Computational Drug Discovery in Diaphragm dysfunction via Text Mining and Biomedical Database.

The diaphragm, which is crucial for ventilation, is the primary muscle responsible for inspiration. Patients with severe burns who experience diaphragmatic dysfunction have an increased risk of mortality. Unfortunately, there are currently no effective medications available to prevent or treat this condition. The objective of our study is to utilize bioinformatics to identify potential genes and drugs associated with diaphragmatic dysfunction. In this study, text mining techniques were utilized to identify genes associated with diaphragmatic dysfunction and recovery. Common genes were then analyzed using GO and KEGG pathway analysis, as well as protein-protein interaction (PPI) network analysis. The obtained hub genes were processed using Cytoscape software, and their expression levels in diaphragmatic dysfunction were validated using quantitative real-time polymerase chain reaction (qRT-PCR) in severe burn rats. Genes that were confirmed were then examined in drug-gene interaction databases to identify potential drugs associated with these genes. Our analysis revealed 96 genes that were common to both the "Diaphragm dysfunction" and "Functional Recovery" text mining concepts. Gene enrichment analysis identified 19 genes representing ten pathways. qRT-PCR showed a significant increase in expression levels of 13 genes, including CCL2, CCL3, CD4, EGF, HGF, IFNG, IGF1, IL17A, IL6, LEP, PTGS2, TGFB1, and TNF, in samples with diaphragmatic dysfunction. Additionally, we found that a total of 56 drugs targeted 5 potential genes. These findings provide new insights into the development of more effective drugs for treating diaphragmatic dysfunction, and also present substantial opportunities for researching new target pharmacology and promoting drugs in the pharmaceutical industry.

[New research direction of organ dysfunction caused by hemorrhagic shock: mechanisms of mitochondrial quality control].

Hemorrhagic shock (HS) is one of the leading causes of death among young adults worldwide. Multiple organ dysfunction in HS is caused by an imbalance between tissue oxygen supply and demand, which is closely related to the poor prognosis of patient. Mitochondrial dysfunction is one of the key mechanisms contributing to multiple organ dysfunction in HS, while mitochondrial quality control regulates mitochondrial function through a series of processes, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, mitochondrial-derived vesicles, and mitochondrial protein homeostasis. Modulating mitochondrial quality control can improve organ dysfunction. This review aims to summarize the effects of mitochondrial dysfunction on organ function in HS and discuss the potential mechanisms of mitochondrial quality control, providing insights into the injury mechanisms underlying HS and guiding clinical management.

Establishment of a Bama miniature pig burn model with different burn depths.

Background: The skin morphological characteristics of the Bama miniature pig are very similar to those of humans; thus, the Bama miniature pig is an ideal choice for establishing a skin burn model. Methods: In this study, 6 ordinary, male, Bama miniature pigs (weight: 23-28 kg and length: 71-75 cm) were used to establish burn models. A mixture of 1 mg of Ketamine and Sumianxin II was used for Bama miniature pigs anesthetizing, and 1 mg of Pentobarbital sodium was added as necessary. The different burn depths were made using a continuous pressure of 1 kg and contact times of 0 s, 10 s, 15 s, 20 s, 25 s, 30 s, 35 s, 40 s, and 45 s by the newly invented electronic burn instrument. The burned tissues were collected and examined with hematoxylin and eosin (H&E) and Masson staining. Results: Burning for 10-15 s caused a first-degree burn; the blood vessels in the superficial dermis were dilated and congested, and necrosis occurred above the basal layer of the epidermis. Burning for 20-25 s caused a superficial partial-thickness burn; the whole epidermal layer was necrotic, and the collagen fibers were slightly deformed. Burning for 30-35 s caused a deep partial-thickness burn; the whole epidermal layer and dermal layers were necrotic with leukocyte infiltration zones, and the collagen fibers were disordered, degenerated, and necrotized. Burning for 40-45 s caused a third-degree burn; the skin layers and adipose tissues were necrotic, and the thick blood vessels in the skin adipose tissues were full of disintegrated and agglutinated red blood cells. Conclusions: Stable burn depth models of Bama miniature pigs were constructed using a new and innovative electronic burn instrument. Our findings provide a basis for further research on the burn mechanism and evaluations of therapeutic drugs.

Protective effect of restrictive resuscitation on vascular endothelial glycocalyx in pigs with traumatic hemorrhagic shock.

Background: Hemorrhagic shock is the leading cause of early traumatic death. Research and discussion on restrictive fluid resuscitation have been ongoing for many years. The purpose of this study was to explore whether restrictive resuscitation can inhibit the shedding of vascular endothelial glycocalyx in the prehospital treatment of traumatic hemorrhagic shock pigs. Methods: Landrace pigs were randomly divided into a restrictive resuscitation group (restrictive group) and a conventional resuscitation group (conventional group), with 6 pigs in each group. The gunshot caused a rupture of the pig's receding right femoral artery, and the average arterial pressure was 40-45 mmHg stable for 30 minutes, which was defined as a successful shock model. The end point of resuscitation in the restrictive group was a mean arterial pressure (MAP) of 55-60 mmHg for 30 minutes, and the end point of resuscitation in the conventional group was a MAP of 70-75 mmHg for 30 minutes. The results of arterial blood gas analysis, hemodynamic indicators, endothelial glycocalyx damage and shedding marker Syndecan1 and soluble thrombomodulin (sTM) expression levels were compared between the two groups of experimental pigs after resuscitation. Results: The two groups of experimental pigs had the same baseline levels before injury in age, body weight, blood loss, cardiac output index, cardiac function index (CFI), extravascular lung water index (ELWI), and pulmonary vascular permeability index (PVPI). The arterial blood gas analysis of the two experimental pigs showed no significant difference in carbon dioxide partial pressure, oxygen partial pressure, blood oxygen saturation, or blood lactic acid after resuscitation. The difference in cardiac output index and CFI at the end of resuscitation between the two groups was not statistically significant; the absolute value and percentage of Syndecan1 level increase in the restrictive resuscitation group were lower than those in the conventional resuscitation group, and the difference was statistically significant. Conclusions: Compared with full resuscitation in a short period of prehospital treatment, restrictive resuscitation can achieve a similar effect in maintaining tissue oxygen supply and can reduce the loss of vascular endothelial glycocalyx to a certain extent.

Preparation and evaluation of chitosan-polyvinyl alcohol/polyhexamethylene guanidine hydrochloride antibacterial dressing to accelerate wound healing for infectious skin repair.

BACKGROUND: Wound infections, especially multidrug-resistant (MDR) bacterial infections, are a major challenge in clinical medicine. METHODS: In this study, a new type of antibacterial sponge was prepared from a solution containing a chitosan-polyvinyl alcohol (CTS-PVA) emulsion with added polyhexamethylene guanidine hydrochloride (PHMG) in a homogeneous medium using lyophilization technology. The antibacterial ability of and CTS-PVA/PHMG sponge against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans, Methicillin-resistant Staphylococcus aureus, multidrug-resistant Pseudomonas aeruginosa, and multidrug-resistant Acinetobacter baumannii in vitro. The structure and physical properties were characterized. The sponge dressing was tested in a Pseudomonas aeruginosa-infected full-thickness mouse skin wound defect model. The effects were evaluated by wound area measurement and histological analysis. RESULTS: The CTS-PVA/PHMG sponge showed broad-spectrum antibacterial ability, including for MDR bacterial stains from clinical sources, while maintaining excellent physicochemical properties, including a high swelling degree and good moisture retention capability. Scanning electron microscopy images displayed the surface morphology of the CTS-PVA/PHMG sponge dressing. The detection of the wound healing rate and histological analysis supported that the new dressing can alleviate the inflammation and accelerate the healing speed of infected wounds and in vivo. CONCLUSIONS: CTS-PVA/PHMG sponge shows broad-spectrum antibacterial activity, which can provide a new pathway for clinical prevention and treatment of superbug-infected wounds.

Down-Regulation of miR-301a-3p Reduces Burn-Induced Vascular Endothelial Apoptosis by potentiating hMSC-Secreted IGF-1 and PI3K/Akt/FOXO3a Pathway.

Vascular endothelium dysfunction plays a pivotal role in the initiation and progression of multiple organ dysfunction. The mesenchymal stem cell (MSC) maintains vascular endothelial barrier survival via secreting bioactive factors. However, the mechanism of human umbilical cord MSC (hMSC) in protecting endothelial survival remains unclear. Here, we found IGF-1 secreted by hMSC suppressed severe burn-induced apoptosis of human umbilical vein endothelial cells (HUVECs) and alleviated the dysfunction of vascular endothelial barrier and multiple organs in severely burned rats. Severe burn repressed miR-301a-3p expression, which directly regulated IGF-1 synthesis and secretion in hMSC. Down-regulation of miR-301a-3p decreased HUVECs apoptosis, stabilized endothelial barrier permeability, and subsequently protected against multiple organ dysfunction in vivo. Additionally, miR-301a-3p negatively regulated PI3K/Akt/FOXO3 signaling through IGF-1. Taken together, our study highlights the protective function of IGF-1 against the dysfunction of multiple organs negatively regulated by miR-301a-3p, which may provide the theoretical foundation for further clinical application of hMSC.

Is Mitochondrial Oxidative Stress the Key Contributor to Diaphragm Atrophy and Dysfunction in Critically Ill Patients?

Diaphragm dysfunction is prevalent in the progress of respiratory dysfunction in various critical illnesses. Respiratory muscle weakness may result in insufficient ventilation, coughing reflection suppression, pulmonary infection, and difficulty in weaning off respirators. All of these further induce respiratory dysfunction and even threaten the patients' survival. The potential mechanisms of diaphragm atrophy and dysfunction include impairment of myofiber protein anabolism, enhancement of myofiber protein degradation, release of inflammatory mediators, imbalance of metabolic hormones, myonuclear apoptosis, autophagy, and oxidative stress. Among these contributors, mitochondrial oxidative stress is strongly implicated to play a key role in the process as it modulates diaphragm protein synthesis and degradation, induces protein oxidation and functional alteration, enhances apoptosis and autophagy, reduces mitochondrial energy supply, and is regulated by inflammatory cytokines via related signaling molecules. This review aims to provide a concise overview of pathological mechanisms of diaphragmatic dysfunction in critically ill patients, with special emphasis on the role and modulating mechanisms of mitochondrial oxidative stress.