Identification of ferroptosis-associated genes and potential pharmacological targets in sepsis-induced myopathy.

Background: The role of Ferroptosis in the course of sepsis-induced myopathy is yet unclear. The objective of our work is to identify key genes connected with Ferroptosis in sepsis-induced myopathy and investigate possible pharmaceutical targets related to this process. This research aims to provide new insights into the management of sepsis-induced myopathy. Methods: We got the GSE13205 dataset from the Gene Expression Omnibus (GEO) and extracted Ferroptosis-associated genes from the FerrDb database. After conducting a functional annotation analysis of these genes, we created a protein-protein interaction network using Cytoscape software to identify important genes. Subsequently, we employed CMap to investigate prospective pharmaceuticals that could target these crucial genes. Results: A total of 61 genes that are expressed differently (DEGs) have been found concerning Ferroptosis. These genes are involved in a wide range of biological functions, including reacting to signals from outside the cell and the availability of nutrients, programmed cell death, controlling apoptosis, and responding to peptides, chemical stressors, and hormones. The KEGG pathway study revealed that these pathways are involved in Ferroptosis, autophagy, P53 signaling, PI3K-Akt signaling, mTOR signaling, HIF-1 signaling, endocrine resistance, and different tumorigenic processes. In addition, we created a network that shows the simultaneous expression of important genes and determined the top 10 medications that have the potential to treat sepsis-induced myopathy. Conclusion: The bioinformatics research undertaken sheds insight into the probable role of Ferroptosis-associated genes in sepsis-induced myopathy. The identified critical genes show potential as therapeutic targets for treating sepsis-induced myopathy, offering opportunities for the development of tailored medicines.

The therapeutic value of vacuum external fixation in polytrauma patients with multiple ribs fracture.

BACKGROUND: Multiple displaced rib fractures often result in a poor prognosis. Open reduction and internal fixation has been shown to provide benefits for patients with displaced rib fractures and flail chest. Nevertheless, for patients who are unwilling or unsuitable for surgery, the therapeutic options are limited. We developed a novel plastic vacuum device for rib fractures external stabilization. This study aims to compare the therapeutic efficacy of this device against a traditional chest strap in polytrauma patients with multiple rib fractures. METHODS: A retrospective investigation was conducted on polytrauma patients with multiple rib fractures admitted to our trauma center between March 2020 and March 2023. Patients were categorized into two groups: vacuum external fixation and chest strap. Comparative analysis was conducted on baseline parameters, injury characteristics, and clinical outcomes between the two groups. RESULTS: In this study, 54 patients were included, with 28 receiving chest strap and 26 undergoing vacuum external fixation. Results showed that, at 3 days and 7 days postintervention, the vacuum external fixation group had significantly lower visual analog scale scores during deep breathing and coughing (P < .05). Vacuum external fixation also reduced pleural drainage duration and volume, as well as lowered the risk of pneumonia and other complications (P < .05). Furthermore, the vacuum external fixation group demonstrated notable improvements in vital capacity, tidal volume, blood-gas test results, and a shorter hospital length of stay. CONCLUSIONS: According to the study findings, vacuum external fixation appears to offer benefits to patients with multiple rib fractures, potentially reducing the risk of complications and improving overall clinical outcomes.

A Randomized Controlled Trial of Surgical Rib Fixation in Polytrauma Patients With Flail Chest.

BACKGROUND: Flail chest (FC) is known to account for high mortality and morbidity and is typically treated with conservative care. Operative fixation of FC has been advocated as an alternative treatment choice. This prospective randomized controlled trial aims to compare surgical and nonsurgical management of FC in patients with severe polytrauma. METHODS: Severe polytrauma patients with FC admitted between January 2015 and July 2017 to our trauma center were investigated. The enrolled patients were randomly assigned to the surgical or nonsurgical group. Basic characteristics of injury and clinical outcomes were compared. RESULTS: Fifty patients entered final analysis, with 25 patients in each group. Operative rib fixation was associated with shorter duration of mechanical ventilation (7 d [interquartile range {IQR} 6-10] versus 9 d [IQR 7-12], P = 0.012), shorter ICU stay (10 d [IQR 7-12] versus 12 d [IQR 9-15], P = 0.032), lower risk of adult respiratory distress syndrome (28% versus 60%, P = 0.045), pneumonia (48% versus 80%, P = 0.038), and thoracic deformity (8% versus 36%, P = 0.037) and less pain while coughing (pain score 6 [IQR 3-8] versus 8 [IQR 4-9], P = 0.029) and deep breathing (pain score 5 [IQR 3-9] versus 7 [IQR 3-9], P = 0.038). Subgroup analysis was conducted by presence of pulmonary contusion. Shorter time on the ventilator use and ICU stay associated with rib surgery was not observed in patients with pulmonary contusion. CONCLUSIONS: This study reveals that surgical rib fixation may provide some critical care benefits for severe polytrauma patients with FC, including less medical resource use and lower risk of complications. Further studies should be designed to optimally identify patients who are most likely to benefit from this surgery.

Oxidative burst of circulating neutrophils following traumatic brain injury in human.

Besides secondary injury at the lesional site, Traumatic brain injury (TBI) can cause a systemic inflammatory response, which may cause damage to initially unaffected organs and potentially further exacerbate the original injury. Here we investigated plasma levels of important inflammatory mediators, oxidative activity of circulating leukocytes, particularly focusing on neutrophils, from TBI subjects and control subjects with general trauma from 6 hours to 2 weeks following injury, comparing with values from uninjured subjects. We observed increased plasma level of inflammatory cytokines/molecules TNF-α, IL-6 and CRP, dramatically increased circulating leukocyte counts and elevated expression of TNF-α and iNOS in circulating leukocytes from TBI patients, which suggests a systemic inflammatory response following TBI. Our data further showed increased free radical production in leukocyte homogenates and elevated expression of key oxidative enzymes iNOS, COX-2 and NADPH oxidase (gp91(phox)) in circulating leukocytes, indicating an intense induction of oxidative burst following TBI, which is significantly greater than that in control subjects with general trauma. Furthermore, flow cytometry assay proved neutrophils as the largest population in circulation after TBI and showed significantly up-regulated oxidative activity and suppressed phagocytosis rate for circulating neutrophils following brain trauma. It suggests that the highly activated neutrophils might play an important role in the secondary damage, even outside the injured brain. Taken together, the potent systemic inflammatory response induced by TBI, especially the intensively increase oxidative activity of circulating leukocytes, mainly neutrophils, may lead to a systemic damage, dysfunction/damage of bystander tissues/organs and even further exacerbate secondary local damage. Controlling these pathophysiological processes may be a promising therapeutic strategy and will protect unaffected organs and the injured brain from the secondary damage.

Effect of ω-3 polyunsaturated fatty acid on toll-like receptors in patients with severe multiple trauma.

This study examined the effects of ω-3 polyunsaturated fatty acid (ω-3PUFA) on the expression of toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4) and some related inflammatory factors in peripheral blood mononuclear cells (PBMCs) of patients with early-stage severe multiple trauma. Thirty-two patients who were admitted to the Department of Traumatic Surgery, Tongji Hospital (Wuhan, China) between May 2010 and November 2010, and diagnosed as having severe multiple trauma with a injury severity score (ISS) no less than 16, were enrolled in the study and divided into two groups at random (n=16 in each): ω-3PUFA group and control group in which routine parenteral nutrition supplemented with ω-3PUFA or not was administered to the patients in two groups for consecutive 7 days. Peripheral blood from these patients was collected within 2 h of admission (day 0), and 1, 3, 5 and 7 days after the nutritional support. PBMCs were isolated and used for detection of the mRNA and protein expression of TLR2 and TLR4 by using real-time PCR and flow cytometry respectively, the levels of NF-κB by quantum dots-based immunofluorescence assay, the levels of TNF-α, IL-2, IL-6 and COX-2 by ELISA, respectively. The results showed that the mRNA and protein expression of TLR2 and TLR4 in PBMCs was significantly lower in ω-3PUFA group than in control group 5 and 7 days after nutrition support (both P<0.05). The levels of TNF-α, IL-2, IL-6 and COX-2 were found to be substantially decreased in PBMCs in ω-3PUFA group as compared with control group at 5th and 7th day (P<0.05 for all). It was concluded that ω-3PUFA can remarkably decrease the expression of TLR2, TLR4 and some related inflammatory factors in NF-κB signaling pathway in PBMCs of patients with severe multiple trauma, which suggests that ω-3PUFA may suppress the excessive inflammatory response meditated by the TLRs/NF-κB signaling pathway.

Lesional expression of EMAPII in macrophages/microglia following cerebral ischemia in rats.

OBJECTIVE: Cerebral ischemia triggers acute inflammation, which exacerbates primary brain damage. Characterization of cytokine expression to the early damaged tissue might aid in further understanding of lesion development and contribute to definition of molecular targets for selective immunotherapy. Endothelial monocyte-activating polypeptide II (EMAPII) is a proinflammatory, antiangiogenic cytokine whose expression following cerebral ischemia remained unknown. Therefore, we studied the spatiotemporal expression of EMAPII in early brain lesions after cerebral ischemia-reperfusion injury. METHODS: Unilateral transient focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 1 hr followed by different reperfusion periods using male Sprague-Dawley rats. Subsequently, rats were sacrificed on Day 1, 3, 5, or 7 following surgery. EMAPII expression was investigated by immunohistochemistry. RESULTS: EMAPII-positive cell accumulation was observed as early as Day 1 postreperfusion and increased steadily. Significant accumulation of EMAPII-positive cells was seen in lesion and penumbra areas but not in the translateral hemisphere. Both amoeboid and ramified EMAPII-positive cells were observed and mainly localized to lesion and penumbra areas, respectively. CONCLUSION: The known pathological functions together with abundant cellular accumulation in cerebral ischemia lesions suggest that EMAPII might contribute to pathophysiological consequences of cerebral ischemia.

Effect of ω-3 Polyunsaturated Fatty Acid on Toll-like Receptors in Patients with Severe Multiple Trauma / 华中科技大学学报（医学）（英德文版）

This study examined the effects of ω-3 polyunsaturated fatty acid (ω-3PUFA) on the expression of toll-like receptor 2 (TLR2),toll-like receptor 4 (TLR4) and some related inflammatory factors in peripheral blood mononuclear cells (PBMCs) of patients with early-stage severe multiple trauma.Thirty-two patients who were admitted to the Department of Traumatic Surgery,Tongji Hospital (Wuhan,China) between May 2010 and November 2010,and diagnosed as having severe multiple trauma with a injury severity score (ISS) no less than 16,were enrolled in the study and divided into two groups at random (n=16 in each):ω-3PUFA group and control group in which routine parenteral nutrition supplemented with ω-3PUFA or not was administered to the patients in two groups for consecutive 7 days.Peripheral blood from these patients was collected within 2 h of admission (day 0),and 1,3,5 and 7days after the nutritional support.PBMCs were isolated and used for detection of the mRNA and protein expression of TLR2 and TLR4 by using real-time PCR and flow cytometry respectively,the levels of NF-κB by quantum dots-based immunofluorescence assay,the levels of TNF-α,IL-2,IL-6 and COX-2 by ELISA,respectively.The results showed that the mRNA and protein expression of TLR2 and TLR4 in PBMCs was significantly lower in ω-3PUFA group than in control group 5 and 7 days after nutrition support (both P＜0.05).The levels of TNF-α,IL-2,IL-6 and COX-2 were found to be substantially decreased in PBMCs in ω-3PUFA group as compared with control group at 5th and 7th day (P＜0.05 for all).It was concluded that ω-3PUFA can remarkably decrease the expression of TLR2,TLR4 and some related inflammatory factors in NF-κB signaling pathway in PBMCs of patients with severe multiple trauma,which suggests that ω-3PUFA may suppress the excessive inflammatory response meditated by the TLRs/NF-κB signaling pathway.

Neuronal Ca2+-activated K+ channels limit brain infarction and promote survival.

Neuronal calcium-activated potassium channels of the BK type are activated by membrane depolarization and intracellular Ca(2+) ions. It has been suggested that these channels may play a key neuroprotective role during and after brain ischemia, but this hypothesis has so far not been tested by selective BK-channel manipulations in vivo. To elucidate the in vivo contribution of neuronal BK channels in acute focal cerebral ischemia, we performed middle cerebral artery occlusion (MCAO) in mice lacking BK channels (homozygous mice lacking the BK channel alpha subunit, BK(-/-)). MCAO was performed in BK(-/-) and WT mice for 90 minutes followed by a 7-hour-reperfusion period. Coronal 1 mm thick sections were stained with 2,3,5-triphenyltetrazolium chloride to reveal the infarction area. We found that transient focal cerebral ischemia by MCAO produced larger infarct volume, more severe neurological deficits, and higher post-ischemic mortality in BK(-/-) mice compared to WT littermates. However, the regional cerebral blood flow was not significantly different between genotypes as measured by Laser Doppler (LD) flowmetry pre-ischemically, intra-ischemically, and post-ischemically, suggesting that the different impact of MCAO in BK(-/-) vs. WT was not due to vascular BK channels. Furthermore, when NMDA was injected intracerebrally in non-ischemic mice, NMDA-induced neurotoxicity was found to be larger in BK(-/-) mice compared to WT. Whole-cell patch clamp recordings from CA1 pyramidal cells in organotypic hippocampal slice cultures revealed that BK channels contribute to rapid action potential repolarization, as previously found in acute slices. When these cultures were exposed to ischemia-like conditions this induced significantly more neuronal death in BK(-/-) than in WT cultures. These results indicate that neuronal BK channels are important for protection against ischemic brain damage.