Study on the preventive effect of dexmedetomidine on anesthetic associated sleep disturbance in young to middle-aged female patients undergoing hysteroscopy: a study protocol for a crossover randomized controlled trial.

BACKGROUND: Postoperative sleep disturbance has a potentially detrimental effect on postoperative recovery. Perioperative patients are affected by several factors. General anesthesia induces a non-physiological state that does not resemble natural sleep. Exposure to propofol/sevoflurane can lead to desynchronization of the circadian rhythm, which may result in postoperative sleep disturbance characterized by mid-cycle advancement of sleep and daytime sleepiness. Dexmedetomidine is a highly selective α2-adrenoceptor agonist with a unique sedative effect that facilitates the transition from sleep to wakefulness. Basic research has shown that dexmedetomidine induces deep sedation, similar to physical sleep, and helps maintain forebrain connectivity, which is likely to reduce delirium after surgery. The aim of this study is to evaluate the influence of exposure to the mono-anesthetic propofol on the development of postoperative sleep disturbance in young and middle-aged female patients undergoing hysteroscopy and whether prophylactic administration of dexmedetomidine influences reducing postoperative sleep disturbance. METHODS: This prospective randomized controlled trial (RCT) will include 150 patients undergoing hysteroscopy at the First Affiliated Hospital of Xiamen University. Participants will be randomly assigned to three groups in a 1:1:1 ratio. The dexmedetomidine group will have two subgroups and will receive a nasal spray of 0.2 µg/kg or 0.5 µg/kg 25 min before surgery, while the control group will receive a saline nasal spray. Three groups will undergo hysteroscopy with propofol-based TIVA according to the same scheme. Sleep quality will be measured using a wearable device and double-blind sleep assessments will be performed before surgery and 1, 3, and 7 days after surgery. SPSS 2.0 is used for statistical analysis. A χ2 test is used to compare groups, and t-test is used to determine statistical the significance of continuous variables. DISCUSSION: The purpose of this study is to investigate the incidence of propofol-associated sleep disorders and to test a combination of dexmedetomidine anesthesia regimen for the prevention of postoperative sleep disorders. This study will help to improve patients' postoperative satisfaction and provide a new strategy for comfortable perioperative medical treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT06281561. Registered on February 24, 2024.

Long-term PM2.5 exposure and peak expiratory flow in middle-aged and older people in China: A quasi-experimental study.

China's Clean Air Act (CCAA) has been demonstrated to reduce the public health burden of ambient air pollution. Few studies have assessed the health effects of CCAA on lung function. We aimed to investigate the effects of CCAA and PM2.5 exposures on peak expiratory flow (PEF) in middle-aged and older people in China. Three waves (2011, 2013, and 2015) of the China Health and Retirement Longitudinal Study (CHARLS) were included in this study. We performed a difference-in-difference (DID) model and mixed effect method to assess the association between CCAA, PM2.5, and PEF. To increase the reliability, multiple environmental factors were considered, and spline function was utilized to fit the spatial autocorrelations. We found that the risk of decreased PEF in the policy intervention group was reduced by 46% (95% CI: 23%~62%). The estimate showed a 10µg/m3 increase in PM2.5 would increase the risk of decreased PEF by 10% (95% CI: 3%~18%). The results of the mixed effect model showed a 10 µg/m3 increase in PM2.5 concentration was associated with a 2.23% (95% CI: 1.35%~3.06%) decrease in the PEF. These results contributed to the limited epidemiology evidence on demonstrating the effect of PM2.5 on lung function.

Photochemical Degradation of the New Nicotine Pesticide Acetamiprid in Water.

Acetamiprid is a novel nicotinic pesticide widely used in modern agriculture because of its low toxicity and specific biological target properties. The objective of this study was to understand the photolysis pattern of acetamiprid in the water column and elucidate its degradation products and mechanism. It was observed that acetamiprid exhibited different photolysis rates under different light source conditions in pure water, with ultraviolet > fluorescence > sunlight; furthermore, its photolysis half-life ranged from 17.3 to 28.6 h. In addition, alkaline conditions (pH 9.0) accelerated its photolysis rate, which increased with pH. Using gas chromatography-mass spectrometry, five direct photolysis products generated during the exposure of acetamiprid to pure water were successfully separated and identified. The molecular structure of acetamiprid was further analyzed using density functional theory, and the active photodegradation sites of acetamiprid were predicted. The mechanism of the photolytic transformation of acetamiprid in water was mainly related to hydroxyl substitution and oxidation. Based on these findings, a comprehensive transformation pathway for acetamiprid was proposed.

Comprehensive Proteomic Profiling of Aqueous Humor in Idiopathic Uveitis and Vogt-Koyanagi-Harada Syndrome.

Idiopathic uveitis (IU) and Vogt-Koyanagi-Harada (VKH) syndrome are common types of uveitis. However, the exact pathological mechanisms of IU and VKH remain unclear. Proteomic analysis of aqueous humor (AH), the most easily accessible intraocular fluid and a key site of uveitis development, may reveal potential biomarkers and elucidate uveitis pathogenesis. In this study, 44 AH samples, including 12 IU cases, 16 VKH cases, and 16 controls, were subjected to label-free quantitative proteomic analysis. We identified 557 proteins from a comprehensive spectral library of 634 proteins across all samples. The AH proteomic profiles of the IU and VKH groups were different from those of the control group. Differential analysis revealed a shared pattern of extracellular matrix disruption and downregulation of retinal cellular proteins in the IU and VKH groups. Enrichment analysis revealed a protein composition indicative of inflammation in the AH of the IU and VKH groups but not in that of the control group. In the IU and VKH groups, innate immunity played an important role, as indicated by complement cascade activation and overexpression of innate immune cell markers. Extreme gradient boosting (XGBoost), an efficient and robust machine learning algorithm, was subsequently used to screen potential biomarkers for classifying the IU, VKH, and control groups. Transferrin and complement factor B were deemed the most important and represent a promising biomarker panel. These proteins were validated by high-resolution multiple reaction monitoring (HR-MRM) in an independent validation cohort. A classification decision tree was subsequently built for the diagnosis. Our findings further the understanding of the underlying molecular mechanisms in IU and VKH and facilitate the development of potential therapeutic and diagnostic strategies.

Engineering tumor-oxygenated nanomaterials: advancing photodynamic therapy for cancer treatment.

Photodynamic therapy (PDT), a promising treatment modality, employs photosensitizers to generate cytotoxic reactive oxygen species (ROS) within localized tumor regions. This technique involves administering a photosensitizer followed by light activation in the presence of oxygen (O2), resulting in cytotoxic ROS production. PDT's spatiotemporal selectivity, minimally invasive nature, and compatibility with other treatment modalities make it a compelling therapeutic approach. However, hypoxic tumor microenvironment (TME) poses a significant challenge to conventional PDT. To overcome this hurdle, various strategies have been devised, including in-situ O2 generation, targeted O2 delivery, tumor vasculature normalization, modulation of mitochondrial respiration, and photocatalytic O2 generation. This review aims to provide a comprehensive overview of recent developments in designing tumor-oxygenated nanomaterials to enhance PDT efficacy. Furthermore, we delineate ongoing challenges and propose strategies to improve PDT's clinical impact in cancer treatment.

Blood biomarkers in dynamic prediction of conversion to Alzheimer's disease: An application of joint modeling.

OBJECTIVES: To investigate the accuracy of longitudinal trajectories of blood biomarkers for predicting future onset of AD among MCI participants as well as to demonstrate dynamic prediction of the individual conversion risk applying joint modeling. METHODS: A total of 446 participants with MCI at baseline from the Alzheimer's Disease Neuroimaging Initiative database were included. We introduced joint modeling to analyze the effects of the longitudinal blood biomarkers on the conversion risk to AD, and further to build individual-specific prediction risk model. RESULTS: During the follow-up, 345 participants remained with MCI and 101 progressed to AD, and were categorized as non-progression and progression group, respectively. Longitudinally, the positive association of the concentration dynamics of plasma p-tau181 and NfL with the conversion risk to AD from MCI was also demonstrated, with Hazard Ratio (HR) = 5.83 and HR = 4.18, respectively. When incorporating plasma p-tau181 and NfL together to predict AD progression, we observed improved performance (AUC = 0.701, Brier Score = 0.119). Two participants were chosen to exemplify the individual-specific risk prediction at different follow-up time for comparative analysis. CONCLUSIONS: Plasma p-tau181 and NfL could serve as biomarkers for the prediction of AD onset, and the individualized prediction opens up the possibility to provide clinical information at a personal level.

Targeting cAMP in D1-MSNs in the nucleus accumbens, a new rapid antidepressant strategy.

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

Long-term effect of extreme temperature on cognitive function of middle-aged and older adults in China.

BACKGROUND: Several studies have explored the association between temperature and cognitive function. However, few studies have examined the effect of extreme temperature on cognitive function. In this study, we aimed to quantify the long-term effect of extreme temperature (e.g., heat waves, cold spells, and hot night excess (HNE)) on cognitive performance in middle-aged and older people in China. METHOD: We investigated 7915 aged >45 years people from the China Health and Retirement Longitudinal Study (CHARLS), surveyed in 2011 and 2015. A structured questionnaire was utilized to assess cognitive function, including four dimensions: episodic memory, attention, orientation, and visuo-construction. Hourly ambient temperature from the ERA5-Land datasets were used to calculate variables indicating extreme temperature. We performed difference-in-difference (DID) models to assess the potential causal relationship between extreme temperature and cognitive function. RESULTS: Non-linear analyses suggested that both sustained increases in temperature and excessive variability in temperature increased the risk of cognitive decline. Meanwhile, we observed the extra risk of global cognitive function decline was 2.3% (95% Confidence interval (95% CI): 0.2%, 4.4%) for heat waves (one unit increase) and 5.9% (95% CI: 0.6%, 11.6%) for HNE (one unit increase), while the association for cold spells was insignificant. Two cognitive dimensions, episodic memory and visuo-construction, were sensitive to these two heat-related factors. CONCLUSION: Extreme temperature was inversely related to cognitive performance in middle-aged and older adults, which was substantial for heat waves and HNE particularly. The effect size varied by cognitive dimensions.

Long-Term PM2.5 Exposure, Lung Function, and Cognitive Function Among Middle-Aged and Older Adults in China.

BACKGROUND: Long-term exposure to PM2.5 is related to poor lung function and cognitive impairment, but less is known about the pathway involved in this association. We aimed to explore whether the effect of PM2.5 on cognitive function was mediated by lung function. METHODS: A total of 7 915 adults older than 45 years old were derived from the China Health and Retirement Longitudinal Study (CHARLS) collected in 2011 and 2015. PM2.5 exposure was estimated using a geographically weighted regression model. Lung function was measured by peak expiratory flow (PEF). Cognitive function was evaluated through a structured questionnaire with 4 dimensions: episodic memory, attention, orientation, and visuoconstruction. Under the counterfactual framework, causal mediation analysis was applied to examine direct and indirect associations. RESULTS: An interquartile range (IQR) increase in PM2.5 change was significantly related to an 8.480 (95% confidence interval [CI]: 3.116, 13.845) decrease in PEF change and a 0.301 (95% CI: 0.100, 0.575) decrease in global cognitive score change. The direct and indirect effects of PM2.5 exposure on global cognitive performance were -0.279 (95% CI: -0.551, -0.060) and -0.023 (95% CI: -0.041, -0.010), respectively. The proportion of the indirect effect was 7.48% (p = .010). The same significant association appeared in only 2 dimensions, episodic memory and attention, which were both mediated by PEF. CONCLUSIONS: Lung function played a partially mediating role in the association between long-term PM2.5 exposure and cognition. More clean air actions should be undertaken to improve lung function and cognitive function in older adults.

Hierarchically supramolecular polymerization of anthraquinone dye to chiral aggregates via 2D-monolayered nanosheets: the unanticipated role of pathway complexity.

An anthraquinone dye underwent supramolecular polymerization, affording 2D-monolayered nanosheets in a kinetically controlled state. The nanosheets then transformed into hierarchically chiral aggregates in a thermodynamically controlled step. The unanticipated role played by pathway complexity was clearly unravelled in this work, highlighting the diversified pathways in the supramolecular polymerization of various building blocks.

Effects of nitric oxide synthase inhibitor on mitochondria apoptosis and meat quality in postmortem Gannan yak (Bos grunniens) meat.

This research aimed to explore the effects of the nitric oxide synthase (NOS) inhibitor (L-NAME) on mitochondria apoptosis in postmortem Gannan yak (Bos grunniens) longissimus dorsi (LD) muscle and to explore its effect on meat quality further. The Gannan yak meat samples were treated with the control group (0.9% NaCl) and L-NAME (20, 60, and 100 mM) for 24 h and then stored for 0, 1, 3, 5, and 7 days at 4°C. NOS activity and NO content were investigated, and the parameters of mitochondrial apoptosis of the postmortem Gannan yak meat were determined. Meanwhile, the meat quality such as the centrifugation loss, meat color, and myofibril fragmentation index (MFI) was evaluated. The results indicated that after treatment with L-NAME, NOS activity and NO content decreased, causing mitochondrial membrane damage, Bax protein, and Cyt-c levels increased, and resulted in increased activities of caspase-9 and -3, promoting the occurrence of mitochondrial apoptosis. Furthermore, it increased the tenderness and water retention of Gannan yak meat. The results indicated that NOS inhibitor played a regulatory role in postmortem Gannan yak meat quality by regulating mitochondria apoptosis during postmortem aging. PRACTICAL APPLICATIONS: The meat's tenderness is often considered the most important factor affecting consumers' willingness to repurchase. The relationship of caspases and MFI suggested that L-NAME played a regulatory role in postmortem Gannan yak meat quality by regulating mitochondria apoptosis during postmortem aging. This study provides valuable information for the development of the Gannan yak economy in Tibetan areas.

Cigarette smoke-induced oxidative stress activates NRF2 to mediate fibronectin disorganization in vascular formation.

Cigarette smoke significantly induces oxidative stress, resulting in cardiovascular disease. NRF2, a well-known antioxidative stress response factor, is generally considered to play protective roles in cardiovascular dysfunction triggered by oxidative stress. Interestingly, recent studies reported adverse effects of NRF2 on the cardiovascular system. These unfavourable pathogenic effects of NRF2 need to be further investigated. Our work shows that cigarette smoke extract (CSE)-induced oxidative stress disturbs fibronectin (FN) assembly during angiogenesis. Furthermore, this effect largely depends on hyperactive NRF2-STAT3 signalling, which consequently promotes abnormal FN deposition. Consistently, disruption of this pathway by inhibiting NRF2 or STAT3 prevents CSE-induced FN disorganization and vasculature disruption in human umbilical vein endothelial cells or zebrafish. Taken together, these findings demonstrate the cardiovascular dysfunction caused by CSE from a novel perspective that NRF2-dependent signalling engages in FN disorganization.

Association of long-term exposure to PM2.5 with hypertension and diabetes among the middle-aged and elderly people in Chinese mainland: a spatial study.

BACKGROUND: Epidemiological evidence has shown an association between long-term exposure to fine particulate matter (PM2.5) and hypertension and diabetes, but few studies have considered the spatial properties of the samples. This study aimed to investigate the long-term effect of PM2.5 exposure on hypertension and diabetes among middle-aged and elderly people in China based on a spatial study. METHODS: We conducted a national cross-sectional study of the most recently launched wave 4 2018 data of the China Health and Retirement Longitudinal Study (CHARLS) to calculate the prevalence of hypertension and diabetes. The exposure data of annual average PM2.5 concentrations were estimated combined with satellite observations, chemical transport modeling, and ground-based monitoring. A shared component model (SCM) was used to explore the association of PM2.5 with hypertension and diabetes, in which these two diseases borrowed information on spatial variations from each other. Then, we evaluated the effect variations in PM2.5 in different periods and smoking status on changes in outcomes. RESULTS: The prevalence of hypertension and diabetes was 44.27% and 18.44%, respectively, among 19,529 participants. The annual average PM2.5 concentration in 31 provinces ranged from 4.4 µg/m3 to 51.3 µg/m3 with an average of 27.86 µg/m3 in 2018. Spatial auto-correlations of the prevalence of hypertension and diabetes and PM2.5 concentrations were seen (Moran's I = 0.336, p = 0.01; Moran's I = 0.288, p = 0.03; Moran's I = 0.490, p = 0.01). An interquartile range (IQR: 16.2 µg/m3) increase in PM2.5 concentrations was significantly associated with a higher prevalence of hypertension and diabetes with odds ratios (ORs) of 1.070 [95% credible interval (95% CrI): 1.034, 1.108] and 1.149 (95% CrI: 1.100, 1.200), respectively. Notably, the effect of PM2.5 on both hypertension and diabetes was relatively stronger among non-smokers than smokers. CONCLUSION: Our nationwide study demonstrated that long-term exposure to PM2.5 might increase the risk of hypertension and diabetes, and could provide guidance to public policymakers to prevent and control hypertension and diabetes according to the spatial distribution patterns of the above effects in China.

Erratum: Activation of the PI3K/Akt/mTOR/p70S6K Pathway is Involved in S100A4-Induced Viability and Migration in Colorectal Cancer Cells: Erratum.

[This corrects the article DOI: 10.7150/ijms.8128.].

Pharmaceutical targeting of succinate dehydrogenase in fibroblasts controls bleomycin-induced lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix in the lung with fibroblast-to-myofibroblast transition, leading to chronically compromising lung function and death. However, very little is known about the metabolic alterations of fibroblasts in IPF, and there is still a lack of pharmaceutical agents to target the metabolic dysregulation. Here we show a glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts from fibrotic lung, and perturbation of glycolysis and FAO affects fibroblasts transdifferentiation. In addition, there is a significant accumulation of succinate both in fibrotic lung tissues and myofibroblasts, where succinate dehydrogenase (SDH) operates in reverse by reducing fumarate to succinate. Then succinate contributes to glycolysis upregulation and FAO downregulation by stabilizing HIF-1α, which promotes the development of lung fibrosis. In addition, we identify a near-infrared small molecule dye, IR-780, as a targeting agent which stimulates mild inhibition of succinate dehydrogenase subunit A (SDHA) in fibroblasts, and which inhibits TGF-ß1 induced SDH and succinate elevation, then to prevent fibrosis formation and respiratory dysfunction. Further, enhanced cell retention of IR-780 is shown to promote severe inhibition of SDHA in myofibroblasts, which may contribute to excessive ROS generation and selectively induces myofibroblasts to apoptosis, and then therapeutically improves established lung fibrosis in vivo. These findings indicate that targeting metabolic dysregulation has significant implications for therapies aimed at lung fibrosis and succinate dehydrogenase is an exciting new therapeutic target to treat IPF.

Correlation between severity of spinal stenosis and multifidus atrophy in degenerative lumbar spinal stenosis.

BACKGROUND: Degenerative lumbar spinal stenosis (DLSS) is a common degenerative condition in older adults. Muscle atrophy (MA) is a leading cause of muscle weakness and disability commonly reported in individuals with spinal stenosis. The purpose of this study was to investigate if the MA correlates with the grade of spinal stenosis in patients with DLSS. METHODS: A retrospective analysis on 48 male and 184 female DLSS patients aged around 54.04 years (54.04 ± 8.93) were involved and divided into 6 groups according to claudication-distance-based grading of spinal stenosis, which confirmed by two independent orthopedic surgeons using T2- weighted images. Using 1.5T MRI scanner, the severity of MA is assessed based on its negative correlation with the ratio of total fat-free multifidus muscle cross-sectional area (TFCSA) to total multifidus muscle cross-sectional area (TCSA). Adobe Photoshop CS6 was used for qualitative image analysis and calculate the TFCSA/TCSA ratio to assess the severity of MA, compare the grade of MA with the spinal stenosis segment, stenosis grade and symptom side. RESULTS: In DLSS group, The TFCSA/TCSA ratio are 74.33 ± 2.18 in L3/4 stenosis, 75.51 ± 2.79 in L4/5 stenosis, and 75.49 ± 2.69 in L5/S1 stenosis. there were significant decreases in the TFCSA/TCSA ratio of stenotic segments compared with non-stenotic segments of the spinal canal (P < 0.05) while no significant difference between the non-stenotic segments (P > 0.05). TFCSA/TCSA ratios is significant differences in the TFCSA/TCSA ratios of the 6 DLSS groups (F = 67.832; P < 0.05). From Group 1 to Group 6, the TFCSA/TCSA ratio of stenotic segments positively correlated with the absolute claudication distance (ACD). (P < 0.001, r = 0.852). Besides, the TFCSA/TCSA ratios are smaller in the symptomatic sides of the spine than the contralateral sides (t = 4.128, P = 0.001). CONCLUSIONS: The stenotic segments of the spinal canal are more atrophied than the non-stenotic segment in DLSS patients. It is shows that a strong positive correlation between the severity of multifidus atrophy and the severity of spinal stenosis.

Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages.

Pro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.

The near-infrared dye IR-61 restores erectile function in a streptozotocin-induced diabetes model via mitochondrial protection.

This study aimed to evaluate the therapeutic effect of IR-61, a novel mitochondrial heptamethine cyanine dye with antioxidant effects, on diabetes mellitus-induced erectile dysfunction (DMED). Eight-week-old male Sprague-Dawley rats were intraperitoneally injected with streptozotocin (STZ) to induce type 1 diabetes. Eight weeks after STZ injection, all rats were divided into three groups: the control group, DM group, and DM + IR-61 group. In the DM + IR-61 group, the rats were administered IR-61 (1.6 mg kg-1) twice a week by intravenous injection. At week 13, erectile function was evaluated by determining the ratio of the maximal intracavernous pressure to mean arterial pressure, and the penises were then harvested for fluorescent imaging, transmission electron microscopy, histological examinations, and Western blot analysis. Whole-body imaging suggested that IR-61 was highly accumulated in the penis after intravenous injection. IR-61 treatment significantly improved the maximal ICP of diabetic rats. Additionally, IR-61 ameliorated diabetes-induced inflammation, apoptosis, and phenotypic transition of corpus cavernosum smooth muscle cells (CCSMCs) in penile tissue. IR-61 also attenuated mitochondrial damage, reduced reactive oxygen species production in the corpus cavernosum and upregulated sirtuin1 (SIRT1), sirtuin3 (SIRT3), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and heme oxygenase expression in penile tissue. In conclusion, IR-61 represents a potential therapeutic option for DMED by protecting the mitochondria of CCSMCs, which may be mediated by activation of the SIRT1, SIRT3, and Nrf2 pathways.

Eye Drops of Metformin Prevents Fibrosis After Glaucoma Filtration Surgery in Rats via Activating AMPK/Nrf2 Signaling Pathway.

Metformin has effective therapeutic effects in anti-tumor and anti-fibrotic diseases. However, how the antifibrotic effect of metformin in the eye and how it is transferred are still unclear. Here, the eye drop of metformin treatment was studied in Sprague-Dawley (SD) rats of glaucoma filtrating surgery (GFS). Rats were administered randomly bilateral drops: control group (without surgery), GFS group, metformin group or mitomycin C (MMC) group (sponge application intraoperatively, 0.02%). Bleb features and intraocular pressure (IOP) were assessed for postoperative week 4. Metformin effectively inhibited fibrosis and improved the surgical outcomes of GFS. In vitro, we found that the degree of oxidative stress and fibrosis in metformin pretreated-Human Conjunctival Fibroblasts (HConFs) were reduced; the pro-fibrotic response of HConFs were decreased by inducing macrophagic polarity changes. Besides, the inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2)/AMP-activated protein kinase (AMPK) and the competition of organic cation transporters (OCTs) effectively reduced the anti-fibrotic capability of metformin. Together, this experiment indicates that metformin enters into HConFs cell with OCTs, which can protect against filtrating blebs scar formation in SD rats of GFS via activating AMPK/Nrf2 axis and the downregulation of profibrogenic and inflammatory biomarkers.