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Backgroud Perioperative neurocognitive disorder (PND) is a prevalent and serious complication in elderly surgical patients, with limited effective therapeutic options available. While our prior research has demonstrated the neuroprotective potential of the adiponectin pathway in PND, the underlying mechanisms remain to be fully elucidated. Methods In a prospective cohort study, we collected serum, cerebrospinal fluid (CSF), and sociodemographic data from 41 elderly hip fracture patients (29 normal and 12 PND patients). Further, twelve-month-old male Sprague-Dawley rats were divided into sham, PND (splenectomy), and PND + Adiporon (APN, 50 mg/kg/day intragastrically) group. Lactate, pyruvate, TNF-α and IL-1β levels in CSF and hippocampus were measured. Additionally, a PND + APN + LY294002 (a PI3K inhibitor, 25 mg/kg/day intraperitoneally) group was established to explore the underlying mechanisms further. Cognitive function was assessed using the Morris Water Maze (MWM) test. Glucose transport (Glut) 1, glycolysis (HK2, PFKFB3 and PKM2), energy production (ATP and Na + /K + -ATPase), microglia-mediated neuroinflammation (Iba1, TNF-α, IL-1β) and synaptic protein (PSD95, SYP and SYN I) were assessed in hippocampus. Results PND elderly patients exhibited lower serum adiponectin levels, which correlated with higher lactate/pyruvate ratio (Pearson’s r correlation: -0.4513; p  = 0.0031) and higher TNF-α level (Pearson’s r correlation: -0.4311; p  = 0.0049) in CSF. In PND rats, APN reduced lactate, lactate/pyruvate ratio, TNF-α, and IL-1β in brain. Mechanistically, APN activated AdipoR1-dependent PI3K/Akt signaling, enhanced Glut1 membrane localization, HK2 activity, and Na + /K + -ATPase activity. APN also inhibited microglia overactivation and neuroinflammation. Activation of the adiponectin pathway improved cognitive performance in the MWM test. Conclusion The adiponectin pathway regulates cerebral metabolic dysfunction and neuroinflammation via the AdipoR1/PI3K/Akt axis, which serves as a potential therapeutic target for improving perioperative cognitive outcomes in elderly patients.

Background: Postoperative neurocognitive dysfunction (PND) represents a form of cognitive impairment related to surgery and anesthesia, which may manifest hours or even weeks after the surgical procedure, persist, and potentially progress into Alzheimer's disease. The etiology of PND is intricate, with central nervous inflammation playing a crucial role. The clinical manifestations of PND are not distinctive, no obvious image alterations are observable, and the diagnosis rate is relatively low, thereby influencing prognosis and augmenting postoperative complications and mortality. The optimal treatment approach for PND lies in timely identification and management of the high-risk factors causing PND and implementing early prevention. We hypothesize that the level of peripheral blood adiponectin (APN) is correlated with PND, potentially through inhibiting the central inflammatory response and regulating brain energy metabolism. Methods: Fifty elderly patients undergoing elective hip arthroplasty under continuous epidural spinal anesthesia (CESA) were included. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) preoperatively and postoperatively at 1, 2, 3, and 7 days. Serum APN and CSF levels of TNF-[alpha], IL-1[beta], lactic acid, and pyruvic acid were measured. The occurrence of PND was recorded, and the patients were divided into a PND group and a non-PND group. Results: PND occurred in 16 patients (34.04%). The PND group had lower serum APN levels and higher cerebrospinal fluid (CSF) concentrations of TNF-[alpha], IL-1[beta], and lactic acid compared to the non-PND group. CSF TNF-[alpha] and IL-1[beta] levels were negatively correlated with serum APN concentration. These biomarkers are associated with PND occurrence and have high diagnostic value. Conclusion: Decreases in serum APN and increases in TNF-[alpha], IL-1[beta], and lactic acid in CSF may be involved in the pathophysiological process of PND in elderly patients after surgery. Keywords: adiponectin, central inflammation, energy metabolism, perioperative neurocognitive dysfunction

Postoperative neurocognitive dysfunction (PND) represents a form of cognitive impairment related to surgery and anesthesia, which may manifest hours or even weeks after the surgical procedure, persist, and potentially progress into Alzheimer's disease. The etiology of PND is intricate, with central nervous inflammation playing a crucial role. The clinical manifestations of PND are not distinctive, no obvious image alterations are observable, and the diagnosis rate is relatively low, thereby influencing prognosis and augmenting postoperative complications and mortality. The optimal treatment approach for PND lies in timely identification and management of the high-risk factors causing PND and implementing early prevention. We hypothesize that the level of peripheral blood adiponectin (APN) is correlated with PND, potentially through inhibiting the central inflammatory response and regulating brain energy metabolism. Fifty elderly patients undergoing elective hip arthroplasty under continuous epidural spinal anesthesia (CESA) were included. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) preoperatively and postoperatively at 1, 2, 3, and 7 days. Serum APN and CSF levels of TNF-α, IL-1β, lactic acid, and pyruvic acid were measured. The occurrence of PND was recorded, and the patients were divided into a PND group and a non-PND group. PND occurred in 16 patients (34.04%). The PND group had lower serum APN levels and higher cerebrospinal fluid (CSF) concentrations of TNF-α, IL-1β, and lactic acid compared to the non-PND group. CSF TNF-α and IL-1β levels were negatively correlated with serum APN concentration. These biomarkers are associated with PND occurrence and have high diagnostic value. Decreases in serum APN and increases in TNF-α, IL-1β, and lactic acid in CSF may be involved in the pathophysiological process of PND in elderly patients after surgery.

The use of exogenous mitochondria to replenish damaged mitochondria has been proposed as a strategy for the treatment of pulmonary fibrosis. However, the success of this strategy is partially restricted by the difficulty of supplying sufficient mitochondria to diseased cells. Herein, we report the generation of high-powered mesenchymal stem cells with promoted mitochondrial biogenesis and facilitated mitochondrial transfer to injured lung cells by the sequential treatment of pioglitazone and iron oxide nanoparticles. This highly efficient mitochondrial transfer is shown to not only restore mitochondrial homeostasis but also reactivate inhibited mitophagy, consequently recovering impaired cellular functions. We perform studies in mouse to show that these high-powered mesenchymal stem cells successfully mitigate fibrotic progression in a progressive fibrosis model, which was further verified in a humanized multicellular lung spheroid model. The present findings provide a potential strategy to overcome the current limitations in mitochondrial replenishment therapy, thereby promoting therapeutic applications for fibrotic intervention. Using healthy mitochondria to restore impaired mitochondrial homeostasis is a promising therapy for pulmonary fibrosis. Here the authors use joint-engineered mesenchymal stem cells for efficient mitochondrial delivery to injured lung cells, showing a successful mitigation of the disease.