Self-Adapting Biomass Hydrogel Embodied with miRNA Immunoregulation and Long-Term Bacterial Eradiation for Synergistic Chronic Wound Therapy.

Chronic wound rescue is critical for diabetic patients but is challenging to achieve with a specific and long-term strategy. The prolonged bacterial inflammation is particularly prevalent in hyperglycemia-induced wounds, usually leading to severe tissue damage. Such a trend could further suffer from an environmental suitability provided by macrophages for persisting Staphylococcus aureus (S. aureus) and even deteriorate by their mutual reinforcement. However, the strategy of both suppressing bacteria growth and immunoreprogramming the inflammatory type of macrophages to break their vicious harm to wound healing is still lacking. Here, a self-adapting biomass carboxymethyl chitosan (CMC) hydrogel comprising immunomodulatory nanoparticles is reported to achieve Gram-negative/Gram-positive bacteria elimination and anti-inflammatory cytokines induction to ameliorate the cutaneous microenvironment. Mechanistically, antibacterial peptides and CMCs synergistically result in a long-term inhibition against methicillin-resistant S. aureus (MRSA) over a period of 7 days, and miR-301a reprograms the M2 macrophage via the PTEN/PI3Kγ/mTOR signaling pathway, consequently mitigating inflammation and promoting angiogenesis for diabetic wound healing in rats. In this vein, immunoregulatory hydrogel is a promising all-biomass dressing ensuring biocompatibility, providing a perspective to regenerate cutaneous damaged tissue, and repairing chronic wounds on skin.

Research Progress on Flavonoids in Traditional Chinese Medicine to Counteract Cardiotoxicity Associated with Anti-Tumor Drugs.

The development of anti-tumor drugs has notably enhanced the survival rates and quality of life for patients with malignant tumors. However, the side effects of these drugs, especially cardiotoxicity, significantly limit their clinical application. The cardiotoxicity associated with anti-tumor drugs has been a subject of extensive attention and research. Traditional to mitigate these side effects have included reducing drug dosages, shortening treatment duration, modifying administration methods, and opting for drugs with lower toxicity. However, either approach may potentially compromise the anti-tumor efficacy of the medications. Therefore, exploring other effective methods for anti-cardiotoxicity will be the focus of future research. The potential of traditional Chinese medicine (TCM) in managing cardiovascular diseases and cancer treatment has gained widespread recognition. TCM is valued for its minimal side effects, affordability, and accessibility, offering promising avenues in the prevention and treatment of cardiotoxicity caused by anti-tumor drugs. Among its constituents, flavonoids, which are present in many TCMs, are particularly notable. These monomeric compounds with distinct structural components have been shown to possess both cardiovascular protective properties and anti-tumor capabilities. In this discussion, we will delve into the classification of anti-tumor drugs and explore the underlying mechanisms of their associated cardiotoxicity. Additionally, we will examine flavonoids found in TCM and investigate their mechanisms of cardiovascular protection. This will include an analysis of how these natural compounds can mitigate the cardiac side effects of anti-tumor therapies while potentially enhancing overall patient health and treatment outcomes.

CDKN2A inhibited ferroptosis through activating JAK2/STAT3 pathway to modulate cisplatin resistance in cervical squamous cell carcinoma.

Cervical squamous cell carcinoma (CESC) is a significant threat to women's health. Resistance to cisplatin (DDP), a common treatment, hinders the therapeutic efficacy. Understanding the molecular basis of DDP resistance in CESC is imperative. Cyclin-dependent kinase inhibitor 2A (CDKN2A) expression was evaluated through quantitative real-time-PCR and western blot in clinical samples from 30 CESC patients and human cervical epithelial cells and CESC cell lines (SiHa, C33A, and Caski). It was also evaluated through bioinformatics analysis in Timer, Ualcan, and GEPIA database. Cell viability was detected by CCK-8. Apoptosis was detected by Calcein AM/PI assay. Lipid reactive oxygen species (ROS), malondialdehyde, glutathione, Fe 2+ , and iron level were detected by kits. Protein level of JAK2, STAT3, p-JAK2, p-STAT3, ACSL4, GPX4, SLC7A11, and FTL were detected by western blot. In CESC, elevated CDKN2A expression was observed. Cisplatin exhibited a dual effect, inhibiting cell proliferation and inducing ferroptosis in CESC. CDKN2A knockdown in a cisplatin-resistant cell line suppressed proliferation and induced ferroptosis. Moreover, CDKN2A was identified as an inhibitor of erastin-induced ferroptosis. Additionally, targeting the JAK2/STAT3 pathway enhanced ferroptosis in cisplatin-resistant cells. CDKN2A could inhibit ferroptosis in CESC through activating JAK2/STAT3 pathway to modulate cisplatin resistance.

Food therapy of scutellarein ameliorates pirarubicin­induced cardiotoxicity in rats by inhibiting apoptosis and ferroptosis through regulation of NOX2­induced oxidative stress.

Pirarubicin (THP) is one of the most commonly used antineoplastic drugs in clinical practice. However, its clinical application is limited due to its toxic and heart­related side effects. It has been reported that oxidative stress, inflammation and apoptosis are closely associated with cardiotoxicity caused by pirarubicin (CTP). Additionally, it has also been reported that scutellarein (Sc) exerts anti­inflammatory, antioxidant, cardio­cerebral vascular protective and anti­apoptotic properties. Therefore, the present study aimed to investigate the effect of food therapy with Sc on CTP and its underlying molecular mechanism using echocardiography, immunofluorescence, western blot, ROS staining, and TUNEL staining. The in vivo results demonstrated that THP was associated with cardiotoxicity. Additionally, abnormal changes in the expression of indicators associated with oxidative stress, ferroptosis and apoptosis were observed, which were restored by Sc. Therefore, it was hypothesized that CTP could be associated with oxidative stress, ferroptosis and apoptosis. Furthermore, the in vitro experiments showed that Sc and the NADPH oxidase 2 (NOX2) inhibitor, GSK2795039 (GSK), upregulated glutathione peroxidase 4 (GPX4) and inhibited THP­induced oxidative stress, apoptosis and ferroptosis. However, cell treatment with the ferroptosis inhibitor, ferrostatin­1, or inducer, erastin, could not significantly reduce or promote, respectively, the expression of NOX2. However, GSK significantly affected ferroptosis and GPX4 expression. Overall, the results of the present study indicated that food therapy with Sc ameliorated CTP via inhibition of apoptosis and ferroptosis through regulation of NOX2­induced oxidative stress, thus suggesting that Sc may be a potential therapeutic drug against CTP.

The role of TRPV4 in programmed cell deaths.

Programmed cell death is a major life activity of both normal development and disease. Necroptosis is early recognized as a caspase-independent form of programmed cell death followed obviously inflammation. Apoptosis is a gradually recognized mode of cell death that is characterized by a special morphological changes and unique caspase-dependent biological process. Ferroptosis, pyroptosis and autophagy are recently identified non-apoptotic regulated cell death that each has its own characteristics. The transient receptor potential vanilloid 4 (TRPV4) is a kind of nonselective calcium-permeable cation channel, which is received more and more attention in biology studies. It is widely expressed in human tissues and mainly located on the membrane of cells. Several researchers have identified that the influx Ca2+ from TRPV4 acts as a key role in the loss of cells by apoptosis, ferroptosis, necroptosis, pyroptosis and autophagy via mediating endoplasmic reticulum (ER) stress, oxidative stress and inflammation. This effect is bad for the normal function of organs on the one hand, on the other hand, it is benefit for anticancer activities. In this review, we will summarize the current discovery on the role and impact of TRPV4 in these programmed cell death pathological mechanisms to provide a new prospect of gene therapeutic target of related diseases.

Method for the extraction of circulating nucleic acids based on MOF reveals cell-free RNA signatures in liver cancer.

Cell-free RNA (cfRNA) allows assessment of health, status, and phenotype of a variety of human organs and is a potential biomarker to non-invasively diagnose numerous diseases. Nevertheless, there is a lack of highly efficient and bias-free cfRNA isolation technologies due to the low abundance and instability of cfRNA. Here, we developed a reproducible and high-efficiency isolation technology for different types of cell-free nucleic acids (containing cfRNA and viral RNA) in serum/plasma based on the inclusion of nucleic acids by metal-organic framework (MOF) materials, which greatly improved the isolation efficiency and was able to preserve RNA integrity compared with the most widely used research kit method. Importantly, the quality of cfRNA extracted by the MOF method is about 10-fold that of the kit method, and the MOF method isolates more than three times as many different RNA types as the kit method. The whole transcriptome mapping characteristics of cfRNA in serum from patients with liver cancer was described and a cfRNA signature with six cfRNAs was identified to diagnose liver cancer with high diagnostic efficiency (area under curve = 0.905 in the independent validation cohort) using this MOF method. Thus, this new MOF isolation technique will advance the field of liquid biopsy, with the potential to diagnose liver cancer.

Bioinformatics and experimental studies jointly reveal that Sacubitril Valsartan improves myocardial oxidative stress and inflammation by regulating the MAPK signaling pathway to treat chemotherapy related cardiotoxicity.

BACKGROUND: CRC is a common but serious complication or sequela of tumor treatment, and new coping strategies are urgently needed. SV is a classic clinical cardiovascular protective drug, which has been widely used in the treatment of heart failure, hypertension and other diseases. It has good therapeutic effect in other cardiovascular diseases such as diabetes cardiomyopathy, ischemic cardiomyopathy and vascular disease, but it has not been proved by research that SV can prevent and treat CRC. METHOD: In this study, DOX was used to induce a rat CRC model and evaluate the therapeutic effect of SV on it. Subsequently, R software was applied to analyze the control group, SV group, and DOX group in databases GSE207283 and GSE22369, and to screen for common differentially expressed genes. Use the DAVID website for enrichment analysis and visualization. Use STRING website to analyze and visualize protein interaction networks of key genes. Finally, experimental verification was conducted on key genes. RESULT: Our research results show that SV has a protective effect on DOX induced myocardial injury by alleviating Weight loss, increasing Ejection fraction, and reducing the level of biomarkers of myocardial injury. Meanwhile, SV can effectively alleviate the above abnormalities. Bioinformatics and KEGG pathway analysis showed significant enrichment of metabolic and MAPK signaling pathways, suggesting that they may be the main regulatory pathway for SV treatment of CRC. Subsequent studies have also confirmed that SV can inhibit DOX induced myocardial injury through the MAPK signaling pathway, and alleviate DOX induced oxidative stress and inflammatory states. CONCLUSION: Our research indicates that SV is a potential drug for treating CRC and preliminarily elucidates its molecular mechanism of regulating the MAPK pathway to improve oxidative stress and inflammation.

Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis.

Cyclophilin D (CypD) is a mitochondrial matrix peptidyl prolidase that regulates the mitochondrial permeability transition pore. Inhibition of CypD was suggested as a therapeutic strategy for acute pancreatitis. Peptide inhibitors emerged as novel binding ligand for blocking receptor activity. In this study, we present our computational approach for designing peptide inhibitors of CypD. The 3-D structure of random peptides were built, and docked into the active center of CypD using Rosetta script integrated FlexPepDock module. The peptide displayed the lowest binding energy against CypD was further selected for virtual iterative mutation based on virtual mutagenesis and molecular docking. Finally, the top 5 peptides with the lowest binding energy was selected for validating their affinity against CypD using inhibitory assay. We showed 4 out of the selected 5 peptides were capable for blocking the activity of CypD, while WACLQ display the strongest affinity against CypD, which reached 0.28 mM. The binding mechanism between WACLQ and CypD was characterized using molecular dynamics simulation. Here, we proved our approach can be a robust method for screening peptide inhibitors.

The SbbHLH041-SbEXPA11 Module Enhances Cadmium Accumulation and Rescues Biomass by Increasing Photosynthetic Efficiency in Sorghum.

In plants, expansin genes are responsive to heavy metal exposure. To study the bioremediary potential of this important gene family, we discovered a root-expressed expansin gene in sorghum, SbEXPA11, which is notably upregulated following cadmium (Cd) exposure. However, the mechanism underlying the Cd detoxification and accumulation mediated by SbEXPA11 in sorghum remains unclear. We overexpressed SbEXPA11 in sorghum and compared wild-type (WT) and SbEXPA11-overexpressing transgenic sorghum in terms of Cd accumulation and physiological indices following Cd. Compared with the WT, we found that SbEXPA11 mediates Cd tolerance by exerting reactive oxygen species (ROS)-scavenging effects through upregulating the expression of antioxidant enzymes. Moreover, the overexpression of SbEXPA11 rescued biomass production by increasing the photosynthetic efficiency of transgenic plants. In the pot experiment with a dosage of 10 mg/kg Cd, transgenic sorghum plants demonstrated higher efficacy in reducing the Cd content of the soil (8.62 mg/kg) compared to WT sorghum plants (9.51 mg/kg). Subsequent analysis revealed that the SbbHLH041 transcription factor has the ability to induce SbEXPA11 expression through interacting with the E-box located within the SbEXPA11 promoter. These findings suggest that the SbbHLH041-SbEXPA11 cascade module may be beneficial for the development of phytoremediary sorghum varieties.

Extracellular Vesicles and Hypertension.

Hypertension implicates multiple organs and systems, accounting for the majority of cardiovascular diseases and cardiac death worldwide. Extracellular vesicles derived from various types of cells could transfer a variety of substances such as proteins, lipids, and nucleic acids from cells to cells, playing essential roles in both physiological and pathological processes. Extracellular vesicles are demonstrated to be closely associated with the development of essential hypertension by mediating the renin-angiotensin-aldosterone system and crosstalk between multiple vascular cells. Extracellular vesicles also participate in various kinds of pathogenesis of secondary hypertensions including acute kidney injury, renal parenchymal diseases, kidney transplantation, secretory diseases (primary aldosteronism, pheochromocytoma and paraganglioma, Cushing's syndrome), and obstructive sleep apnea. Extracellular vesicles have been proved to have the potential to be served as new biomarkers in the diagnosis, treatment, and prognosis assessment of hypertension. In the future, large multicenter cohorts are highly in demand for further verifying the sensitivity and specificity of extracellular vesicles as biomarkers.

Computer-Aided Designing Peptide Inhibitors of Human Hematopoietic Prostaglandin D2 Synthase Combined Molecular Docking and Molecular Dynamics Simulation.

Human hematopoietic prostaglandin D2 synthase (HPGDS) is involved in the production of prostaglandin D2, which participates in various physiological processes, including inflammation, allergic reactions, and sleep regulation. Inhibitors of HPGDS have been investigated as potential anti-inflammatory agents. For the investigation of potent HPGDS inhibitors, we carried out a computational modeling study combining molecular docking and molecular dynamics simulation for selecting and virtual confirming the designed binders. We selected the structure of HPGDS (PDB ID: 2CVD) carrying its native inhibitor compound HQL as our research target. The random 5-mer peptide library was created by building the 3-D structure of random peptides using Rosetta Buildpeptide and performing conformational optimization. Molecular docking was carried out by accommodating the peptides into the location of their native binder and then conducting docking using FlexPepDock. The two peptides RMYYY and VMYMI, which display the lowest binding energy against HPGDS, were selected to perform a comparative study. The interaction of RMYYY and VMYMI against HPGDS was further confirmed using molecular dynamics simulation and aligned with its native binder, HQL. We show the selected binders to have stronger binding energy and more frequent interactions against HPGDS than HQL. In addition, we analyzed the solubility, hydrophobicity, charge, and bioactivity of the generated peptides, and we show that the selected strong binder may be further used as therapeutic drugs.

A new IRES-mediated truncated Cx32 isoform inhibits global mRNA translation to suppress glioblastoma.

Glioblastoma (GBM) is the most lethal malignant primary brain tumor. Although multimodal therapy has been applied for GBM, the median survival time remains less than 16 months. Thus, better therapeutic targets in GBM are urgently needed. Herein, we first identified five new N-terminal-truncated Cx32 isoforms (GJB1-28k, GJB1-22k, GJB1-20k, GJB1-15k, and GJB1-13k) and further demonstrated that they were generated via cap-independent internal translation through internal ribosome entry sites (IRESs) in the coding sequence of GJB1 mRNA. Among these isoforms, GJB1-13k inhibited proliferation, promoted apoptosis, and limited cell cycle progression in GBM cells by inhibiting global mRNA translation. In vivo experiments further confirmed the antitumor activity of GJB1-13k against GBM cells. In addition, TSR3, a ribosomal maturation factor, was demonstrated to directly interact with GJB1-13k. Moreover, GBM cells with high TSR3 expression exhibited low sensitivity to GJB1-13k treatment, while GJB1-13k sensitivity was restored by TSR3 knockdown. Our work identifies a new IRES-mediated protein, GJB1-13k, and suggests that overexpression of GJB1-13k in GBM cells with low TSR3 expression or combined targeting of GJB1-13k and TSR3 in GBM cells with high TSR3 expression constitutes a potential therapeutic strategy for GBM.

Ring finger protein 10 improves pirarubicin-induced cardiac inflammation by regulating the AP-1/Meox2 signaling pathway.

OBJECTIVES: Pirarubicin (THP) is widely used in clinical antitumor therapy, but its cardiotoxicity seriously affects the therapeutic effect in patients. In the study, we investigated the role of ring finger protein 10 (RNF10) in cardiotoxicity induced by THP. MATERIALS AND METHODS: A cardiac toxicity model in Sprague-Dawley (SD) rats induced by THP was established. Changes in diet, weight, electrocardiogram (ECG), and echocardiography were observed. Serum levels of brain natriuretic peptide (BNP), creatine kinase MB (CK-MB), cardiac troponin T (cTnT), and lactate dehydrogenase (LDH) were measured. The expression of RNF10 in myocardium was observed by immunohistochemistry. The expressions of RNF10, activator protein-1 (AP-1), mesenchyme homeobox 2 (Meox2), total nuclear factor (NF)-κB p65 (T-P65), phosphorylated NF-κB p65 (PP65), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and mature IL-1ß were detected by Western blot. A THP-induced H9c2 myocardial cell injury model was established. RNF10 was downregulated or overexpressed by RNF10 siRNA and a RNF10 lentiviral vector, respectively. Then, cell viability was measured. The expression of RNF10 in H9c2 cells was observed by immunofluorescence. All of the above signaling pathways were verified by Western blots. FINDINGS: THP caused a series of cardiotoxic manifestations in SD rats. Our studies suggested that THP caused cardiac inflammation by inhibiting the expression of RNF10, while overexpression of RNF10 antagonized the cardiotoxicity induced by THP. SIGNIFICANCE: Our study showed RNF10 improved THP-induced cardiac inflammation by regulating the AP-1/Meox2 signaling pathway. RNF10 may be a new target to treat THP-induced cardiotoxicity.

Inhibitors against Two PDZ Domains of MDA-9 Suppressed Migration of Breast Cancer Cells.

Melanoma differentiation-associated gene 9 (MDA-9) is a small adaptor protein with tandem PDZ domains that promotes tumor progression and metastasis in various human cancers. However, it is difficult to develop drug-like small molecules with high affinity due to the narrow groove of the PDZ domains of MDA-9. Herein, we identified four novel hits targeting the PDZ1 and PDZ2 domains of MDA-9, namely PI1A, PI1B, PI2A, and PI2B, using a protein-observed nuclear magnetic resonance (NMR) fragment screening method. We also solved the crystal structure of the MDA-9 PDZ1 domain in complex with PI1B and characterized the binding poses of PDZ1-PI1A and PDZ2-PI2A, guided by transferred paramagnetic relaxation enhancement. The protein-ligand interaction modes were then cross-validated by the mutagenesis of the MDA-9 PDZ domains. Competitive fluorescence polarization experiments demonstrated that PI1A and PI2A blocked the binding of natural substrates to the PDZ1 and PDZ2 domains, respectively. Furthermore, these inhibitors exhibited low cellular toxicity, but suppressed the migration of MDA-MB-231 breast carcinoma cells, which recapitulated the phenotype of MDA-9 knockdown. Our work has paved the way for the development of potent inhibitors using structure-guided fragment ligation in the future.

A CRISPR-Cas and Tat Peptide with Fluorescent RNA Aptamer System for Signal Amplification in RNA Imaging.

We reported on an efficient RNA imaging strategy based on a CRISPR-Cas and Tat peptide with a fluorescent RNA aptamer (TRAP-tag). Using modified CRISPR-Cas RNA hairpin binding proteins fused with a Tat peptide array that recruits modified RNA aptamers, this simple and sensitive strategy is capable of visualizing endogenous RNA in cells with high precision and efficiency. In addition, the modular design of the CRISPR-TRAP-tag facilitates the substitution of sgRNAs, RNA hairpin binding proteins, and aptamers in order to optimize imaging quality and live cell affinity. With CRISPR-TRAP-tag, exogenous GCN4, endogenous mRNA MUC4, and lncRNA SatIII were distinctly visualized in single live cells.

RING Finger Protein 10 Regulates AP-1/Meox2 to Mediate Pirarubicin-Induced Cardiomyocyte Apoptosis.

Pirarubicin (THP) is one of the classic chemotherapy drugs for cancer treatment. It is often clinically limited because of its cardiotoxicity. The occurrence and development of THP-mediated chemotherapy-related cardiotoxicity (CRC) may be reversed by RING finger protein 10 (RNF10). This study was performed with the aim of evaluating the inhibitory effect of RNF10 on THP-mediated CRC and its molecular mechanism. In vivo, we found that the expression of RNF10 decreased in THP-induced CRC rats, accompanied by Meox2 inhibition and AP-1 activation, resulting in increased cardiomyocyte apoptosis. After small interfering RNA (siRNA) and lentivirus transfection (Lv) of RNF10 in vitro, the expression of RNF10, Meox2, and AP-1 proteins and the degree of cardiomyocyte apoptosis were detected. We found that overexpression of RNF10 in H9C2 cardiomyocytes significantly promoted Meox2 and inhibited AP-1, alleviated apoptosis, and showed further inhibitory activity on THP-induced cardiomyocyte toxicity. Silencing RNF10 showed the opposite result. Our study showed that RNF10 inhibited THP-induced CRC through the activity of Meox2 and AP-1 proteins. RNF10 may be the next drug target for the treatment of CRC and other related cardiovascular diseases.

Assessing multiple factors affecting the gut microbiome structure of very preterm infants

The composition and diversity of the gut microbiota are essential for the health and development of the immune system of infants. However, there is limited information on factors that influence the gut microbiota of very preterm infants. In this study, we analyzed factors that affect the gut microbiota of very preterm infants. The stool samples from 64 very preterm infants with a gestational age less than 32 weeks were collected for 16S rRNA gene sequencing. The infants were divided according to the delivery mode, antibiotic use during pregnancy, and feeding methods. The abundance of Proteobacteria was high in both cesarean (92.7%) and spontaneous (55.5%) delivery groups and then shifted to Firmicutes after the first week of birth. In addition, Proteobacteria was also the dominant phylum of infant gut microbiome for mothers with antibiotic use, with more than 50% after the first week of birth. In comparison, the dominant phylum for mothers without antibiotic use was Firmicutes. Proteobacteria level was also high in breastfeeding and mixed-feeding groups, consisting of more than 90% of the community. By contrast, Proteobacteria was the dominant phylum at the first week of birth but then shifted to Firmicutes for the formula-fed group. The alterations of gut microbiota in infants can affect their health condition during growth. This study confirmed that the different feeding types, delivery modes, and use of antibiotics during pregnancy can significantly affect the composition of the gut microbiota of very preterm infants.

Upregulated FKBP1A Suppresses Glioblastoma Cell Growth via Apoptosis Pathway.

Glioblastoma (GBM), the most deadly primary brain tumor, presents a major medical difficulty. The need for better therapeutic targets in GBM is therefore urgent. A growing body of evidence suggests that the gene FKBP1A plays an important role in tumor progression and may be therapeutically useful. However, the role of FKBP1A in glioblastoma and the underlying biologic mechanism remain unclear. The purpose of this study was to identify the role of FKBP1A in GBM and its molecular mechanism. We demonstrated that FKBP1A was the hub gene in GBM via a weighted correlation network analysis (WGCNA) and differentially expressed genes (DEGs) analysis based on the bulk RNA-seq data from TCGA and GTEx. Afterwards, we proved that the upregulated FKBP1A protein could promote GBM cell death by CCK-8 assays in U87MG and t98g GBM cell lines. We further demonstrated two key pathways of FKBP1A in GBM by bioinformatics methods: 'Apoptosis' and 'mTOR signaling pathway'. Subsequently, the key pathways were verified by flow cytometry and Western blot. We identified that upregulated FKBP1A could inhibit GBM growth via the apoptosis pathway. Together, these findings may contribute to future GBM treatment.