[Nuclear factor E2-related factor 2 protein mediates sepsis-associated liver injury by regulating ferroptosis].

OBJECTIVE: To investigate the effect of nuclear factor E2-related factor 2 (Nrf2) protein on ferroptosis in mice with sepsis-associated liver injury (SALI). METHODS: he male Sprague-Dawley (SD) mice were divided into 6 groups according to the random number table method, with 6 mice in each group. The SALI model of mice was established by cecal ligation and puncture (CLP), and the Sham group was only treated with laparotomy. CLP+Fer-1 group, CLP+Erastin group, CLP+ML385 group and CLP+Curcumin group were intraperitoneally injected with iron death inhibitor Ferrostatin-1 (Fer-1) 10 mg×kg-1×d-1, iron death activator Erastin 20 mg×kg-1×d-1, Nrf2 inhibitor ML385 30 mg×kg-1×d-1 and Nrf2 activator Curcumin 100 mg×kg-1×d-1 after CLP, respectively; Sham group and CLP group were given normal saline 10 mg×kg-1×d-1, each group was administered continuously for 10 days. Ten days after operation, the serum and liver tissues of mice were collected to detect the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, and the levels of malondialdehyde (MDA), glutathione (GSH) and Fe2+; in liver homogenate. The pathological changes of liver tissue were observed under light microscope after hematoxylin-eosin (HE) staining. The shape and length of mitochondria in liver cells were observed under transmission electron microscope. The protein expressions of Nrf2, glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) in liver tissue were detected by Western blotting. RESULTS: Compared with Sham group, the serum levels of ALT and AST in the CLP group were significantly increased; histologically, the hepatic cord was disordered, the cells were swollen and necrotic, and the length of mitochondria was significantly shortened; the levels of MDA and Fe2+ in liver tissue increased significantly, and the content of GSH decreased significantly; the protein expressions of Nrf2 and GPX4 in liver tissue decreased, and the protein expression of PTGS2 increased significantly. Compared with CLP group, the serum levels of ALT and AST in CLP+Fer-1 group and CLP+Curcumin group were significantly decreased [ALT (U/L): 80.65±19.44, 103.45±20.52 vs. 283.50±37.12, AST (U/L): 103.33±11.90, 127.33±15.79 vs. 288.67±36.82, all P < 0.05]; microscopically, the hepatic cord was irregular, the cells were slightly swollen, and the mitochondrial length was significantly increased (µm: 1.42±0.09, 1.43±0.21 vs. 1.07±0.25, both P < 0.05); the levels of MDA and Fe2+; in liver tissue decreased significantly, and the content of GSH increased significantly [MDA (mol/g): 0.87±0.23, 1.85±0.43 vs. 4.47±0.95, Fe2+ (µg/g): 63.80±7.15, 67.48±6.28 vs. 134.52±14.32, GSH (mol/g): 1.95±0.29, 1.95±0.45 vs. 0.55±0.29, all P < 0.05]; the protein expressions of Nrf2 and GPX4 in liver tissue were significantly increased, and the protein expression of PTGS2 was significantly decreased (Nrf2/GAPDH: 1.80±0.28, 2.10±0.43 vs. 0.70±0.24, GPX4/GAPDH: 0.80±0.06, 0.93±0.07 vs. 0.48±0.02, PTGS2/GAPDH: 0.76±0.05, 0.84±0.01 vs. 1.02±0.09, all P < 0.05). However, the results of the above indexes in the CLP+Erastin group and CLP+ML385 group were opposite, and the serum levels of ALT and AST were significantly increased [ALT (U/L): 344.52±40.79, 321.70±21.10 vs. 283.50±37.12, AST (U/L): 333.50±27.90, 333.00±16.67 vs. 288.67±36.82, all P < 0.05]; microscopically, the arrangement of hepatic cords was disordered, the cells were obviously swollen and necrotic, and the length of mitochondria was significantly shortened (µm: 0.78±0.13, 0.67±0.07 vs. 1.07±0.25, both P < 0.05); the levels of MDA and Fe2+ in liver tissue increased significantly, and the content of GSH decreased significantly [MDA (mol/g): 5.92±1.06, 5.62±0.56 vs. 4.47±0.95, Fe2+ (µg/g): 151.40±8.03, 151.88±8.68 vs. 134.52±14.32, GSH (mol/g): 0.25±0.08, 0.23±0.11 vs. 0.55±0.29, all P < 0.05]; the protein expressions of Nrf2 and GPX4 in liver tissue were significantly decreased, and the protein expression of PTGS2 was significantly increased (Nrf2/GAPDH: 0.46±0.09, 0.46±0.11 vs. 0.70±0.24, GPX4/GAPDH: 0.34±0.05, 0.40±0.01 vs. 0.48±0.02, PTGS2/GAPDH: 1.24±0.13, 1.16±0.11 vs. 1.02±0.09, all P < 0.05). CONCLUSIONS: CLP-induced SALI can lead to ferroptosis in mice hepatocytes, and Nrf2 protein in liver tissue can mediate SALI by regulating ferroptosis.

Effect of Tan Tui combined with kinesio taping on the posture control of patients with PFPS: protocol for a randomized controlled trial.

BACKGROUND: Patellofemoral pain syndrome (PFPS) is a chronic disease. Its early symptoms are mild and can be relieved by rest after the pain. If there is no effective rehabilitation, it may develop into patellofemoral arthritis. Physiotherapy and appropriate exercise intervention can improve PFPS and postural control during exercise. Tan Tui (TT) is an effective means to improve postural control. Whether combined kinesio taping (KT) can be used as an effective treatment for PFPS patients' recovery has not yet been confirmed. METHODS/DESIGN: Seventy-two eligible patients with early-stage PFPS will be recruited and randomized into 4 groups: TT + KT group (n = 18), TT + KTp group (n = 18), KT group (n = 18), and CON group (n = 18). The TT + KT group was treated with TT combined with KT intervention; the TT + KTp group was treated with TT and KT placebo technical intervention; the KT group was treated with KT intervention alone; the CON group was treated with routine activities. All 4 groups received 30 min, three times a week, for a total of 6 weeks of intervention training. Measurements will be performed at baseline, mid-intervention (4 weeks), and post-intervention (6 weeks) with visual analog scale/score, (VAS), Knee joint Lysholm function score (Lysholm), UniPedal Stance Test (UST), Star Excursion Balance Test ( SEBT), Relative Peak Torque, (RPT), and Knee joint Position PercePtion (KJPP), to check the maintenance of the effect of any intervention. DISCUSSION: For the first time in this trial, the impact will be evaluated. If the results are the same as expected, they will provide evidence that TT combined with KT sticking intervention can promote the posture control of patients with early PFPS. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100051166. Registered on 15 September 2021.

Robust Mechanical Destruction to the Cell Membrane of Carbon Nitride Polyaniline (C3N): A Molecular Dynamics Simulation Study.

The drug-resistant bacteria, particularly multidrug-resistant bacteria, has emerged as a major global public health concern posing serious threats to human life and survival. Nanomaterials, including graphene, have shown promise as effective antibacterial agents owing to their unique antibacterial mechanism compared with traditional drugs. Despite the structural similarity to graphene, the potential antibacterial activity of carbon nitride polyaniline (C3N) remains unexplored. In this study, we employed molecular dynamics simulations to investigate the effects of the interaction between the C3N nanomaterial and the bacterial membrane to evaluate the potential antibacterial activity of C3N. Our results suggest that C3N is capable of inserting deep into the bacterial membrane interior, regardless of the presence or absence of positional restraints in the C3N. The insertion process also resulted in local lipid extraction by the C3N sheet. Additional structural analyses revealed that C3N induced significant changes in membrane parameters, including mean square displacement, deuterium order parameters, membrane thickness, and area per lipid. Docking simulations, where all the C3N are restraint to a specific positions, confirmed that C3N can extract lipids from the membrane, indicating the strong interaction between the C3N material and the membrane. Free-energy calculations further revealed that the insertion of the C3N sheet is energetically favorable and that C3N exhibits membrane insertion capacity comparable to that observed for graphene, suggesting their potential for similar antibacterial activity. This study provides the first evidence of the potential antibacterial properties of C3N nanomaterials via bacterial membrane damage and underscores the potential for its use as antibacterial agents in the future applications.

Acute Tai Chi Chuan exercise enhances sustained attention and elicits increased cuneus/precuneus activation in young adults.

BACKGROUND: The potential for acute exercise to enhance attention has been discussed in the literature. However, the neural mechanisms by which acute exercise affects attention remain elusive. METHOD: In this study, we first identified an optimized acute Tai Chi Chuan (ATCC) exercise protocol that enhances sustained attention performance and then aimed to determine the neural substrates of exercise-enhanced attention. Reaction time (RT) from the psychomotor vigilance test (PVT) was used to evaluate sustained attention. In Experiment 1, improvements in RTs were compared among six different exercise protocols. In Experiment 2, the participants completed the PVT in an MRI scanner on both rest and exercise days. RESULTS: Experiment 1 showed that practicing TCC 3 times for a total of 20 minutes, followed by 10-minute rest periods, resulted in the largest improvements in RTs. Experiment 2 showed that ATCC enhanced sustained attention, as evidenced by shorter RTs, and resulted in greater cuneus/precuneus activation after exercise than in the rest condition. Exercise-induced changes in brain activities across a distributed network exhibited significant correlations with attention. CONCLUSION: Therefore, this study indicates that ATCC effectively enhances sustained attention and underscores the key role of the cuneus/precuneus and frontoparietal-cerebellar regions in facilitating vigilance among young adults.

Paeonol inhibits chronic constriction injury-induced astrocytic activation and neuroinflammation in rats via the HDAC/miR-15a pathway.

Neuropathic pain affects millions of people in the worldwide, but the major therapeutics perform limited effectiveness. Paeonol (PAE) is widely distributed in Paeonis albiflora, and has manifested anti-inflammatory and antioxidative effects in multiple diseases. The present study aims to elucidate the effect of Paeonol (PAE) on neuropathic pain (NP) and the potential targets. Chronic constriction injury model was established to mimic NP in vivo in rats. The expression of GFAP, HDAC2, AHDAC3, Ac-H3K9, Histone-H3, Ac-H4K12, Histone-H4, TNF-α, IL-1ß, and IL-6 was assessed by real-time polymerase chain reaction, western blot, and/or enzyme-linked immunosorbent assay kits. Ultimately, results indicated that intervention of PAE significantly blocked neuroinflammation and astrocytic activation via blocking HDAC/miR-15a signaling in CCI rats. These data revealed PAE is a novel therapeutic target for the treatment of neuropathic pain.

Valsartan alleviates the blood-brain barrier dysfunction in db/db diabetic mice.

Type 2 diabetes (T2D)-related neurological complication is the risk factor for neurodegenerative disorders. The pathological changes from T2D-caused blood-brain barrier (BBB) dysfunction plays a critical role in developing neurodegeneration. The hyper-activation of the Angiotensin II type 1 receptor (AT1R) in the brain is associated with neurovascular impairment. The AT1R antagonist Valsartan is commonly prescribed to control high blood pressure, heart failure, and diabetic kidney diseases. In this study, we investigated the beneficial effects of Valsartan in db/db diabetic mice and isolated brain endothelial cells. We showed that 2 weeks of Valsartan administration (30 mg/Kg body weight) mitigated the increased permeability of the brain-blood barrier and the reduction of gap junction proteins VE-Cadherin and Claudin 2. In human brain microvascular cells (HBMVECs), we found that Valsartan treatment ameliorated high glucose-induced hyperpermeability by measuring Dextran uptake and transendothelial electrical resistance (TEER). Furthermore, Valsartan treatment recovered high glucose-repressed endothelial VE-Cadherin and Claudin 2 expression. Moreover, Valsartan significantly suppressed the expressions of pro-inflammatory cytokines such as macrophage chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) against high glucose. Mechanistically, Valsartan ameliorated high glucose-repressed endothelial cAMP-responsive element-binding protein (CREB) signaling activation. The blockage of CREB activation by PKA inhibitor H89 abolished the action of Valsartan, suggesting its dependence on CREB signaling. In conclusion, Valsartan shows a neuroprotective effect in diabetic mice by ameliorating BBB dysfunction. These effects of Valsartan require cellular CREB signaling in brain endothelial cells.

MiR-15a attenuates peripheral nerve injury-induced neuropathic pain by targeting AKT3 to regulate autophagy.

OBJECTIVE: Aim of this study was to detect the expression of miR-15a in rats following chronic constriction injury (CCI) and to investigate the regulatory functions of miR-15a during neuropathic pain (NP) development. METHODS: CCI was performed in adult Sprague-Dawley rats to set up the rat model of neuropathic pain. MiR-15a agomir and scrambled control were delivered into the implanted catheter of rats. The mechanical allodynia and thermal hyperalgesia were assessed in both CCI- and sham-operated groups. Rat lumbar spinal cord tissues were harvested for mRNA and protein analyses. The primary spinal microglia were isolated from adult Sprague-Dawley rats and transfected with miR-15a mimics, scramble miRNA, miR-15a inhibitor or its corresponding negative control. Cell lysates were collected for mRNA and protein analyses. RESULTS: Compared to sham-operated group, the expression of miR-15a in CCI rats was significantly reduced, whereas neuroinflammation in spinal cord tissues was increased. Intrathecal administration of miR-15a agomir significantly attenuated CCI-induced NP and the levels of proinflammatory cytokines, including IL-6, IL-1ß, and TNF-α. AKT3 was predicted and confirmed as a miR-15a-regulated gene. We further demonstrated that miR-15a overexpression downregulated the level of AKT3 in primary rat microglia and rat CCI model. Moreover, the upregulation of miR-15a induced the expressions of autophagy-associated proteins, suggesting that the regulation mechanism of miR-15a in NP development involves AKT3-mediated autophagy via inhibiting the expression of AKT3. CONCLUSION: Our findings indicated that miR-15a might serve as a promising therapeutic target for the management of NP through the stimulation of autophagic process.

[A meta-analysis on the efficacy of stem cells transplantation therapy on the prevention of cardiac remodeling and main adverse cardiovascular event in patients with chronic heart failure].

OBJECTIVE: Stem cells transplantation is a promising strategy in cardiology. This meta-analysis summarizes the efficacy and safety of stem cells transplantation on top of standard medication on chronic heart failure patients. METHODS: The following databases were searched, including Cochrane Library (Issue 4, 2011), PubMed (1980 to 2011), Embase (1990 to 2011), CBM (1978 to 2011), CNKI (1994 to 2011), VIP (1989 to 2011), and WanFang Data (1998 to 2011). Search criteria:studies were screened and the quality was evaluated according to predefined inclusion and exclusion criteria. Intervention measures: the treatment group using stem cell transplantation therapy on top of standard drug treatment, while the control group using standard drug treatments. RESULTS: A total of 31 studies involving 2375 patients were included. The results show that the improvement of LVEDV in the stem cell treatment group is greater than in the control group [SMD = -11.8% (95%CI: -0.223 - 0.013), P = 0.027] and the relative-risk of cardiac events is lower in stem cell treatment group [RR = 0.77 (95%CI: 0.66 - 0.90), P < 0.01] than in control group. CONCLUSION: Stem cells therapy is effective in improving cardiac remodeling and reducing the relative-risk of cardiac events in patients with chronic heart failure.