts stabilizing effect on SOX4 in HCC, associated EMT process, by directly sponging miR-138, which post-transcriptionally modulates SOX4's regulating gene.