Semisynthesis and antitumor activity of endertiin B and related triterpenoids from Ganoderma lucidum.

Ganoderma lucidum, a fungus used in traditional Chinese medicine, is known for its medicinal value attributed to its active components called Ganoderma triterpenoids (GTs). However, the limited isolation rate of these GTs has hindered their potential as promising drug candidates. Therefore, it is imperative to achieve large-scale preparation of GTs. In this study, four GTs were effectively synthesised from lanosterol. The antitumor activity of these GTs was evaluated in vivo. Endertiin B exhibited potent inhibitory activity against breast cancer cells (9.85 ± 0.91 µM and 12.12 ± 0.95 µM). Further investigations demonstrated that endertiin B significantly upregulated p21 and p27 and downregulated cyclinD1 expression, arresting the cell cycle at the G0/G1 phase and inducing apoptosis by decreasing BCL-2 and increasing BAX and BAK levels. Additionally, endertiin B was found to reduce the expression of proteins associated with the PI3K-AKT signaling pathway. To summarize, endertiin B effectively inhibited cell proliferation by blocking the cell cycle and inducing apoptosis through the PI3K-AKT pathway.

The Therapeutic Potential of Four Main Compounds of Zanthoxylum nitidum (Roxb.) DC: A Comprehensive Study on Biological Processes, Anti-Inflammatory Effects, and Myocardial Toxicity.

Zanthoxylum nitidum (Roxb.) DC. (Z. nitidum) is a traditional Chinese medicinal plant that is indigenous to the southern regions of China. Previous research has provided evidence of the significant anti-inflammatory, antibacterial, and anticancer properties exhibited by Z. nitidum. The potential therapeutic effects and cardiac toxicity of Z. nitidum remain uncertain. The aim of this research was to investigate the potential therapeutic properties of the four main compounds of Z. nitidum in cardiovascular diseases, their impact on the electrical activity of cardiomyocytes, and the underlying mechanism of their anti-inflammatory effects. We selected the four compounds from Z. nitidum with a high concentration and specific biological activity: nitidine chloride (NC), chelerythrine chloride (CHE), magnoflorine chloride (MAG), and hesperidin (HE). A proteomic analysis was conducted on the myocardial tissues of beagle dogs following the administration of NC to investigate the role of NC in vivo and the associated biological processes. A bioinformatic analysis was used to predict the in vivo biological processes that MAG, CHE, and HE were involved in. Molecular docking was used to simulate the binding between compounds and their targets. The effect of the compounds on ion channels in cardiomyocytes was evaluated through a patch clamp experiment. Organ-on-a-chip (OOC) technology was developed to mimic the physiological conditions of the heart in vivo. Proteomic and bioinformatic analyses demonstrated that the four compounds of Z. nitidum are extensively involved in various cardiovascular-related biological pathways. The findings from the patch clamp experiments indicate that NC, CHE, MAG, and HE elicit a distinct activation or inhibition of the IK1 and ICa-L in cardiomyocytes. Finally, the anti-inflammatory effects of the compounds on cardiomyocytes were verified using OOC technology. NC, CHE, MAG, and HE demonstrate anti-inflammatory effects through their specific interactions with prostaglandin-endoperoxide synthase 2 (PTGS2) and significantly influence ion channels in cardiomyocytes. Our study provides a foundation for utilizing NC, CHE, MAG, and HE in the treatment of cardiovascular diseases.

Lysimachia capillipes Hemsl. saponins ameliorate colorectal cancer in mice via regulating gut microbiota and restoring metabolic profiles.

Lysimachia capillipes Hemsl., a traditional Chinese medicine (TCM), is commonly prescribed for its anti-inflammatory and anti-tumor properties. Pharmacological studies have demonstrated that Lysimachia capillipes Hemsl. saponins (LCS) are the primary bioactive component. However, its mechanism for treating colorectal cancer (CRC) is still unknown. Increasing evidence suggests a close relationship between CRC, intestinal flora, and host metabolism. Thus, this study aims to investigate the mechanism of LCS amelioration of CRC from the perspective of the gut microbiome and metabolome. As a result, seven gut microbiotas and fourteen plasma metabolites were significantly altered between the control and model groups. Among them, one gut microbiota genera (Monoglobus) and six metabolites (Ureidopropionic acid, Cytosine, L-Proline, 3-hydroxyanthranilic acid, Cyclic AMP and Suberic acid) showed the most pronounced callback trend after LCS administration. Subsequently, the correlation analysis revealed significant associations between 68 pairs of associated metabolites and gut microbes, with 13 pairs of strongly associated metabolites regulated by the LCS. Taken together, these findings indicate that the amelioration of CRC by LCS is connected to the regulation of intestinal flora and the recasting of metabolic abnormalities. These insights highlight the potential of LCS as a candidate drug for the treatment of CRC.

Integrative physiological, metabolomic, and transcriptomic analysis reveals the drought responses of two apple rootstock cultivars.

BACKGROUND: Drought is considered the main environmental factor restricting apple production and thus the development of the apple industry. Rootstocks play an important role in enhancing the drought tolerance of apple plants. Studies of the physiology have demonstrated that 'ZC9-3' is a strong drought-resistant rootstock, whereas 'Jizhen-2' is a weak drought-resistant rootstock. However, the metabolites in these two apple rootstock varieties that respond to drought stress have not yet been characterized, and the molecular mechanisms underlying their responses to drought stress remain unclear. RESULTS: In this study, the physiological and molecular mechanisms underlying differences in the drought resistance of 'Jizhen-2' (drought-sensitive) and 'ZC9-3' (drought-resistant) apple rootstocks were explored. Under drought stress, the relative water content of the leaves was maintained at higher levels in 'ZC9-3' than in 'Jizhen-2', and the photosynthetic, antioxidant, and osmoregulatory capacities of 'ZC9-3' were stronger than those of 'Jizhen-2'. Metabolome analysis revealed a total of 95 and 156 differentially accumulated metabolites in 'Jizhen-2' and 'ZC9-3' under drought stress, respectively. The up-regulated metabolites in the two cultivars were mainly amino acids and derivatives. Transcriptome analysis revealed that there were more differentially expressed genes and transcription factors in 'ZC9-3' than in 'Jizhen-2' throughout the drought treatment. Metabolomic and transcriptomic analysis revealed that amino acid biosynthesis pathways play key roles in mediating drought resistance in apple rootstocks. A total of 13 metabolites, including L-α-aminoadipate, L-homoserine, L-threonine, L-isoleucine, L-valine, L-leucine, (2S)-2-isopropylmalate, anthranilate, L-tryptophan, L-phenylalanine, L-tyrosine, L-glutamate, and L-proline, play an important role in the difference in drought resistance between 'ZC9-3' and 'Jizhen-2'. In addition, 13 genes encoding O-acetylserine-(thiol)-lyase, S-adenosylmethionine synthetase, ketol-acid isomeroreductase, dihydroxyacid dehydratase, isopropylmalate isomerase, branched-chain aminotransferase, pyruvate kinase, 3-dehydroquinate dehydratase/shikimate 5-dehydrogenase, N-acetylglutamate-5-P-reductase, and pyrroline-5-carboxylate synthetase positively regulate the response of 'ZC9-3' to drought stress. CONCLUSIONS: This study enhances our understanding of the response of apple rootstocks to drought stress at the physiological, metabolic, and transcriptional levels and provides key insights that will aid the cultivation of drought-resistant apple rootstock cultivars. Especially, it identifies key metabolites and genes underlying the drought resistance of apple rootstocks.

Naringenin nanoparticles targeting cyclin B1 suppress the progression of rheumatoid arthritis-associated lung cancer by inhibiting fibroblast-to-myofibroblast transition.

There is growing evidence of an elevated risk of lung cancer in patients with rheumatoid arthritis. The poor prognosis of rheumatoid arthritis-associated lung cancer and the lack of therapeutic options pose an even greater challenge to the clinical management of patients. This study aimed to identify potential molecular targets associated with the progression of rheumatoid arthritis-associated lung cancer and examine the efficacy of naringenin nanoparticles targeting cyclin B1. Mendelian randomizatio analysis revealed that rheumatoid arthritis has a positive correlation with the risk of lung cancer. Cyclin B1 was significantly upregulated in patients with rheumatoid arthritis-associated lung cancer and was significantly overexpressed in synovial tissue fibroblasts. Furthermore, the overexpression of cyclin B1 in rheumatoid arthritis fibroblast-like synoviocytes, which promotes their proliferation and fibroblast-to-myofibroblast transition, can significantly contribute to the growth and infiltration of lung cancer cells. Importantly, our prepared naringenin nanoparticles targeting cyclin B1 effectively attenuated proliferation and fibroblast-to-myofibroblast transition by blocking cells at the G2/M phase. In vivo experiments, naringenin nanoparticles targeting cyclin B1 significantly alleviated the development of collagen-induced arthritis and lung orthotopic tumors. Collectively, our results reveal that naringenin nanoparticles targeting cyclin B1 can suppress the progression of rheumatoid arthritis-associated lung cancer by inhibiting fibroblast-to-myofibroblast transition. These findings provide new insights into the treatment of rheumatoid arthritis-associated lung cancer therapy.

Nobiletin enhances mitochondrial function by regulating SIRT1/PGC-1α signaling in porcine oocytes during in vitro maturation.

Nobiletin is a natural flavonoid found in citrus fruits with beneficial effects, including anti-inflammatory, anti-cancer and anti-oxidation effects. The aim of this study was to investigate whether nobiletin improves mitochondrial function in porcine oocytes and examine the underlying mechanism. Oocytes enclosed by cumulus cells were cultured in TCM-199 for 44 h with 0.1% dimethyl sulfoxide (control), or supplemented with 5, 10, 25, and 50 µM of nobiletin (Nob5, Nob10, Nob25, and Nob50, respectively). Oocyte maturation rate was significantly enhanced in Nob10 (70.26 ± 0.45%) compared to the other groups (control: 60.12 ± 0.47%; Nob5: 59.44 ± 1.63%; Nob25: 63.15 ± 1.38%; Nob50: 46.57 ± 1.19%). The addition of nobiletin reduced the levels of reactive oxygen species and increased glutathione levels. Moreover, Nob10 promoted mitochondrial biogenesis by upregulating the protein levels of sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α). This resulted in an increase in the number of active mitochondria, mitochondrial DNA copy number, mitochondrial membrane potential, and ATP production, thereby enhancing mitochondrial function. The protein level of p53 decreased, followed by the phosphorylation of B-cell lymphoma 2, suggesting a reduction in mitochondria-mediated apoptosis in the Nob10 group. Additionally, the release of cytochrome c from the mitochondria was significantly diminished along with a decrease in the protein expression of caspase 3. Thus, nobiletin has a great potential to promote the in vitro maturation of porcine oocytes by suppressing oxidative stress and promoting mitochondrial function through the upregulation of the SIRT1/PGC-1α signaling pathway.

Role of artificial intelligence in digital pathology for gynecological cancers.

The diagnosis of cancer is typically based on histopathological sections or biopsies on glass slides. Artificial intelligence (AI) approaches have greatly enhanced our ability to extract quantitative information from digital histopathology images as a rapid growth in oncology data. Gynecological cancers are major diseases affecting women's health worldwide. They are characterized by high mortality and poor prognosis, underscoring the critical importance of early detection, treatment, and identification of prognostic factors. This review highlights the various clinical applications of AI in gynecological cancers using digitized histopathology slides. Particularly, deep learning models have shown promise in accurately diagnosing, classifying histopathological subtypes, and predicting treatment response and prognosis. Furthermore, the integration with transcriptomics, proteomics, and other multi-omics techniques can provide valuable insights into the molecular features of diseases. Despite the considerable potential of AI, substantial challenges remain. Further improvements in data acquisition and model optimization are required, and the exploration of broader clinical applications, such as the biomarker discovery, need to be explored.

CAISHI: A benchmark histopathological H&E image dataset for cervical adenocarcinoma in situ identification, retrieval and few-shot learning evaluation.

A benchmark histopathological Hematoxylin and Eosin (H&E) image dataset for Cervical Adenocarcinoma in Situ (CAISHI), containing 2240 histopathological images of Cervical Adenocarcinoma in Situ (AIS), is established to fill the current data gap, of which 1010 are images of normal cervical glands and another 1230 are images of cervical AIS. The sampling method is endoscope biopsy. Pathological sections are obtained by H&E staining from Shengjing Hospital, China Medical University. These images have a magnification of 100 and are captured by the Axio Scope. A1 microscope. The size of the image is 3840 × 2160 pixels, and the format is ".png". The collection of CAISHI is subject to an ethical review by China Medical University with approval number 2022PS841K. These images are analyzed at multiple levels, including classification tasks and image retrieval tasks. A variety of computer vision and machine learning methods are used to evaluate the performance of the data. For classification tasks, a variety of classical machine learning classifiers such as k-means, support vector machines (SVM), and random forests (RF), as well as convolutional neural network classifiers such as Residual Network 50 (ResNet50), Vision Transformer (ViT), Inception version 3 (Inception-V3), and Visual Geometry Group Network 16 (VGG-16), are used. In addition, the Siamese network is used to evaluate few-shot learning tasks. In terms of image retrieval functions, color features, texture features, and deep learning features are extracted, and their performances are tested. CAISHI can help with the early diagnosis and screening of cervical cancer. Researchers can use this dataset to develop new computer-aided diagnostic tools that could improve the accuracy and efficiency of cervical cancer screening and advance the development of automated diagnostic algorithms.

Role of uranium toxicity and uranium-induced oxidative stress in advancing kidney injury and endothelial inflammation in rats.

OBJECTIVE: Uranium exposure may cause serious pathological injury to the body, which is attributed to oxidative stress and inflammation. However, the pathogenesis of uranium toxicity has not been clarified. Here, we evaluated the level of oxidative stress to determine the relationship between uranium exposure, nephrotoxic oxidative stress, and endothelial inflammation. METHODS: Forty male Sprague-Dawley rats were divided into three experimental groups (U-24h, U-48h, and U-72h) and one control group. The three experimental groups were intraperitoneally injected with 2.0 mg/kg uranyl acetate, and tissue and serum samples were collected after 24, 48, and 72 h, respectively, whereas the control group was intraperitoneally injected with 1.0 ml/kg normal saline and samples were collected after 24 h. Then, we observed changes in the uranium levels and oxidative stress parameters, including the total oxidative state (TOS), total antioxidant state (TAS), and oxidative stress index (OSI) in kidney tissue and serum. We also detected the markers of kidney injury, namely urea (Ure), creatine (Cre), cystatin C (CysC), and neutrophil gelatinase-associated lipocalin (NGAL). The endothelial inflammatory markers, namely C-reactive protein (CRP), lipoprotein phospholipase A2 (Lp-PLA2), and homocysteine (Hcy), were also quantified. Finally, we analyzed the relationship among these parameters. RESULTS: TOS (z = 3.949; P < 0.001), OSI (z = 5.576; P < 0.001), Ure (z = 3.559; P < 0.001), Cre (z = 3.476; P < 0.001), CysC (z = 4.052; P < 0.001), NGAL (z = 3.661; P < 0.001), and CRP (z = 5.286; P < 0.001) gradually increased after uranium exposure, whereas TAS (z = -3.823; P < 0.001), tissue U (z = -2.736; P = 0.001), Hcy (z = -2.794; P = 0.005), and Lp-PLA2 (z = -4.515; P < 0.001) gradually decreased. The serum U level showed a V-shape change (z = -1.655; P = 0.094). The uranium levels in the kidney tissue and serum were positively correlated with TOS (r = 0.440 and 0.424; P = 0.005 and 0.007) and OSI (r = 0.389 and 0.449; P = 0.013 and 0.004); however, serum U levels were negatively correlated with TAS (r = -0.349; P = 0.027). Partial correlation analysis revealed that NGAL was closely correlated to tissue U (rpartial = 0.455; P = 0.003), CysC was closely correlated to serum U (rpartial = 0.501; P = 0.001), and Lp-PLA2 was closely correlated to TOS (rpartial = 0.391; P = 0.014), TAS (rpartial = 0.569; P < 0.001), and OSI (rpartial = -0.494; P = 0.001). Pearson correlation analysis indicated that the Hcy levels were negatively correlated with tissue U (r = -0.344; P = 0.030) and positively correlated with TAS (r = 0.396; P = 0.011). CONCLUSION: The uranium-induced oxidative injury may be mainly reflected in enhanced endothelial inflammation, and the direct chemical toxicity of uranium plays an important role in the process of kidney injury, especially in renal tubular injury. In addition, CysC may be a sensitive marker reflecting the nephrotoxicity of uranium; however, Hcy is not suitable for evaluating short-term endothelial inflammation involving oxidative stress.

Enterovirus D68 3C protease antagonizes type I interferon signaling by cleaving signal transducer and activator of transcription 1.

Following the successful control of poliovirus, the re-emergence of respiratory enterovirus D68 (EV-D68), a prominent non-polio enterovirus, has become a serious public health concern worldwide. Host innate immune responses are the primary defense against EV-D68 invasion; however, the mechanism underlying viral evasion of the antiviral activity of interferons (IFN) remains unclear. In this study, we found that EV-D68 inhibited type I IFN signaling by cleaving signal transducer and activator of transcription 1 (STAT1), a crucial factor in cellular responses to interferons and other cytokines. We observed that the prototype and circulating EV-D68 strains conserved their ability to induce STAT1 cleavage and attenuate IFN signal transduction. Further investigation revealed that EV-D68 3C protease cleaves STAT1 at the 131Q residue. Interestingly, not all enterovirus-encoded 3C proteases exhibited this ability. EV-D68 and poliovirus 3C proteases efficiently induced STAT1 cleavage; whereas, 3C proteases from EV-A71, coxsackievirus A16, and echoviruses did not. STAT1 cleavage also abolished the nuclear translocation capacity of STAT1 in response to IFN stimulation to activate downstream signaling elements. Overall, these results suggest that STAT1, targeted by viral protease 3C, is utilized by EV-D68 to subvert the host's innate immune response.IMPORTANCEEnterovirus D68 (EV-D68) has significantly transformed over the past decade, evolving from a rare pathogen to a potential pandemic pathogen. The interferon (IFN) signaling pathway is an important defense mechanism and therapeutic target for the host to resist viral invasion. Previous studies have reported that the EV-D68 virus blocks or weakens immune recognition and IFN production in host cells through diverse strategies; however, the mechanisms of EV-D68 resistance to IFN signaling have not been fully elucidated. Our study revealed that EV-D68 relies on its own encoded protease, 3C, to directly cleave signal transducer and activator of transcription 1 (STAT1), a pivotal transduction component in the IFN signaling pathway, disrupting the IFN-mediated antiviral response. Previous studies on human enteroviruses have not documented direct cleavage of the STAT1 protein to evade cellular immune defenses. However, not all enteroviral 3C proteins can cleave STAT1. These findings highlight the diverse evolutionary strategies different human enteroviruses employ to evade host immunity.

SARS-CoV-2 and oncolytic EV-D68-encoded proteases differentially regulate pyroptosis.

Pyroptosis, a pro-inflammatory programmed cell death, has been implicated in the pathogenesis of coronavirus disease 2019 and other viral diseases. Gasdermin family proteins (GSDMs), including GSDMD and GSDME, are key regulators of pyroptotic cell death. However, the mechanisms by which virus infection modulates pyroptosis remain unclear. Here, we employed a mCherry-GSDMD fluorescent reporter assay to screen for viral proteins that impede the localization and function of GSDMD in living cells. Our data indicated that the main protease NSP5 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) blocked GSDMD-mediated pyroptosis via cleaving residues Q29 and Q193 of GSDMD. While another SARS-CoV-2 protease, NSP3, cleaved GSDME at residue G370 but activated GSDME-mediated pyroptosis. Interestingly, respiratory enterovirus EV-D68-encoded proteases 3C and 2A also exhibit similar differential regulation on the functions of GSDMs by inactivating GSDMD but initiating GSDME-mediated pyroptosis. EV-D68 infection exerted oncolytic effects on human cancer cells by inducing pyroptotic cell death. Our findings provide insights into how respiratory viruses manipulate host cell pyroptosis and suggest potential targets for antiviral therapy as well as cancer treatment.IMPORTANCEPyroptosis plays a crucial role in the pathogenesis of coronavirus disease 2019, and comprehending its function may facilitate the development of novel therapeutic strategies. This study aims to explore how viral-encoded proteases modulate pyroptosis. We investigated the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory enterovirus D68 (EV-D68) proteases on host cell pyroptosis. We found that SARS-CoV-2-encoded proteases NSP5 and NSP3 inactivate gasdermin D (GSDMD) but initiate gasdermin E (GSDME)-mediated pyroptosis, respectively. We also discovered that another respiratory virus EV-D68 encodes two distinct proteases 2A and 3C that selectively trigger GSDME-mediated pyroptosis while suppressing the function of GSDMD. Based on these findings, we further noted that EV-D68 infection triggers pyroptosis and produces oncolytic effects in human carcinoma cells. Our study provides new insights into the molecular mechanisms underlying virus-modulated pyroptosis and identifies potential targets for the development of antiviral and cancer therapeutics.

LncRNA AGAP2 antisense RNA 1 stabilized by insulin-like growth factor 2 mRNA binding protein 3 promotes macrophage M2 polarization in clear cell renal cell carcinoma through regulation of the microRNA-9-5p/THBS2/PI3K-Akt pathway.

BACKGROUND: Increasing evidence highlights the potential role of long non-coding RNAs (lncRNAs) in the biological behaviors of renal cell carcinoma (RCC). Here, we explored the mechanism of AGAP2-AS1 in the occurrence and development of clear cell RCC (ccRCC) involving IGF2BP3/miR-9-5p/THBS2. METHODS: The expressions of AGAP2-AS1, IGF2BP3, miR-9-5p, and THBS2 and their relationship were analyzed by bioinformatics. The targeting relationship between AGAP2-AS1 and miR-9-5p and between miR-9-5p and THBS2 was evaluated with their effect on cell biological behaviors and macrophage polarization assayed. Finally, we tested the effect of AGAP2-AS1 on ccRCC tumor formation in xenograft tumors. RESULTS: IGF2BP3 could stabilize AGAP2-AS1 through m6A modification. AGAP2-AS1 was highly expressed in ccRCC tissues and cells. The lentivirus-mediated intervention of AGAP2-AS1 induced malignant behaviors of ccRCC cells and led to M2 polarization of macrophages. In addition, THBS2 promoted M2 polarization of macrophages by activating the PI3K/AKT signaling pathway. AGAP2-AS1 could directly bind with miR-9-5p and promote the expression of THBS2 downstream of miR-9-5p. These results were further verified by in vivo experiments. CONCLUSION: AGAP2-AS1 stabilized by IGF2BP3 competitively binds to miR-9-5p to up-regulate THBS2, activating the PI3K/AKT signaling pathway and inducing macrophage M2 polarization, thus facilitating the development of RCC.

Gasdermin D: A Potential New Auxiliary Pan-Biomarker for the Detection and Diagnosis of Diseases.

Pyroptosis is a form of programmed cell death mediated by gasdermins, particularly gasdermin D (GSDMD), which is widely expressed in tissues throughout the body. GSDMD belongs to the gasdermin family, which is expressed in a variety of cell types including epithelial cells and immune cells. It is involved in the regulation of anti-inflammatory responses, leading to its differential expression in a wide range of diseases. In this review, we provide an overview of the current understanding of the major activation mechanisms and effector pathways of GSDMD. Subsequently, we examine the importance and role of GSDMD in different diseases, highlighting its potential as a pan-biomarker. We specifically focus on the biological characteristics of GSDMD in several diseases and its promising role in diagnosis, early detection, and differential diagnosis. Furthermore, we discuss the application of GSDMD in predicting prognosis and monitoring treatment efficacy in cancer. This review proposes a new strategy to guide therapeutic decision-making and suggests potential directions for further research into GSDMD.

FLED: a full-length eccDNA detector for long-reads sequencing data.

Reconstructing the full-length sequence of extrachromosomal circular DNA (eccDNA) from short sequencing reads has proved challenging given the similarity of eccDNAs and their corresponding linear DNAs. Previous sequencing methods were unable to achieve high-throughput detection of full-length eccDNAs. Herein, a novel algorithm was developed, called Full-Length eccDNA Detection (FLED), to reconstruct the sequence of eccDNAs based on the strategy that combined rolling circle amplification and nanopore long-reads sequencing technology. Seven human epithelial and cancer cell line samples were analyzed by FLED and over 5000 full-length eccDNAs were identified per sample. The structures of identified eccDNAs were validated by both Polymerase Chain Reaction (PCR) and Sanger sequencing. Compared to other published nanopore-based eccDNA detectors, FLED exhibited higher sensitivity. In cancer cell lines, the genes overlapped with eccDNA regions were enriched in cancer-related pathways and cis-regulatory elements can be predicted in the upstream or downstream of intact genes on eccDNA molecules, and the expressions of these cancer-related genes were dysregulated in tumor cell lines, indicating the regulatory potency of eccDNAs in biological processes. The proposed method takes advantage of nanopore long reads and enables unbiased reconstruction of full-length eccDNA sequences. FLED is implemented using Python3 which is freely available on GitHub (https://github.com/FuyuLi/FLED).

Doxorubicin-Loaded Liposome with the Function of "Killing Two Birds with One Stone" against Glioma.

The blood-brain barrier (BBB) continues to be one of the main clinical obstacles in the treatment of glioma. Current chemotherapies always bring many different side effects, some even permanent. To date, nanomaterial-based vehicles have shown great potential in treating glioma. Herein, we developed a dual targeting liposomal delivery vector loaded with the anticancer drug doxorubicin (DOX) to treat glioma. SS31, a small peptide, has shown dual targeting effects of penetrating the BBB and specifically targeting mitochondria. In this study, a new liposomal delivery system, LS-DOX, was prepared by modifying DOX-loaded liposomes with SS31 for the treatment of in situ glioma. The liposomes demonstrated a high drug encapsulation rate and drug-loading capacity, satisfactory biocompatibility, high glioma accumulation ability, and good stability in vitro. Experimental results showed that the liposomes could effectively cross the BBB and target gliomas, and mitochondria-targeting of SS31 enhances cell uptake. In addition, the liposomes showed a good therapeutic effect on nude mice with glioma in situ with no obvious toxicity and side effects. Therefore, the present research will provide a novel alternative and reference for the effective treatment of glioma.

Design of a novel multi-epitope vaccine candidate against endometrial cancer using immunoinformatics and bioinformatics approaches.

Endometrial cancer (EC) is one of the most common cancers of the female reproductive system. Multi-epitope vaccine may be a promising and effective strategy against EC. In this study, we designed a novel multi-epitope vaccine based on the antigenic proteins PRAME and TMPRSS4 using immunoinformatics and bioinformatics approaches. After a rigorous selection process, 14 cytotoxic T lymphocyte (CTL) epitopes, 6 helper T lymphocyte (HTL) epitopes, and 8 B cell epitopes (BCEs) were finally selected for vaccine construction. To enhance the immunogenicity of the vaccine candidate, the pan HLA DR-binding epitope was included in the vaccine design as an adjuvant. The final vaccine construct had 455 amino acids and a molecular weight of 49.8 kDa, and was predicted to cover 95.03% of the total world population. Docking analysis showed that there were 10 hydrogen bonds and 19 hydrogen bonds in the vaccine-HLA-A*02:01 and vaccine-HLA-DRB1*01:01 complexes, respectively, indicating that the vaccine has a good affinity to MHC molecules. This was further supported by molecular dynamics (MD) simulation. Immune simulation showed that the designed vaccine was able to induce higher levels of immune cell activity, with the secretion of numerous cytokines. The codon adaptation index (CAI) value and GC content of the optimised codon sequences of the vaccine were 0.986 and 54.43%, respectively, indicating that the vaccine has the potential to be highly expressed. The in silico analysis suggested that the designed vaccine may provide a novel therapeutic option for the individualised treatment of EC patients in the future.Communicated by Ramaswamy H. Sarma.

Effect of Achiral Glycine Residue on the Handedness of Surfactant-Like Short Peptide Self-Assembly Nanofibers.

Surfactant-like short peptides are a kind of ideal model for the study of chiral self-assembly. At present, there are few studies on the chiral self-assembly of multicharged surfactant-like peptides. In this study, we adopted a series of short peptides of Ac-I4KGK-NH2 with different combinations of L-lysine and D-lysine residues as the model molecules. TEM, AFM and SANS results showed that Ac-I4LKGLK-NH2, Ac-I4LKGDK-NH2, and Ac-I4DKGLK-NH2 formed the morphologies of nanofibers, and Ac-I4DKGDK-NH2 formed nanoribbons. All the self-assembled nanofibers, including the intermediate nanofibers of Ac-I4DKGDK-NH2 nanoribbons, showed the chirality of left handedness. Based on the molecular simulation results, it has been demonstrated that the supramolecular chirality was directly dictated by the orientation of single ß strand. The insertion of glycine residue demolished the effect of lysine residues on the single strand conformation due to its high conformational flexibility. The replacement of L-isoleucine with Da-isoleucine also confirmed that the isoleucine residues involved in the ß-sheet determined the supramolecular handedness. This study provides a profound mechanism of the chiral self-assembly of short peptides. We hope that it will improve the regulation of chiral molecular self-assembly with achiral glycine, as well.

Tetrahydroberberrubine prevents peritoneal adhesion by suppressing inflammation and extracellular matrix accumulation.

Peritoneal adhesion is a common abdominal surgical complication that induces abdominal haemorrhage, intestinal obstruction, infertility, and so forth. The high morbidity and recurrence rate of this disease indicate the need for novel therapeutic approaches. Here, we revealed the protective roles of tetrahydroberberrubine (THBru), a novel derivative of berberine (BBR), in preventing peritoneal adhesion and identified its underlying mechanism in vivo and in vitro. Abrasive surgery was used to create a peritoneal adhesion rat model. We found that THBru administration markedly ameliorated peritoneal adhesion, as indicated by a lowered adhesion score and ameliorated caecal tissue damage. By comparison, THBru exhibited more potent anti-adhesion effects than BBR at the same dose. Mechanistically, THBru inhibited inflammation and extracellular matrix (ECM) accumulation in the microenvironment of adhesion tissue. THBru suppressed the expression of inflammatory cytokines including interleukin-1ß (IL-1ß), IL-6, transforming growth factor ß (TGF-ß), tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1), by regulating the transforming growth factor beta-activated kinase 1 (TAK1)/c-Jun N-terminal kinase (JNK) and TAK1/nuclear factor κB (NF-κB) signaling pathways. However, THBru promoted the activation of MMP-3 by directly blocking the TIMP-1 activation core and subsequently decreased collagen deposition. Taken together, this study identifies THBru as an effective anti-adhesion agent that regulates diverse mechanisms, thereby outlining its potential therapeutic implications for the treatment of peritoneal adhesion.

Y-box binding protein 1 influences zygotic genome activation by regulating N6-methyladenosine in porcine embryos.

Y-box binding protein 1 (YBX1) is a member of the family of DNA- and RNA-binding proteins that play crucial roles in multiple aspects, including RNA stabilization, translational repression, and transcriptional regulation; however, its roles in embryo development remain less known. In this study, to investigate the function of YBX1 and its mechanism of action in porcine embryo development, YBX1 was knocked down by microinjecting YBX1 siRNA at the one-cell stage. YBX1 is located in the cytoplasm during embryonic development. The mRNA level of YBX1 was increased from the four-cell stage to the blastocyst stage but was significantly decreased in YBX1 knockdown embryos compared with the control. Moreover, the percentage of blastocysts was decreased following YBX1 knockdown compared with the control. Defecting YBX1 expression increased maternal gene mRNA expression and decreased zygotic genome activation (ZGA) gene mRNA expression and histone modification owing to decreased levels of N6-methyladenosine (m6A) writer N6-adenosine-methyltransferase 70 kDa subunit (METTL3) and reader insulin-like growth factor 2 mRNA-binding protein (IGF2BP1). In addition, IGF2BP1 knockdown showed that YBX1 regulated the ZGA process through m6A modification. In conclusion, YBX1 is essential for early embryo development because it regulates the ZGA process.

A novel cosmetic approach for partial matricectomy in treating ingrown toenails.

BACKGROUND: Toenails play a great part in protecting toes and peripheral soft tissues, simultaneously playing a cosmetic role. The ideal treatment should result in a functional and aesthetic outcome. OBJECTIVE: To describe a novel, aesthetic and minimally invasive method to treat ingrown toenail. METHODS: We retrospectively analyzed 436 lesions of 395 ingrown toes in 353 patients with a mean age of 26.0 ± 13.4 (range 10-55) from June 2014 to March 2020 in our department. A novel cosmetic approach for partial matricectomy in treating ingrown toenails was undergone. The average follow-up time was 27.5 ± 2.8 months. The average period prior to work resumption, recurrence rate, and infection rate were measured. Mean pain Visual Analogue Scale (VAS) and Mean satisfaction VAS were used to evaluate the foot appearance. RESULTS: The average period prior work resumption was 2.2 ± 2.1 days (range, 0-7 days). The recurrence rate was 1.6% (7 lesions in 6 patients) at more than 2 years of follow-up. There was no critical complication except infection (0.46%). Mean pain VAS reduced from a preoperative score of 7.7 ± 1.5 points (range, 6-10 points) to a postoperative 3-day score of 2.2 ± 1.0 points (range, 1-4 points; p < 0.001) while Mean satisfaction VAS improved from 1.5 ± 1.3 points (range, 0-3 points) to 9.2 ± 0.6 points (range, 8-10 points; p < 0.001). CONCLUSION: Our proposed approach is minimally invasive relative to conventional methods, which can achieve comparable efficacy to treat ingrown toenails with granulation tissue. Therefore, it can serve as another option to treat this specific type of ingrown toenails.