Search

Sijunzi Decoction (SJZD) is a renowned formula for the treatment of spleen deficiency syndrome (SDS) in traditional Chinese medicine (TCM). Its non-polysaccharides (NPS) component, dominated by various compounds of SJZD, has shown the remarkable efficacy in SDS, especially in gastrointestinal injury. However, the principle of compatibility of SJZD and the micro-mechanism of effect on SDS are still unclear. To elucidate the scientific implications of SJZD compatibility and its micro-mechanism in the treatment of SDS-induced intestinal injury. First, the chemical composition of NPS in SJZD and incomplete SJZD (iSJZD, including SJZD-R, SJZD-A, SJZD-P, SJZD-G) were comprehensively analyzed by UPLC-QTOF-MS, and comparing their chemical composition by multivariate statistical analysis to reveal the effect of a single herb on SJZD compatibility. Second, network pharmacology and molecular docking were used to uncover the micro-mechanisms of potential active compounds in SJZD for the treatment of SDS, and develop an active component combination (ACC) by accurate quantification. Subsequently, the action of the potential active compounds and ACC was verified through in vivo and in vitro. A total of 112, 77, 93, 87, and 67 compounds were detected in NPS of SJZD, SJZD-R, SJZD-A, SJZD-P, and SJZD-G, respectively. Changes in the chemical components of SJZD_NPS and iSJZD_NPS revealed that RG and RAM, as well as RAM and Poria significantly affected the dissolution of each other's chemical components, and the co-decoction of four herbs promoted the dissolution of the active compounds and inhibited toxic compounds. Furthermore, network pharmacology showed that 274 compounds of 15 categories in SJZD_NPS acted on the 186 key targets to treat SDS by inhibiting inflammation, enhancing immunity, and regulating gastrointestinal function and metabolism. Finally, through in vitro experiments, six compounds among 18 potential compounds were verified to markedly repair intestinal epithelium injury by modulating the FAK/PI3K/Akt or LCK/Ras/PI3K/Akt signaling pathway. It is worth mentioning that ACC, composed of 11 compounds accurately quantified, demonstrated significant in vivo treatment effects on intestinal damage with SDS similar to NPS or SJZD. This study elucidates the scientific evidence of the " Jun-Chen-Zuo-Shi " and "detoxification and synergistic" in the decocting process of SJZD. An ACC, the active component of SJZD, ameliorate SDS-induced intestinal injury by the FAK/PI3K/Akt signaling pathway, which provides a strategy for screening alternatives to effective combinations of TCMs. [Display omitted] • Uncovering the principle of "Jun-Chen-Zuo-Shi" and "detoxification and synergistic" of four herbs in SJZD. • Various types of compounds in SJZD_NPS treat SDS through inhibiting inflammation, enhancing immunity, and regulating metabolism and gastrointestinal function. • Six potential active compounds and active component combination repaired the SDS with intestinal injury via modulating FAK/PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

This toxicology study was conducted to assess the impact of formaldehyde, a common air pollutant found in Chinese gymnasiums, on the brain function of athletes. In this research, a total of 24 Balb/c male mice of SPF-grade were divided into four groups, each consisting of six mice. The mice were exposed to formaldehyde at different concentrations, including 0 mg/m3, 0.5 mg/m3, 3.0 mg/m3, and 3.0 mg/m3 in combination with an injection of L-NMMA (NG-monomethyl-L-arginine), which is a nitric oxide synthase antagonist. Following a one-week test period (8 h per day, over 7 days), measurements of biomarkers related to the nitric oxide (NO)/cGMP-cAMP signaling pathway were carried out on the experimental animals post-treatment. The study found that: (1) Exposure to formaldehyde can lead to brain cell apoptosis and neurotoxicity; (2) Additionally, formaldehyde exposure was found to alter the biomarkers of the NO/cGMP-cAMP signaling pathway, with some changes being statistically significant (p < 0.05 or p < 0.01); (3) The use of L-NMMA, an antagonist of the NO/cGMP-cAMP signaling pathway, was found to prevent these biomarker changes and had a protective effect on brain cells. The study suggests that the negative impact of formaldehyde on the brain function of mice is linked to the regulation of the NO/cGMP-cAMP signaling pathway. [ABSTRACT FROM AUTHOR]

Epidemiological evidence indicates a significant relationship between exposure to diisononyl phthalate and allergic asthma. Despite this, the mechanism underlying this association remains unclear. Previous toxicological researches have suggested that the development of allergic asthma may involve the activation of endoplasmic reticulum stress (ERS) and the nuclear factor κ-B (NF-κB) pathways. Nevertheless, it is currently unknown whether these specific signaling pathways are implicated in diisononyl phthalate (DINP)-induced allergic asthma. The objective of this research was to understand how DINP exacerbates allergic asthma in Balb/c mice through ERS and NF-κB pathways. To systematically examine the aggravated effects of DINP in Balb/c mice, we measured airway hyperresponsiveness (AHR), lung tissue pathology, cytokines, and ERS and NF-κB pathway biomarkers. Additionally, we applied the ERS antagonist phenylbutyric acid (4-PBA) or the NF-κB antagonist pyrrolidine dithiocarbamate (PDTC) to verify the mediating effects of ERS and NF-κB on DINP-exacerbated allergic asthma. The results of our experiment show that oral DINP exposure may exacerbate airway hyperresponsiveness and airway remodeling. This deterioration is accompanied by an imbalance in immunoglobulin levels, Th17/Treg cells, ERS, and NF-κB biomarkers, leading to the activation of pro-inflammatory pathways. Furthermore, our study found that the blocking effect of 4-PBA or PDTC can inhibit the Th17/Treg imbalance and effectively alleviate symptoms resembling allergic asthma. In conclusion, ERS and NF-κB signaling pathways play an important role in regulating DINP-induced allergic asthma exacerbations. [Display omitted] • Exposure to diisononyl phthalate aggravates allergic asthma in Balb/c mice. • Endoplasmic reticulum stress and NF-κB pathway is involved in allergic asthma exacerbated by diisononyl phthalate. • Exposure to diisononyl phthalate triggers Th17/Treg immune imbalance in Balb/c mice. • 4-PBA or PDTC treatment can alleviate allergic asthma caused by combined exposure to ovalbumin and diisononyl phthalate. [ABSTRACT FROM AUTHOR]

Interactions of Ephrins and Eph receptors at cell membranes play crucial role in boundary formation and axon guidance. Extracellular vesicles (EVs), such as exosomes, are formed by cells communicating with each other in paracrine or endocrine manner. Until now, it is thought that direct cell–cell contact is necessary for ephrin and Eph receptor signal transduction. In this review, we discuss recent data that indicate the existence of a novel Eph‐ephrin family anchored exosome signaling pathway in long‐range intercellular communication and provide evidence that this type of signaling elicits cellular responses in cancer cells, independent of juxtacrine interactions. We emphasize that exosome‐anchored Eph/ephrin involves a variety of biological processes and transduction signals, which may serve as a potential diagnostic biomarker. [ABSTRACT FROM AUTHOR]

Guajadial, one of natural dialdehyde meroterpenoids, demonstrated significant antineoplasmic activity. The present research was to investigate the inhibitory effects of guajadial by using two NSCLC cells (A549 and H1650) proliferation and migration. Western blotting was employed to explore the underlying mechanisms of VEGF receptor (VEGFR)2-mediated. This research indicated that guajadial not only inhibited endothelial cell proliferation and migration but also suppress tumor growth in human NSCLC xenograft mouse models. It is also suggested that guajadial inhibited A549 proliferation via blocking the Ras/MAPK pathway. [ABSTRACT FROM AUTHOR]

Mume Fructus (MF) is processed from the near-ripe fruit of Prunus mume (Siebold) Siebold & Zucc by drying at low temperature until the color turns black. MF is often used in Chinese medicine for the treatment of chronic diarrhea and dysentery. Previous studies have shown that the active components of MF against Crohn's disease (CD) are mainly citrate and hydroxycinnamate derivatives, which can alleviate the CD-induced inflammatory response and intestinal barrier damage. However, their molecular mechanisms on CD still need further elucidation. To investigate the protective effects and underlying mechanisms of citrate and hydroxycinnamate derivatives in MF on intestinal epithelial injury. Network pharmacology technology was used to predict the anti-CD targets and molecular mechanisms of 4 citrate and 11 hydroxycinnamate derivative prototypes and 5 hydroxycinnamate derivative metabolites in the 40% ethanol fraction of MF (MFE40), the active anti-CD ingredient group of MF. Lipopolysaccharide (LPS)-treated IEC-6 cells were used to investigate the effects of the above components on the proliferation of damaged IEC-6 cells and to verify the molecular mechanism of their regulation on the FAK/PI3K/AKT signaling pathways for the promotion of the proliferation of IEC-6 cells. A "compound-target-pathway" network was constructed based on network pharmacology analysis, including 20 citrate and hydroxycinnamate derivatives that target 316 core proteins and 36 CD-related pathways, of which PI3K-AKT pathway and focal adhesion were the most enriched pathways. Further cell validation experiments showed that 1 citric acid (CA) compound and 10 hydroxycinnamate derivatives, including 3- O -caffeoylquinic acid (3CQA), 4- O -caffeoylquinic acid (4CQA), 5- O -caffeoylquinic acid (5CQA), caffeic acid (CFA), p-coumaric acid (PCMA), m-coumaric acid (MCMA), ferulic acid (FUA), isoferulic acid (IFUA), 3-hydroxyphenylpropionic acid (3HPPA) and hippuric acid (HPP), could promote the proliferation of IEC-6 cells and inhibit the damage of LPS to IEC-6 cells. Ethyl caffeate (ECFA), a hydroxycinnamic acid derivative, had no effect on promoting the proliferation of IEC-6 cells and was weak in inhibiting the damage of IEC-6 cells caused by LPS. Further mechanistic verification experiments showed that 7 citrate and hydroxycinnamate derivatives (CA, CFA, 3CQA, MCMA, FUA, 3HPPA, and HPP) could upregulate the expression of p-FAK, p-PI3K, and p-AKT proteins. Among them, CA had the better effect on activating the FAK-PI3K-AKT signaling pathway. Citrate and hydroxycinnamate derivatives in MF can ameliorate LPS-induced intestinal epithelial cell injury to demonstrate potential for Crohn's disease alleviation. This protective effect can be achieved by upregulating FAK/PI3K/AKT pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

Treating neuropathic pain continues to be a major clinical challenge and underlying mechanisms of neuropathic pain remain elusive. We have recently demonstrated that Wnt signaling, which is important in developmental processes of the nervous systems, plays critical roles in the development of neuropathic pain through the β-catenin-dependent pathway in the spinal cord and the β-catenin-independent pathway in primary sensory neurons after nerve injury. Here, we report that Wnt signaling may contribute to neuropathic pain through the atypical Wnt/Ryk signaling pathway in rats. Sciatic nerve injury causes a rapid-onset and long-lasting expression of Wnt3a, Wnt5b, and Ryk receptors in primary sensory neurons, and dorsal horn neurons and astrocytes. Spinal blocking of the Wnt/Ryk receptor signaling inhibits the induction and persistence of neuropathic pain without affecting normal pain sensitivity and locomotor activity. Blocking activation of the Ryk receptor with anti-Ryk antibody, in vivo or in vitro, greatly suppresses nerve injury-induced increased intracellular Ca and hyperexcitability of the sensory neurons, and also the enhanced plasticity of synapses between afferent C-fibers and the dorsal horn neurons, and activation of the NR2B receptor and the subsequent Ca-dependent signals CaMKII, Src, ERK, PKCγ, and CREB in sensory neurons and the spinal cord. These findings indicate a critical mechanism underlying the pathogenesis of neuropathic pain and suggest that targeting the Wnt/Ryk signaling may be an effective approach for treating neuropathic pain. [ABSTRACT FROM AUTHOR]

Pulmonary vascular remodeling was shown to lead to pulmonary arterial hypertension (PAH), further trigger excessive apoptosis of cardiomyocytes, and ultimately cause right ventricular failure (RVF), which involves the activation of Rho A/ROCK signaling pathway. Betaine has been found efficacious for attenuating PAH through its anti-inflammatory effects in our previous research while its effects on RVF due to PAH remains inconclusive. Thus, we attempted to elucidate the protective effects of betaine on PAH, RVF due to PAH as well as the potential mechanisms. To this end, male Sprague Dawley rats received a single subcutaneous injection of monocrotaline (50 mg/kg) to imitate PAH and RVF, and subsequently oral administration of betaine (100, 200, and 400 mg/kg/day). Betaine treatment improved the hemodynamics and histomorphological parameters and echocardiographic changes. Moreover, betaine also alleviated the pulmonary vascular remodeling and cardiomyocyte apoptosis. The mechanisms study revealed that administration of betaine significantly increased the expression of Rho A, ROCK1, and ROCK2. Furthermore, betaine alleviated the changes of its downstream molecules P53, Bcl-2, Bax, phosphorylated MYPT1 (p-MYPT1), total MYPT1 (t-MYPT1), p27kip1, and Cleaved Caspase-3. According to what we observed, this study indicated that betaine treatment could protect RVF due to PAH, which may be achieved through an altered Rho A/ROCK signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Impaired GABAergic inhibitory synaptic transmission plays an essential role in the pathogenesis of selective neuronal cell death following transient global ischemia. GABAA receptor (GABAAR), K+–Cl− co-transporter 2 (KCC2), Na+–K+–Cl− co-transporter 1 (NKCC1) and astrocytes are of particular importance to GABAergic transmission. The present study was designed to explore whether the neuroprotective effect of topiramate (TPM) was linked with the alterations of GABAergic signaling and astrocytes. The bilateral carotid arteries were occluded, and TPM (80mg/kg/day (divided twice daily), i.p.) was injected into gerbils. At day 1, 3 and 7 post-ischemia, neurological deficit was scored and changes in hippocampal neuronal cell death were evaluated by Nissl staining. The apoptosis-related regulatory proteins (procaspase-3, caspase-3, Bax and Bcl-2) and GABAergic signal molecules (GABAAR α1, GABAAR γ2, KCC2 and NKCC1) were also detected using western blot assay. In addition, the fluorescent intensity and protein level of glial fibrillary acidic protein (GFAP), a major component of astrocyte, were examined by confocal and immunoblot analysis. Our results showed that TPM treatment significantly decreased neurological deficit scores, attenuated the ischemia-induced neuronal loss and remarkably decreased the expression levels of procaspase-3, caspase-3 as well as the ratio of Bax/Bcl-2. Besides, treatment with TPM also resulted in the increased protein expressions of GABAAR α1, GABAAR γ2 and KCC2 together with the decreased protein level of NKCC1 in gerbils hippocampus. Furthermore, fluorescent intensity and protein level of GFAP were evidently reduced in TPM-treated gerbils. These findings suggest that the therapeutic effect of TPM on global ischemia/reperfusion injury appears to be associated with the enhancement of GABAergic signaling and the inhibition of astrogliosis in gerbils. [Copyright &y& Elsevier]