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Non-alcoholic fatty liver disease (NAFLD) is among the most prevalent primary liver diseases worldwide and can develop into various conditions, ranging from simple steatosis, through non-alcoholic steatohepatitis (NASH), to fibrosis, and eventually cirrhosis and hepatocellular carcinoma. Nevertheless, there is no effective treatment for NAFLD due to the complicated etiology. Recently, activation of the NLPR3 inflammasome has been demonstrated to be a contributing factor in the development of NAFLD, particularly as a modulator of progression from initial hepatic steatosis to NASH. NLRP3 inflammasome, as a caspase-1 activation platform, is critical for processing key pro-inflammatory cytokines and pyroptosis. Various stimuli involved in NAFLD can activate the NLRP3 inflammasome, depending on the diverse cellular stresses that they cause. NLRP3 inflammasome-related inhibitors and agents for NAFLD treatment have been tested and demonstrated positive effects in experimental models. Meanwhile, some drugs have been applied in clinical studies, supporting this therapeutic approach. In this review, we discuss the activation, biological functions, and treatment targeting the NLRP3 inflammasome in the context of NAFLD progression. Specifically, we focus on the different types of therapeutic agents that can inhibit the NLRP3 inflammasome and summarize their pharmacological effectiveness for NAFLD treatment. [ABSTRACT FROM AUTHOR]

Metastasis is a multistep process that depends on the interactions between tumor cells and their microenvironment. Macrophages in the tumor microenvironment show high polarization plasticity and have a paradoxical role in cancer progression. Hijacked by tumor-promoting signals, the polarization status of macrophages was pathologically disturbed and believed to be the decisive mechanism forcing the progression of metastasis. In this study, we explored the immunological activity of Chamaejasmin B (ICJ), a previously proved inhibitor for metastasis, in macrophages from metastatic microenvironment. When intravenously injected of 4T1 cells in mice, ICJ significantly inhibited its metastatic outgrowth. Taking tumor cell and macrophage as a functional integrity, an adoptive transfer model was established in vitro to exclude the direct effect of ICJ on tumor. The findings suggest a dual influence of ICJ on both tumors and macrophages, as indicated by the rebalance of macrophage polarization and suppression of clonogenic potential in tumor cells. Mechanistically, ICJ redirected M2-dominant polarization of tumor-associated macrophage in an IL-4-mTOR-dependent manner. Collectively, our study revealed that ICJ rebalanced macrophage polarization in malignant microenvironment and showed promising effect in suppressing metastatic outgrowth in breast cancer model. [ABSTRACT FROM AUTHOR]

Background/Aim: Macrophage polarization and phenotypic switching of smooth muscle cells (SMCs) are multi-faceted events dominating atherosclerosis (AS) progression. TGF-β was proved to been one of the bridge on the crosstalk between macrophage and SMC. ShenLian (SL) was extracted from a potent anti-atherosclerotic formula. However, its exact mechanism rebalancing inflammatory microenvironment of AS remain largely unknown. Within the entirety of macrophage and SMC, this study investigated the pharmacological effects of SL on stabilizing atherosclerotic plaques. Methods: The main components of SL were examined by high performance liquid chromatography. Co-culture and conditioned medium models of macrophage/SMC interactions were designed to identify the relationship between macrophage polarization and switching of SMC phenotypes. Flow cytometry, immunofluorescent staining, RT-PCR, western blotting, and ELISA were used to determine the expression of molecules relating to AS progression. An atherosclerosis animal model, established by placing a perivascular collar on the right common carotid artery in ApoE−/− mice, was used to investigate whether TGF-β is the key molecular mediator of SL in crosstalk between macrophage and SMC. Plaque size was defined by nuclear magnetic resonance imaging. Key markers related to phenotypic transformation of macrophage and SMC were determined by immunohistochemical staining. Results: Results revealed that, accompanied by rebalanced M2 macrophage polarization, SL supported SMC phenotypic transformation and functionally reconstruct the ECM of plaques specifically in macrophage-SMC co-cultural model. Molecularly, such activity of SL closely related to the activation of STAT3/SOCS3 pathway. Furthermore, in co-culture system, up-regulation of α-SMA induced by SL could neutralized by 1D11, a TGF-β neutralizing antibody, indicating that SL mediated Macrophage-SMC communication by enhancing TGF-β. In the AS model constructed by ApoE−/− mice, effects of SL on phenotypic transformation of macrophage and SMC has been well verified. Specific blocking of TGF-β largely attenuated the aforementioned effects of SL. Conclusion: Our findings highlighted that TGF-β might be the responsive factor of SL within macrophage and SMC communication. This study revealed that crosstalk between macrophage and SMC forms a holistic entirety promoting atherosclerotic plaque stability. [ABSTRACT FROM AUTHOR]

Besides pathogen evading, Acute Lung Injury (ALI), featuring the systematic inflammation and severe epithelial damages, is widely believed to be the central non-infectious factor controlling the progression of infectious diseases. ALI is partly caused by host immune responses. Under the inspiration of unsuccessful treatment in COVID-19, recent insights into pathogen–host interactions are leading to identification and development of a wide range of host-directed therapies with different mechanisms of action. The interaction unit consisting of macrophages and the alveolar epithelial cells has recently revealed as the therapeutic basis targeting ALI. Lian Hua Qing Wen capsule is the most effective and commonly-used clinical formula in treating respiratory infection for thousands of years in China. However, little is known about its relevance with ALI, especially its protective role against ALI-induced alveolar tissue damages. Aiming to evaluate its contribution in antibiotics-integrating therapies, this study pharmacologically verified whether LHQW could alleviate lipopolysaccharide (LPS)-induced ALI and explore its potential mechanisms in maintaining the physiology of macrophage-epithelial unit. In ALI mouse model, the pathological parameters, including the anal temperature, inflammation condition, lung edema, histopathological structures, have all been systematically analyzed. Results consistently supported the effectiveness of the combined strategy for LHQW and low-dose antibiotics. Furthermore, we established the macrophages-alveolar epithelial cells co-culture model and firstly proved that LHQW inhibited LPS-induced ER stress and TRAIL secretion in macrophages, thereby efficiently protected epithelial cells against TRAIL-induced apoptosis. Mechanistically, results showed that LHQW significantly deactivated NF-κB and reversed the SOCS3 expression in inflammatory macrophages. Furthermore, we proved that the therapeutic effects of LHQW were highly dependent on JNK-AP1 regulation. In conclusion, our data proved that LHQW is an epithelial protector in ALI, implying its promising potential in antibiotic alternative therapy. [ABSTRACT FROM AUTHOR]

Posttranscriptional modification of mRNA sequences through RNA editing can increase transcriptome and proteome diversity in eukaryotes. Studies of fetal and adult tissues showed that adenosine‐to‐inosine RNA editing plays a crucial role in early human development, but there is a lack of global understanding of dynamic RNA editing during mammalian early embryonic development. Therefore, here we used RNA sequencing data from human, pig and mouse during early embryonic development to detect edited genes that may regulate stem cell pluripotency. We observed that although most of the RNA editing sites are located in intergenic, intron and UTR, a few editing sites are in coding regions and may result in nonsynonymous amino acid changes. Some editing sites are predicted to change the structure of a protein. We also report that HNF1A, TBX3, ACLY, ECI1 and ERDR1 are related to embryonic development and cell division. [ABSTRACT FROM AUTHOR]

The neovascularization functions essentially for malignant upgrading and predicts poor prognosis in multiple cancers, which make it the highly effective strategy for clinical treatment. Unfortunately, the known anti-angiogenic therapies show low effectiveness against breast cancer. Recently, rebalancing the pro-angiogenic property in microenvironment shows great advantages and attracts increasing attention for breast cancer treatment. Herein, we for the first time reported that Chamaejasmine B (ICJ), extracted from Stellera chamaejasme L., possessed potent anti-angiogenic effect in breast cancer. By Transwell, tube formation and aortic-ring assays, ICJ efficiently suppressed the neovascularization potential in tumor-HUVEC co-culture model. In Matrigel plug assay, the efficacy of ICJ was further identified in vivo. Mechanistically, with little influence on HUVEC apoptosis, ICJ obviously induced autophagy as proved by the elevated LC3I/II ratio, dotted distribution of LC3 and upregulated Beclin-1. Moreover, by associating with LC3 and in turn, inhibiting the level of VEGFR2, the anti-angiogenesis efficacy was closely dependent on the initiation of autophagy. Above results proved that, by attenuating the pro-angiogenic communication through VEGFR2, ICJ is a novel angiogenic inhibitor and will be a promising supplement for anti-angiogenic chemotherapy for breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: In the freezing process of boar sperm, there are obvious differences in freezability between individuals. Studies suggest that specific freezability markers might be useful in good (GFE) and poor freezability ejaculate (PFE) selection prior to cryopreservation. Therefore, we performed UHPLC-qTOF-MS analysis to explore the difference in the metabolic level of seminal plasma between boars with differential freezability, and the results showed that the content of D-aspartic acid, N-acetyl-L-glutamate (NAG), and inosine were significantly different. These findings present new insights into the role of metabolism in sperm freezability and provide research directions for exploring potential biomarkers of freezability. Some potential markers of boar sperm freezability have been found in spermatozoa, but little attention has been paid to seminal plasma. The seminal plasma is composed of secretions from the testis, epididymis, and accessory sex glands. The exposure of spermatozoa to small molecules such as metabolites can affect sperm function. However, details and significance of the seminal plasma metabolome related to boar sperm freezability are unknown. Therefore, the main aim of this study was to explore the differences in the metabolic level of seminal plasma between boars with differential freezability and to explore the candidate biomarkers of semen freezability. A total of 953 metabolites were identified in boar semen plasma by UHPLC-qTOF-MS analysis, and 50 metabolites showed significant change between the GFE group and PFE group. Further, twelve metabolites were subjected to metabolic target analysis, and three metabolites (D-aspartic acid, N-acetyl-L-glutamate (NAG), and inosine) showed differences. In conclusion, there is significant difference in the metabolome of seminal plasma between GFE and PFE individuals. D-aspartic acid, NAG, and inosine in seminal plasma may be potential markers for assessing sperm cryopreservation resistance in boars. [ABSTRACT FROM AUTHOR]

The modern study of the traditional Chinese medicine (TCM) compound recipes is a complex issue because of the large number of components in the recipes that would produce several metabolites after entering the body. The TCM compound recipes are known to have the advantage of synergistic treatment by multiple targets due to diverse components. Therefore, a research method that can reflect the overall effect of compounds with multi-components is essential. The pharmacological studies of the classic TCM compound recipes mainly use the sero-pharmacological method. It is a semi- in vivo study method, and the drug to be tested in the in vitro experiment is the drug-containing serum from the model animals (the drug to be tested is a mixed drug system containing the prototype drugs in animal bodies that have pharmacodynamic effects and the metabolites). Herein, a safe and effective external TCM recipe was used to develop another semi- in vivo experimental method to reflect the overall effects of TCM. To observe the effects of in-vitro intestinal absorption liquid of aqueous extracts of the TCM compound recipe—Guangtongxiao foam aerosol (Guangtongxiao)—on the tension of isolated rectal rings of mouse and investigate the underlying mechanisms of antispasmodic and amelioration of muscular spasm-induced pain. Intestinal absorption liquid of the Guangtongxiao aqueous extract at the five time points (30, 45, 75, 105, and 120 min) was prepared using a non-everted gut sac method. The isolated rectal rings of mice were prepared by pre-contraction using potassium chloride (KCl) or acetylcholine chloride (ACh) to make steady contraction. The intestinal absorption liquid were added cumulatively to the sink with the constricted rectal rings. The effects of the five groups of the intestinal absorption liquid with different drug concentration were observed on the tension of the isolated rectal rings. Then the ex vivo perfusion of the mouse rectal ring was performed as same as Guangtongxiao intestinal absorption liquid experiments, and the effects of two major components of Guangtongxiao, paeoniflorin (Pae) and tetrahydropalmatine (THP), on the rectal ring pre-treated with high concentration of KCl and ACh to induce contraction were studied. The relaxation rate of the five groups of the intestinal canals increased significantly with 3200 μL cumulative sample volume as compared to the blank group (P < 0.01). It suggested that the relaxation activity of the intestinal absorption liquid enhanced significantly with the prolongation of the interaction between isolated rectal rings and intestinal absorption liquid in a time-dependent manner. Also, significant differences were detected while comparing between the 120-min intestinal absorption liquid group and the blank group with respect to various cumulative sampling volumes (P < 0.01). In addition, the intestinal relaxation rate elevated gradually with the increase in sampling volume, indicating that the concentrations of active substances in the intestinal absorption liquid prepared by the non-everted gut sac model increased and the intestinal relaxation activity was enhanced with the prolongation of the absorption time in a dose-dependent manner. And Pae and THP in a concentration-dependent manner caused relaxation of the rectal ring, which is pretreated with high K+(KCl) and ACh to induce contraction. The EC 50 of Pae and THP was 8.67 × 10−5 M (6.68 × 10−5-1.13 × 10−4) and 1.41 × 10−4 M (1.24 × 10−4-1.61 × 10−4) in the contraction model induced by KCl, and was 6.15 × 10−5 M (4.47 × 10−5-8.45 × 10−5), and 1.31 × 10−4 M(1.22 × 10−4-1.42 × 10−4) in the model induced by ACh, respectively. The intestinal absorption liquid of Guangtongxiao exerted a remarkable relaxation activity for the rectal rings, and relaxation of the smooth muscle tension might be one of the antispasmodic mechanisms of Guangtongxiao compound recipe. Also, adopting a semi-in-vivo experimental method to study the efficacy of topical external TCM recipe medicine is optimal. Image 1 [ABSTRACT FROM AUTHOR]

The resistance of sperm to freezing varies widely among boars. The semen ejaculate of different boars can be grouped into poor freezability ejaculate (PFE) and good freezability ejaculate (GFE). In this study, five Yorkshire boars each of the GFE and PFE were selected by comparing the changes in sperm motility before and after cryopreservation. Firstly, we found that the sperm plasma membrane of the PFE group showed weak integrity after PI and 6-CFDA staining. Then the electron microscopy results verified that the plasma membrane condition of all segments of GFE was better than that of PFE segments. Furthermore, the lipid composition of sperm plasma membranes in GPE and PFE sperm was analyzed by using mass spectrometry, and 15 lipids showed differences between the two groups. Among those lipids, only phosphatidylcholine (PC) (14:0/20:4) and phosphatidylethanolamine (PE) (14:0/20:4) were higher in PFE. The remaining lipid contents, including those of dihydroceramide (18:0/18:0), four hexosylceramides (18:1/20:1, 18:0/22:1, 18:1/16:0, 18:1/18:0), lactosylceramide (18:1/16:0), two hemolyzed phosphatidylethanolamines (18:2, 20:2), five phosphatidylcholines (16:1/18:2, 18:2/16:1, 14:0/20:4, 16:0/18:3, 18:1/20:2), and two phosphatidylethanolamines (14:0/20:4, 18:1/18:3), were all positively correlated with resistance to cryopreservation (p < 0.05, r > 0.6). Moreover, we analyzed the metabolic profile of sperm using untarget metabolomic. KEGG annotation analysis revealed that the altered metabolites were mainly involved in fatty acid biosynthesis. Finally, we determined that the contents of oleic acid, oleamideetc, N8-acetylspermidine etc., were different between GFE and PFE sperm. In summary, the different lipid metabolism levels and long-chain polyunsaturated fatty acids (PUFAs) in plasma membrane may be key factors contributing to differences in sperm resistance to cryopreservation among boars. • We screened out two groups of boars with significant differences in sperm freezability. • The plasma membrane of poor freezability sperms has low integrity. • Based on membrane lipidomics and metabolomics analysis, we determined that the level of metabolism and plasma membrane lipid composition were obvious different between good and poor freezability sperm. • Some potential biomarkers of boar sperm freezability were identified. [ABSTRACT FROM AUTHOR]

Shenlian (SL) extract, a Chinese medicinal compound mainly pointing at inflammation response of atherosclerosis, is composed of Salvia miltiorrhizae Bunge and Andrographis paniculata (Burm.f.) Nees. Salvia miltiorrhizae Bunge has been reported to activate blood to remove stasis, while another herb, Andrographis paniculata (Burm.f.) Nees , has been revealed to clear endogenous heat toxins. The anti-atherosclerotic effects of these two herbs have been reported closely relating to inflammation. However, from the point of view of adventitial inflammation, the in-depth study of SL extract in anti-atherosclerotic effects by relieving adventitial inflammation is still unknown. To explore the effects of adventitial inflammation in atherosclerosis progression and if SL extract could reverse the process. A novel atherosclerosis model based on adventitial inflammation was established. High-fat diet-fed ApoE-/- mice were implanted a cotton thread soaked with LPS on the right common carotid artery (RCCA). Meanwhile, three time points were set (week 2, 4, and 12) to accurately evaluate the effect of SL extract on the whole process of atherosclerosis with adventitial inflammation. The pathological changes of phenotype transformation of VAFs, vascular cell proliferation and collagen synthesis were observed dynamically by immunohistochemistry (IHC), BrdU method and sirius red staining. Then primary VAFs were stimulated by LPS to mirror the process of adventitial inflammation in vitro. The VAFS phenotype conversion and its function alterations including proliferation, migration, inflammatory secretion was assessed. Finally, we established a co-culture model of activated VAFs and vascular smooth muscle cells (VSMCs) to observe the impacts of activated VAFs on phenotype transformation and migration of VSMCs. SL extract improved atherosclerosis progression by reducing lipid content, adventitial inflammation and plaque formation. HE results showed sham-operated group (Sham) appeared light infiltrated inflammation only in adventitia at week 2, and the degree of inflammation infiltrated in model was more severe than that in Sham at week 2, 4, and 12. At week 12, the sham and model group showed evidently thickened media and intima. The phenotypic transformation, proliferation and migration of vascular adventitial fibroblasts (VAFs) as well as inflammatory secretion enhanced remarkably in vivo and vitro , but SL extract reversed these changes. Moreover, SL extract downregulated JAK2-STAT3-MMP2 signal pathway. The VSMCs transformed from contractile phenotype into synthetic phenotype and the migration of VSMCs increased after co-culture with activated VAFs. In contrast, SL extract could suppress theses effects. Taken together, atherosclerotic inflammation could be a "outside-in" signaling. Adventitial inflammation not only accelerated intimal plaque formation in atherosclerosis, but also worsened the degree of vascular lesion. And SL extract improved atherosclerosis by relieving adventitial inflammation, and the underlying mechanisms could be associated with curbing phenotypic transformation, proliferation and migration of VAFs and VSMCs. [Display omitted] • SL extract delayed the atherosclerotic progression caused by adventitial inflammation via inhibiting VAFs phenotype transformation. • SL extract affected JAK2-STAT3-MMP-2 pathway, which might be related to the roles of VAFs transformation and migration. • SL extract influenced VSMCs functions through exerting effect on VAFs to inhibit the development of atherosclerosis. [ABSTRACT FROM AUTHOR]