PolyphyllinVI alleviates the spared nerve injury-induced neuropathic pain based on P2X3 receptor-mediated the release of inflammatory mediators.

ETHNOPHARMACOLOGICAL RELEVANCE: PolyphyllinVI (PPⅥ) is the main bioactive component of Chonglou which is a traditional Chinese herbal with various effects, including antitumor, anti-inflammatory, and analgesia. AIM OF THE STUDY: This study aimed to investigate the properties and mechanisms of the analgesia of PPⅥ by using neuropathic pain (NPP) mice. MATERIALS AND METHODS: The potential targets and mechanisms of PPⅥ in alleviating NPP were excavated based on the network pharmacology. Subsequently, the construction of a spared nerve injury (SNI) mice model was used to evaluate the effect of PPⅥ on NPP and the expression of the P2X3 receptor. We identified the signaling pathways of PPⅥ analgesia by RNA sequencing. RESULTS: The results of network pharmacology showed that BCL2, CASP3, JUN, STAT3, and TNF were the key targets of the analgesic effect of PPⅥ. PPⅥ increased the MWT and TWL of SNI mice and decreased the level of P2X3 receptors in the dorsal root ganglion (DRG) and spinal cord (SC). Additionally, PPⅥ reduced the release of pro-inflammatory mediators (TNF-α, IL-1ß, and IL-6) in the DRG, SC, and serum. Based on the KEGG enrichment of differentially expressed genes (DEGs) identified by RNA-Seq, PPVI may relieve NPP by regulating the AMPK/NF-κB signaling pathway. Western blotting results showed that the AMPK signaling pathway was activated, followed by inhibition of the NF-κB signaling pathway. CONCLUSION: PPⅥ increased the MWT and TWL of SNI mice maybe by inhibiting the expression of the P2X3 receptor and the release of inflammatory mediators. The properties of the analgesia of PPⅥ may be based on the AMPK/NF-κB pathway.

Anti-inflammatory and analgesic properties of Polyphyllin VI revealed by network pharmacology and RNA sequencing.

Inflammatory pain, sustained by a complex network of inflammatory mediators, is a severe and persistent illness affecting many of the general population. We explore possible anti-inflammatory pathways of Polyphyllin VI (PPVI) based on our prior study, which showed that PPVI reduces inflammation in mice to reduce pain. Network pharmacology and RNA-Seq identified the contribution of the MAPK signaling pathway to inflammatory pain. In the LPS/ATP-induced RAW264.7 cell model, pretreatment with PPVI for 1 h inhibited the release of IL-6 and IL-8, down-regulated expression of the P2X7 receptor(P2X7R), and decreased phosphorylation of p38 and ERK1/2 components of the MAPK pathway. Moreover, PPVI decreased expression of IL-6 and IL-8 was observed in the serum of the inflammatory pain mice model and reduced phosphorylation of p38 and ERK1/2 in the dorsal root ganglia while the reductions of expression of IL-6 and phosphorylation of ERK1/2 were not observed after the pre-treatment with A740003 (an antagonist of the P2X7R). These results suggest that PPVI may inhibit the release of IL-8 by regulating P2X7R to reduce the phosphorylation of p38. However, the modulation of PPVI on the release of IL-6 and phosphorylation of ERK1/2 may mediated by other P2X7R-independent signals.

Effects of empagliflozin on serum uric acid level of patients with type 2 diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: Serum uric acid levels are higher in patients with type 2 diabetes and prediabetes compared to healthy individuals, and hyperuricemia causes a significant rate of complications and mortality through heart and kidney diseases. Accordingly, the present systematic review and meta-analysis aimed to investigate the effect of empagliflozin on serum uric acid levels. MATERIALS AND METHODS: Electronic databases, including PubMed, Scopus, Web of Science, Cochrane, and Google Scholar, were used to search papers until May 22, 2023. Data analysis was conducted by STATA Version 14, and P-value < 0.05 were considered statistically significant. RESULTS: The results obtained from the combination of 12 studies with 7801 samples of diabetic patients indicated that in the empagliflozin group, the serum uric acid levels of the patients decreased ([standardized mean difference (SMD): - 1.97 (95%CI - 3.39, - 0.55)], Systolic blood pressure (SBP) [SMD: - 2.62 (95%CI - 3.87, - 1.37)] and diastolic blood pressure (DBP) [SMD: - 0.49 (95%CI - 0.68, - 0.29)]). On the other side, empagliflozin treatment did not affect the patients' HbA1c levels ([SMD: - 2.85 (95%CI - 6.14, 0.45)], eGFR [SMD: 0.78 (95%CI - 0.63, 2.18)], creatinine [SMD:0.11 (95%CI - 0.10, 0.31)], LDL [SMD: 0.14 (95%CI - 0.43, 0.71)], and HDL [SMD:1.38 (95%CI - 0.22, 2.99)]). Compared with the placebo, empagliflozin was more effective in reducing the uric acid levels ([SMD: - 1.34 (95%CI - 2.05, - 0.63)], SBP [SMD: - 2.11 (95%CI - 3.89, - 0.33)], and HbA1c [SMD: - 1.04 (95%CI - 1.95, - 0.13)]). Moreover, compared with sitagliptin also, empagliflozin was more effective in reducing uric acid levels ([SMD: - 1 (95%CI - 1.78, - 0.22)], and creatinine [SMD: - 1.60 (95%CI - 2.28, - 0.92)]) and increasing eGFR levels [SMD: 0.99 (95%CI: 0.37, 1.62)] of the patients. Compared with dapagliflozin also, empagliflozin caused a reduction in eGFR level [SMD: - 0.45 (95%CI - 0.82, - 0.08)]. CONCLUSION: Empagliflozin treatment was effective in controlling diabetic patients' hyperuricemia and hypertension.

Polyphyllin VI screened from Chonglou by cell membrane immobilized chromatography relieves inflammatory pain by inhibiting inflammation and normalizing the expression of P2X3 purinoceptor.

Objective: Inflammatory pain is one of the most common diseases in daily life and clinic. In this work, we analysed bioactive components of the traditional Chinese medicine Chonglou and studied mechanisms of their analgesic effects. Material and methods: Molecular docking technology and U373 cells overexpressing P2X3 receptors combined with the cell membrane immobilized chromatography were used to screen possible CL bioactive molecules interacting with the P2X3 receptor. Moreover, we investigated the analgesic and anti-inflammatory effects of Polyphyllin VI (PPIV), in mice with chronic neuroinflammatory pain induced by CFA (complete Freund's adjuvant). Results: The results of cell membrane immobilized chromatography and molecular docking showed that PPVI was one of the effective compounds of Chonglou. In mice with CFA-induced chronic neuroinflammatory pain, PPVI decreased the thermal paw withdrawal latency and mechanical paw withdrawal threshold and diminished foot edema. Additionally, in mice with CFA-induced chronic neuroinflammatory pain, PPIV reduced the expression of the pro-inflammatory factors IL-1, IL-6, TNF-α, and downregulated the expression of P2X3 receptors in the dorsal root ganglion and spinal cord. Conclusion: Our work identifies PPVI as a potential analgesic component in the Chonglou extract. We demonstrated that PPVI reduces pain by inhibiting inflammation and normalizing P2X3 receptor expression in the dorsal root ganglion and spinal cord.

Cationic Gelatin Cross-Linked with Transglutaminase and Its Electrospinning in Aqueous Solution.

Gelatin (GE) is a renewable biopolymer with abundant active groups that are beneficial for manufacturing functional biomaterials via GE modification. An antibacterial fibrous GE film was prepared by electrospinning the modified GE in an aqueous solution. The original GE was modified by reacting it with N,N-dimethyl epoxypropyl octadecyl ammonium chloride (QAS), and then it was cross-linked with transglutaminase (TGase). FTIR analysis illustrated that QAS was grafted onto GE through the epoxy ring-opening reaction, and the modification did not influence the main GE skeleton structure. The investigation of the solution properties showed that the grafted cationic QAS group was the main factor that decreased the surface tension of the solution, increased the electrical conductivity of the solution, and endowed GE with antibacterial activity. TGase cross-linking clearly influenced the rheological properties such that the flow pattern of the spinning solution varied from Newton-type to shear thinning, and the aqueous solution of GE-QAS-TGs transformed from liquid-like to solid-like and even induced gelatinization with increasing TGase content. A satisfactory fibrous morphology of 200-500 nm diameter was obtained using a homemade instrument under the optimized electrospinning conditions of a temperature of 35 °C, a distance between electrodes of 12 cm, and a voltage of 15 kV. The study of film properties showed that the antibacterial activity of the fibrous GE film depended only on the grafted quaternary ammonium, whereas the thermostability, wettability, and permeability were greatly influenced by both the TGase cross-linking and film-forming methods. Cytotoxicity was tested using the CCK-8 and live/dead kit staining methods in vitro, which showed that the modified GE had good biocompatibility.

The exploration of the potential mechanism of oxymatrine-mediated antipruritic effect based on network pharmacology and weighted gene co-expression network analysis.

The treatment of chronic itch is considered to be a challenge for its non-histamine dependence and the search for alternative medicine is still striving. The pathology of the chronic itch is closely related to immune system regulation and inflammatory response. Oxymatrine (OMT) is a traditional Chinese medicine ingredient extracted from the roots of Sophora flavescens Aiton with significant antitumor, analgesic, and anti-inflammatory effects. However, the underlying mechanism of OMT on chronic itch is obscure, which limits clinical application. Hence, this study is aimed to clarify the pruritus alleviation mechanism of OMT by combining network pharmacology analysis, weighted gene co-expression analysis (WGCNA), and molecular docking. We screened 125 common targets of OMT regulating inflammation and pruritus with pharmacology technology, the GO enrichment function analysis and KEGG signaling pathway analysis to demonstrate the close relation to the signaling pathways regulating inflammation such as MAPK signaling pathway and PI3K-AKT signaling pathway. We adopted the most relevant templates for pruritus diseases, combined with network pharmacology to preliminarily screen out 3 OMT functions and regulatory targets, exerting a good connection and correlation with the target at the screened disease targets. Further experiments were conducted to explore the potential mechanism of OMT using the LPS-induced RAW264.7 cell inflammation model. The results showed that pretreatment with different concentrations of OMT (25 µM, 50 µM, and 100 µM) for 24 h, inhibited expression of IL-6, iNOS TLR4 and TGFR-1 as well as apoptosis of Raw264.7 cells induced by LPS. Moreover, OMT effectively inhibited LPS-induced MAPK pathway activation and the expression of related sites MAP2K1, MAPK8 MAP2K4, and MAPKAP-K2 in RAW 264.7 cells. The OMT also reduced the phosphorylation of p-38, associated with site in the activation of MAPK signaling pathway. These results could contribute to a better understanding of the mechanisms underlying how OMT alleviates inflammation to treat chronic pruritic diseases and provide a potential drug for the treatment of chronic itch.

Application of Fiber Biochar-MOF Matrix Composites in Electrochemical Energy Storage.

Fiber biochar-metal organic framework (MOF) composites were successfully prepared by three different biochar preparation methods, namely, the ionic liquid method, the pyrolysis method, and the direct composite method. The effects of the different preparation methods of fiber biochar on the physical and chemical properties of the biochar-MOF composites showed that the composite prepared by the ionic liquid method with the Zeolite-type imidazolate skeleton -67 (ZIF-67) composite after high temperature treatment exhibited a better microstructure. Electrochemical tests showed that it had good specific capacity, a fast charge diffusion rate, and a relatively good electrochemical performance. The maximum specific capacity of the composite was 63.54 F/g when the current density was 0.01 A/g in 1 mol/L KCl solution. This work explored the preparation methods of fiber biochar-MOF composites and their application in the electrochemical field and detailed the relationship between the preparation methods of the composites and the electrochemical properties of the electrode materials.

A network pharmacology technique used to investigate the potential mechanism of Ligustilide's effect on atherosclerosis.

Ligustilide (LIG) is a major active ingredient in traditional Chinese medicines that is also found in plant rhizomes such as carrot, coriander, and others, and it has been demonstrated to have cardiovascular preventive benefits. However, the mechanisms through which LIG protects the cardiovascular and cerebrovascular systems in atherosclerosis (AS) remain unknown. This study was aimed to investigate the mechanisms of LIG in AS utilizing the network pharmacology and molecular docking, and then to validate the putative mechanism through experiments. The network pharmacological analysis indicated that a total of 55 were performed on LIG and AS intersection targets. The genes of LIG and AS intersection targets enriched in the regulation of receptor and enzyme activity, cytokines-related, and transcription factors, indicating that these targets were primarily involved in cell proliferation and migration, regulating cell differentiation and skeletal activities in the development of AS. Finally, molecular docking was used to validate the major targets of LIG and AS intersection targets. Further experiments revealed that LIG may inhibit cell migration induced by AngII by reducing calcium influx, and regulating phenotypic translation-related proteins SM-22α and OPN. The present study investigated the potential targets and signaling pathways of LIG, which provides new insight into its anti-atherosclerosis actions in terms of reducing inflammation, cell proliferation, and migration, and may constitute a novel target for the treatment of AS. PRACTICAL APPLICATIONS: LIG has been shown to have cardiovascular protective benefits, the mechanism by which it protects the cardiovascular and cerebrovascular systems in AS remains unknown. This study uses a holistic network pharmacology strategy to investigate putative treatment pathways and conducts exploratory experimentation. The findings demonstrate that LIG reduces VSMC migration in the treatment of AS, acts as an anti-inflammatory agent, and prevents excessive cell proliferation and migration. Finally, the goal of our research is to uncover the molecular mechanism of LIG's influence on AS. The findings will provide a new research avenue for LIG as well as suggestions for the study of other herbal treatments. These research results will provide a new research direction for LIG and provide guidance for the research of other herbal medicines. This work revealed the multi-component, multi-target, multi-pathway, and multi-disease mechanism of LIG.

Ligustilide inhibited Angiotensin II induced A7r5 cell autophagy via Akt/mTOR signaling pathway.

Autophagy is essential to vessel homeostasis and function in the cardiovascular system. Ligustilide (LIG) is one of the main active ingredients extracted from traditional Chinese medicines, such as Ligusticum chuanxiong, Angelica, and other umbelliferous plants, and reported to have cardiovascular protective effects. In this study, we explore the effects and the potential mechanism of ligustilide on the Ang II-induced autophagy in A7r5 cells. Our results showed that ligustilide inhibited the Ang II-induced autophagy in A7r5 cells and down regulated the expression of autophagy-related proteins LC3, ULK1, and Beclin-1. Ligustilide exerted a protective effect on the reduction of the concentrations of reactive oxygen species and Ca2+ and upregulated the nitric oxide concentration in A7r5 cells with Ang II-induced autophagy. Additionally, the analyses of network pharmacological targets and potential signal pathways indicated that the target of ligustilide to regulate autophagy was related to the Akt/mTOR signaling pathway. Furthermore, ligustilide could upregulate the expression of p-Akt and p-mTOR and inhibit the expression of LC3II in A7r5 cells with Ang II-induced autophagy. These findings showed that ligustilide inhibited the autophagic flux in A7r5 cells induced by Ang II via the activation of the Akt/mTOR signaling pathway.

Ligustilide Inhibited Rat Vascular Smooth Muscle Cells Migration via c-Myc/MMP2 and ROCK/JNK Signaling Pathway.

Vascular smooth muscle cells (VSMCs) excessive migration, a basic change of pathological intimal thickening, can lead to serious cardiovascular diseases such as atherosclerosis, myocardial infarction, and stroke. Ligustilide (LIG), the main active ingredient of angelica volatile oil, has been demonstrated to exert protective effects on the cardiovascular and cerebrovascular, circulatory system, and immune function. However, whether it protects against intimal thickening and VSMCs excessive migration and its underlying mechanism remains largely unknown. The aim of this study is to investigate the effect of LIG on VSMCs migration and its underlying mechanism. The protective effect of LIG on VSMCs excessive migration was assessed using an atherosclerotic spontaneously hypertensive rat model and an angiotensin II (AngII)-induced VSMCs migration model. The results showed that LIG exerted a protective effect against pathological intimal thickening as demonstrated by decreasing VSMCs migration in vivo and in vitro. In vivo, intimal thickening and VSMCs migration were inhibited and LIG performed a suppressive effect on the expression of c-Myc protein while enhanced phenotypic transformation related proteins α-SMA expression. Meanwhile, the administration of LIG significantly lowered the blood pressure and blood lipids level in atherosclerotic spontaneously hypertensive rats. In vitro, LIG suppressed AngII-induced VSMCs migration and downregulated the expression of migration related protein c-Myc, MMP2, ROCK1, ROCK2, p-JNK, and JNK. These findings suggested the protective effect of LIG on VSMCs migration was associated with the decrement of c-Myc/MMP2 signaling pathway and ROCK-JNK signaling pathway. Thus, LIG may serve as a novel therapeutic agent for preventing cardiovascular disease.