Cepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug discovery.

Cepharanthine is a secondary metabolite isolated from Stephania. It has been reported that it has anti-conronaviruses activities including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we assemble three Stephania genomes (S. japonica, S. yunnanensis, and S. cepharantha), propose the cepharanthine biosynthetic pathway, and assess the antiviral potential of compounds involved in the pathway. Among the three genomes, S. japonica has a near telomere-to-telomere assembly with one remaining gap, and S. cepharantha and S. yunnanensis have chromosome-level assemblies. Following by biosynthetic gene mining and metabolomics analysis, we identify seven cepharanthine analogs that have broad-spectrum anti-coronavirus activities, including SARS-CoV-2, Guangxi pangolin-CoV (GX_P2V), swine acute diarrhoea syndrome coronavirus (SADS-CoV), and porcine epidemic diarrhea virus (PEDV). We also show that two other genera, Nelumbo and Thalictrum, can produce cepharanthine analogs, and thus have the potential for antiviral compound discovery. Results generated from this study could accelerate broad-spectrum anti-coronavirus drug discovery.

Head and neck squamous cell carcinoma-specific prognostic signature and drug sensitive subtypes based on programmed cell death-related genes.

Background: As a complex group of malignancies, head and neck squamous cell carcinoma (HNSC) is one of the leading causes of cancer mortality. This study aims to establish a reliable clinical classification and gene signature for HNSC prognostic prediction and precision treatments. Methods: A consensus clustering analysis was performed to group HNSC patients in The Cancer Genome Atlas (TCGA) database based on genes linked to programmed cell death (PCD). Differentially expressed genes (DEGs) between subtypes were identified using the "limma" R package. The TCGA prognostic signature and PCD-related prognostic genes were found using a least absolute shrinkage and selection operator (LASSO) regression analysis and univariate Cox regression analysis. The robustness of the LASSO analysis was validated using datasets GSE65858 and GSE41613. A cell counting kit-8 (CCK-8) test, Western blot, and real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) were used to evaluate the expression and viability of prognostic genes. Results: Four molecular subtypes were identified in PCD-related genes. Subtype C4 had the best prognosis and the highest immune score, while subtype C1 exhibited the most unfavorable outcomes. Three hundred shared DEGs were identified among the four subtypes, and four prognostic genes (CTLA4, CAMK2N1, PLAU and CALML5) were used to construct a TCGA-HNSC prognostic model. High-risk patients manifested poorer prognosis, more inflammatory pathway enrichment, and lower immune cell infiltration. High-risk patients were more prone to immune escape and were more likely to be resistant to Cisplatin and 5-Fluorouracil. Prognosis prediction was validated in external datasets. The expression of CTLA4, CAMK2N1, PLAU and CALML5 was enhanced in CAL-27 and SCC-25 cell lines, and CALML5 inhibited CAL-27 and SCC-25 cell viability. Conclusion: This study shares novel insights into HNSC classification and provides a reliable PCD-related prognostic signature for prognosis prediction and treatment for patients with HNSC.

Successful treatment of a severe Takotsubo syndrome case complicated by liver abscess.

The main manifestations of Takotsubo syndrome (TTS) are a spherical expansion of the left ventricle or near the apex and decreased systolic function. TTS is mostly thought to be induced by emotional stress, and the induction of TTS by severe infection is not often reported. A 72-year-old female patient with liver abscess reported herein was admitted due to repeated fever with a history of hypertension and impaired glucose tolerance. Her severe infection caused TTS, and her blood pressure dropped to 80/40 mmHg. IABP treatment was performed immediately and continued for 10 days, and comprehensive medication was administered. Based on her disease course and her smooth recovery, general insights and learnings may be: Adding to mental and other pathological stress reaction, serious infections from pathogenic microorganism could be of great important causation of stress reaction leading to TTS, while basic diseases such as coronary heart disease, hypertension, and diabetes were be of promoting factors; In addition to effective drug therapies for TTS, the importance of the timely using of IABP should be emphasized.

Engineering High Strength and Super-Toughness of Unfolded Structural Proteins and their Extraordinary Anti-Adhesion Performance for Abdominal Hernia Repair.

The utility of unfolded structural proteins with diverse sequences offers multiple potentials to create functional biomaterials. However, it is challenging to overcome their structural defects for the development of biological fibers with a combination of high strength and high toughness. Herein, robust fibers from a recombinant unfolded protein consisting of resilin and supercharged polypeptide are fabricated via wet-spinning approaches. Particularly, the highly ordered structures induced by supramolecular complexation significantly improve the fiber's mechanical performance. In contrast to chemical fibers with high strength and low toughness (or vice versa), the present fibers demonstrate exceptional high strength and super-toughness, showing a breaking strength of ≈550 MPa and a toughness of ≈250 MJ m-3 , respectively, surpassing many polymers and artificial protein fibers. Remarkably, the outstanding biocompatibility and superior mechanical properties allow application of the constructed fiber patches for efficient abdominal hernia repair in rat models. In stark contrast to clinical patches, there is no observed tissue adhesion by this treatment. Therefore, this work provides a new type of engineered protein material for surgical applications.

Ultra-strong bio-glue from genetically engineered polypeptides.

The development of biomedical glues is an important, yet challenging task as seemingly mutually exclusive properties need to be combined in one material, i.e. strong adhesion and adaption to remodeling processes in healing tissue. Here, we report a biocompatible and biodegradable protein-based adhesive with high adhesion strengths. The maximum strength reaches 16.5 ± 2.2 MPa on hard substrates, which is comparable to that of commercial cyanoacrylate superglue and higher than other protein-based adhesives by at least one order of magnitude. Moreover, the strong adhesion on soft tissues qualifies the adhesive as biomedical glue outperforming some commercial products. Robust mechanical properties are realized without covalent bond formation during the adhesion process. A complex consisting of cationic supercharged polypeptides and anionic aromatic surfactants with lysine to surfactant molar ratio of 1:0.9 is driven by multiple supramolecular interactions enabling such strong adhesion. We demonstrate the glue's robust performance in vitro and in vivo for cosmetic and hemostasis applications and accelerated wound healing by comparison to surgical wound closures.

The effects of pressure intervention on wound healing and scar formation in a Bama minipig model.

Pressure therapy has been widely used in clinical practice for the prevention or treatment of hypertrophic scars resulted from aberrations in wound healing. However, the precise molecular mechanisms of this process are only partially understood. In the present study, we established a Bama minipig model to observe the effect of pressure intervention on wound healing and scar formation. Transcriptome sequencing was performed to analyze the gene expression profiles in the injured and pressure-treated tissues. Furthermore, expression of the critical factors associated with IGF-1/IGF-1R pathways including PI3K/AKT and MEK/ERK and collagens were further analyzed by quantitative polymerase chain reaction (q-PCR) and Western blot. We observed that the mRNA expression of IGF-1 and IGF-1R were down-regulated in the pressure treated groups. Following pressure intervention, the trend in expression of PI3K/AKT decreased, whereas that of MEK/ERK expression increased, when quantified by q-PCR. Moreover, the level of PI3K protein expression decreased significantly after pressure treatment for one month but there was no significant difference in AKT protein expression. Interestingly, the trend in MEK/ERK protein expression was opposite to that indicated by q-PCR analysis. Furthermore, collagen I and III mRNA clearly declined after one month pressure treatment. Taken together, these results indicated that pressure intervention alleviated scar formation may via inhibiting the IGF-1/IGF-1R signaling pathway and collagen expression in the Bama minipig model.

RNA-seq-based analysis of the hypertrophic scarring with and without pressure therapy in a Bama minipig model.

Pressure therapy has been proved to be an effective treatment for hypertrophic scars in a clinical setting. However, evidence-based data are controversial and the precise mechanism of action of this technique remains unknown. The aim of this study was to investigate the potential molecular mechanisms of pressure therapy for hypertrophic scars. We established a Bama minipig (Sus scrofa) model of hypertrophic scarring in which the scars were treated with pressure to explore the mechanism of action of the treatment. There were 568 differentially expressed genes (289 upregulated, 279 downregulated) after pressure therapy at 90 days post-injury, whereas only 365 genes were differentially expressed (250 upregulated, 115 downregulated) at 120 days post-injury. These genes were associated with metabolic pathways, ECM-receptor interaction, the PI3K-Akt and MAPK signaling pathways, focal adhesion and cytokine-cytokine receptor interaction. In addition, the qRT-PCR results indicated that the trend of gene expression following pressure therapy was mostly consistent across the two methods. In conclusion, our systematic analysis of the transcriptome has provided a better understanding of the molecular mechanisms involved in pressure therapy and offers an important basis for further studies of the complex signaling pathways regulated by the treatment.