Neuroprotective effects of annexin A1 tripeptide in rats with sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is characterized by high incidence and mortality rates, with limited treatment options available. The underlying mechanisms and pathogenesis of SAE remain unclear. Annexin A1 (ANXA1), a membrane-associated protein, is involved in various in vivo pathophysiological processes. This study aimed to explore the neuroprotective effects and mechanisms of a novel bioactive ANXA1 tripeptide (ANXA1sp) in SAE. Forty Sprague-Dawley rats were randomly divided into four groups (n = 10 each): control, SAE (intraperitoneal injection of lipopolysaccharide), vehicle (SAE + normal saline), and ANXA1sp (SAE + ANXA1sp) groups. Changes in serum inflammatory factors (interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α]), hippocampal reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and adenosine triphosphate (ATP) levels were measured. The Morris water maze and Y maze tests were used to assess learning and memory capabilities in the rats. Further, changes in peroxisome proliferator-activated receptor-gamma (PPAR-γ) and apoptosis-related protein expression were detected using western blot. The IL-6, TNF-α, and ROS levels were significantly increased in the SAE group compared with the levels in the control group. Intraperitoneal administration of ANXA1sp led to a significant decrease in the IL-6, TNF-α, and ROS levels (p < 0.05). Compared with the SAE group, the ANXA1sp group exhibited reduced escape latency on day 5, a significant increase in the number of platform crossings and the percent spontaneous alternation, and significantly higher hippocampal MMP and ATP levels (p < 0.05). Meanwhile, the expression level of PPAR-γ protein in the ANXA1sp group was significantly increased compared with that in the other groups (p < 0.05). The expressions of apoptosis-related proteins (nuclear factor-kappa B [NF-κB], Bax, and Caspase-3) in the SAE and vehicle groups were significantly increased, with a noticeable decrease in Bcl-2 expression, compared with that noted in the control group. Moreover, the expressions of NF-κB, Bax, and Caspase-3 were significantly decreased in the ANXA1sp group, and the expression of Bcl-2 was markedly increased (p < 0.05). ANXA1sp can effectively reverse cognitive impairment in rats with SAE. The neuroprotective effect of ANXA1sp may be attributed to the activation of the PPAR-γ pathway, resulting in reduced neuroinflammatory response and inhibition of apoptosis.

Sepsis-associated encephalopathy: Autophagy and miRNAs regulate microglial activation.

Sepsis-associated encephalopathy (SAE) describes diffuse or multifocal cerebral dysfunction caused by the systemic inflammatory response to sepsis. SAE is a common neurological complication in patients in the middle and late stages of sepsis in the intensive care unit. Microglia, resident macrophages of the central nervous system, phagocytose small numbers of neuronal cells and apoptotic cells, among other cells, to maintain the dynamic balance of the brain's internal environment. The neuroinflammatory response induced by activated microglia plays a central role in the pathogenesis of various central nervous system diseases. In this paper, we systematically describe the functions and phenotypes of microglia, summarize how microglia mediate neuroinflammation and contribute to the occurrence and development of SAE, and discuss recent progress in autophagy- and microRNA-mediated regulation of microglial activation to provide a theoretical basis for the prevention and treatment of SAE and identify related therapeutic targets.

The possible mechanisms of ferroptosis in sepsis-associated acquired weakness.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, and its morbidity and mortality rates are increasing annually. It is an independent risk factor for intensive care unit-acquired weakness (ICU-AW), which is a common complication of patients in ICU. This situation is also known as sepsis-associated acquired weakness (SAW), and it can be a complication in more than 60% of patients with sepsis. The outcomes of SAW are often prolonged mechanical ventilation, extended hospital stays, and increased morbidity and mortality of patients in ICUs. The pathogenesis of SAW is unclear, and an effective clinical treatment is not available. Ferroptosis is an iron-dependent type of cell death with unique morphological, biochemical, and genetic features. Unlike other forms of cell death such as autophagy, apoptosis, and necrosis, ferroptosis is primarily driven by lipid peroxidation. Cells undergo ferroptosis during sepsis, which further enhances the inflammatory response. This process leads to increased cell death, as well as multi-organ dysfunction and failure. Recently, there have been sporadic reports suggesting that SAW is associated with ferroptosis, but the exact pathophysiological mechanisms remain unclear. Therefore, we reviewed the possible pathogenesis of ferroptosis that leads to SAW and offer new strategies to prevent and treat SAW.

Unraveling the causes of sarcopenia: Roles of neuromuscular junction impairment and mitochondrial dysfunction.

Sarcopenia is a systemic skeletal muscle disease characterized by a decline in skeletal muscle mass and function. Originally defined as an age-associated condition, sarcopenia presently also encompasses muscular atrophy due to various pathological factors, such as intensive care unit-acquired weakness, inactivity, and malnutrition. The exact pathogenesis of sarcopenia is still unknown; herein, we review the pathological roles of the neuromuscular junction and mitochondria in this condition. Sarcopenia is caused by complex and interdependent pathophysiological mechanisms, including aging, neuromuscular junction impairment, mitochondrial dysfunction, insulin resistance, lipotoxicity, endocrine factors, oxidative stress, and inflammation. Among these, neuromuscular junction instability and mitochondrial dysfunction are particularly significant. Dysfunction in neuromuscular junction can lead to muscle weakness or paralysis. Mitochondria, which are plentiful in neurons and muscle fibers, play an important role in neuromuscular junction transmission. Therefore, impairments in both mitochondria and neuromuscular junction may be one of the key pathophysiological mechanisms leading to sarcopenia. Moreover, this article explores the structural and functional alterations in the neuromuscular junction and mitochondria in sarcopenia, suggesting that a deeper understanding of these changes could provide valuable insights for the prevention or treatment of sarcopenia.

ANXA1sp modulates the protective effect of Sirt3-induced mitophagy against sepsis-induced myocardial injury in mice.

AIM: Sepsis-induced myocardial injury (SIMI) may be associated with insufficient mitophagy in cardiomyocytes, but the exact mechanism involved remains unknown. Sirtuin 3 (Sirt3) is mainly found in the mitochondrial matrix and is involved in repairing mitochondrial function through means such as the activation of autophagy. Previously, we demonstrated that the annexin-A1 small peptide (ANXA1sp) can promote Sirt3 expression in mitochondria. In this study, we hypothesized that the activation of Sirt3 by ANXA1sp induces mitophagy, thereby providing a protective effect against SIMI in mice. METHODS: A mouse model of SIMI was established via cecal ligation and puncture. Intraperitoneal injections of ANXA1sp, 3TYP, and 3MA were administered prior to modeling. After successful modeling, IL-6, TNF-α, CK-MB, and CTn-I levels were measured; cardiac function was assessed using echocardiography; myocardial mitochondrial membrane potential, ROS, and ATP production were determined; myocardial mitochondrial ultrastructure was observed using transmission electron microscopy; and the expression levels of Sirt3 and autophagy-related proteins were detected using western blotting. RESULTS: ANXA1sp significantly reduced serum IL-6, TNF-α, CK-MB, and CTn-I levels; decreased myocardial ROS production; increased mitochondrial membrane potential and ATP synthesis; and improved myocardial mitochondrial ultrastructure in septic mice. Furthermore, ANXA1sp promoted Sirt3 expression and activated the AMPK-mTOR pathway to induce myocardial mitophagy. These protective effects of ANXA1sp were reversed upon treatment with the Sirt3 blocker, 3-TYP. CONCLUSION: ANXA1sp can reverse SIMI, and the underlying mechanism may be related to the activation of the AMPK-mTOR pathway following upregulation of Sirt3 by ANXA1sp, which, in turn, induces autophagy.