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.

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.