Liquiritin alleviates spinal cord injury through suppression of inflammation, oxidative stress, and cell apoptosis in a rat model

Purpose: Liquiritin is an extract from Glycyrrhiza Radix, one of the oldest traditional Chinese herbal medicines, which is commonly used to treat various injuries and swellings. This study is aimed to determine whether liquiritin can protect spinal cord injuries (SCIs) from secondary injuries. Methods: A rat SCI model was established. After liquiritin treatment, the neural-function of Rats was determined by Basso, Beattie and Bresnahan (BBB) scores, paw withdrawal threshold (PWT), and thermal withdrawal latency (PWL). The effects of anti-inflammation, anti-oxidation, and anti-apoptosis of liquiritin were also examined in the rats with SCI. Moreover, the activities of several signaling elements, such as, inflammation-associated nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), toll-like receptor 4 (TLR4), proliferative-related p38 mitogen-activated protein kinases (MAPK) and myeloid differentiation primary response 88 (MyD88) which was involved in the TLR4 signaling, were used for further investigation of the underlying molecular mechanisms. Results: Liquiritin improved locomotor function recovery, alleviated allodynia and hyperalgesia, and decreased water content of spinal cord in SCI rats. Also, liquiritin reduced SCI–induced inflammatory responses by decreasing the levels of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and IL-6. Liquiritin inhibited SCI–induced oxidative stress by decreasing malondialdehyde (MDA) level and increasing the levels of uperoxide dismutase (SOD) (p < 0.05), glutathione (GSH) (p < 0.01), and GSH-PX (p < 0.001). In addition, liquiritin alleviated spinal cord injury (SCI) –induced apoptosis of neural cells by decreasing the expression of cleaved caspase-9, -3 and cleaved poly ADP-ribose polymerase (PARP). Finally, liquiritin decreased spinal cord injury (SCI) -induced up-regulation of TLR4/MyD88/NF-κB and p38 MAPK signaling cascades. Conclusion: Liquiritin exerts protective role in SCI by reducing excessive inflammation, suppressing oxidative stress, and inhibiting neural cell apoptosis in a rat model of SCI. Thus, the agent can potentially be used for the management of SC

pLMFPPred: a novel approach for accurate prediction of functional peptides integrating embedding from pre-trained protein language model and imbalanced learning

Functional peptides have the potential to treat a variety of diseases. Their good therapeutic efficacy and low toxicity make them ideal therapeutic agents. Artificial intelligence-based computational strategies can help quickly identify new functional peptides from collections of protein sequences and discover their different functions.Using protein language model-based embeddings (ESM-2), we developed a tool called pLMFPPred (Protein Language Model-based Functional Peptide Predictor) for predicting functional peptides and identifying toxic peptides. We also introduced SMOTE-TOMEK data synthesis sampling and Shapley value-based feature selection techniques to relieve data imbalance issues and reduce computational costs. On a validated independent test set, pLMFPPred achieved accuracy, Area under the curve - Receiver Operating Characteristics, and F1-Score values of 0.974, 0.99, and 0.974, respectively. Comparative experiments show that pLMFPPred outperforms current methods for predicting functional peptides.The experimental results suggest that the proposed method (pLMFPPred) can provide better performance in terms of Accuracy, Area under the curve - Receiver Operating Characteristics, and F1-Score than existing methods. pLMFPPred has achieved good performance in predicting functional peptides and represents a new computational method for predicting functional peptides.Comment: 20 pages, 5 figures,under revie

Inhibition of TLR4 Signalling-Induced Inflammation Attenuates Secondary Injury after Diffuse Axonal Injury in Rats

Increasing evidence suggests that secondary injury after diffuse axonal injury (DAI) damages more axons than the initial insult, but the underlying mechanisms of this phenomenon are not fully understood. Recent studies show that toll-like receptor 4 (TLR4) plays a critical role in promoting adaptive immune responses and have been shown to be associated with brain damage. The purpose of this study was to investigate the role of the TLR4 signalling pathway in secondary axonal injury in the cortices of DAI rats. TLR4 was mainly localized in microglial cells and neurons, and the levels of TLR4 downstream signalling molecules, including TLR4, myeloid differentiation primary response gene 88, toll/IR-1-(TIR-) domain-containing adaptor protein inducing interferon-beta, interferon regulatory factor 3, interferon β, nuclear factor κB (NF-κB) p65, and phospho-NF-κB p65, significantly increased and peaked at 1 d after DAI. Inhibition of TLR4 by TAK-242 attenuated apoptosis, neuronal and axonal injury, and glial responses. The neuroprotective effects of TLR4 inhibition were associated with decreases in the levels of TLR4 downstream signalling molecules and inflammatory factors, including interleukin-1β, interleukin-6, and tumour necrosis factor-α. These results suggest that the TLR4 signalling pathway plays an important role in secondary injury and may be an important therapeutic target following DAI

Involvement of Toll Like Receptor 2 Signaling in Secondary Injury during Experimental Diffuse Axonal Injury in Rats

Treatment of diffuse axonal injury (DAI) remains challenging in clinical practice due to the unclear pathophysiological mechanism. Uncontrolled, excessive inflammation is one of the most recognized mechanisms that contribute to the secondary injury after DAI. Toll like receptor 2 (TLR2) is highlighted for the initiation of a vicious self-propagating inflammatory circle. However, the role and detailed mechanism of TLR2 in secondary injury is yet mostly unknown. In this study, we demonstrated the expression of TLR2 levels in cortex, corpus callosum, and internal capsule and the localization of TLR2 in neurons and glial cells in rat DAI models. Intracerebral knockdown of TLR2 significantly downregulated TLR2 expression, attenuated cortical apoptosis, lessened glial response, and reduced the secondary axonal and neuronal injury in the cortex by inhibiting phosphorylation of mitogen-activated protein kinases (MAPK) including Erk, JNK, and p38, translocation of NF-κB p65 from the cytoplasm to the nucleus, and decreasing levels of proinflammatory cytokines including interleukin-6, interleukin-1β, and tumor necrosis factor-α. On the contrary, administration of TLR2 agonist to DAI rats achieved an opposite effect. Collectively, we demonstrated that TLR2 was involved in mediating secondary injury after DAI by inducing inflammation via the MAPK and NF-κB pathways