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Aging can cause degenerative changes in multiple tissues and organs. Gastrointestinal diseases and dysfunctions are common in the elderly population. In this study, we investigated the effects of Astragalus membranaceus polysaccharide (APS) and Astragalus membranaceus ethanol extract (AEE) on age-related intestinal dysfunction and gut microbiota dysbiosis in naturally aging mice. The energy expenditure and physical activity of 23-month-old C57BL6/J mice were recorded using a metabolic cage system. Pathological changes in the intestine were evaluated using Alcian blue staining. The protein levels of leucine-rich repeats containing G protein-coupled receptor 5 (Lgr5) and Stat3 in the small intestine were determined using immunohistochemistry. The intestinal cell migration distance was assessed using bromodeoxyuridine (BrdU) immunofluorescence staining. The gene transcription levels of intestinal stem cell (ISC) markers and ISC-related signaling pathways were detected using quantitative real-time PCR (qRT-PCR). Microbiota analysis based on 16S rDNA was performed to evaluate the composition of the gut microbiota. APS and AEE improved a series of aging phenotypes in female but not in male aging mice. APS and AEE ameliorate intestinal dysfunction and histopathological changes in aging mice. APS had a more significant anti-aging effect than AEE, particularly on intestinal dysfunction. APS promotes ISC regeneration by activating the IL-22 signaling pathway. Cohousing (CH) experiments further confirmed that APS induced the IL-22 signaling pathway by increasing the abundance of Lactobacillus, thereby promoting the regeneration of ISCs. Our results show that APS may serve as a promising agent for improving age-related intestinal dysfunction. [ABSTRACT FROM AUTHOR]

In this study, the expression of Cripto-1 and the role of macrophage polarization in immune response after allogeneic transfusion were analyzed by constructing a mouse model of allogeneic transfusion. In order to analyze the effects of miR-449a on the PI3K/AKT/NF-κB signaling pathway and the expression of downstream related regulatory factors under normal and abnormal conditions, we adopt in vitro and in vivo experiments separately. The molecular mechanism of PI3K/AKT/NF-κB signaling pathway was analyzed by blocking or activating gene expression and western blotting. Experiment in vitro has confirmed that inhibition of miR-449a increased the protein expression of Cripto-1. In vivo experiments confirmed that allogeneic transfusion reduced the expression of Cripto-1, which further inhibited NF-κB signaling pathway through AKT/PI3K phosphorylation, regulated macrophage polarization, inhibited M1 polarization of macrophages, promoted M2 polarization, and thus affected immune response of the body. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance The leaves of Nelumbo nucifera Gaertn are recorded in the earliest written documentation of traditional Chinese medicinal as “Ben Cao Gang Mu”, a medicinal herb for blood clotting, dysentery and dizziness. Recently, nuciferine (NF), one of N. nucifera Gaertn leaf extracts has been shown to possess several pharmacological properties, including anti-viral and anti-cancer. The aim of this study is to investigate the underlying molecular mechanism of the anti-cancer activity of NF in NSCLC progression induced by nicotine Materials and methods The effect of NF on proliferation of A549 (human lung adenocarcinoma epithelial cell line) pretreated with or without nicotine was detected by tumor cell proliferation assay. TOP-Flash reporter assay was applied to investigate the activity of Wnt/β-catenin signaling in tumor cells in the presence of NF and/or nicotine. Apoptosis was measured using a FITC-Annexin V and PI detection kit by flow cytometry. In addition, mRNA or protein expression levels were respectively tested by quantitative RT-PCR or western blot. In vivo experiments, tumor samples were fixed in formalin and embedded in paraffin for additional analyses by immunohistochemistry and TUNEL staining. Results NF significantly inhibited the proliferation of NSCLC cells in the presence of nicotine, suppressed the activity of Wnt/β-catenin signaling, enhanced the stabilization of Axin, and induced apoptosis. NF down-regulated the expression levels of β-catenin and its downstream targets including c-myc, cyclin D and VEGF-A. NF also decreased the ratio of Bcl-2/Bax, which may explain the pro-apoptosis effect of NF. In tumor xenograft nude mice, NF not only inhibited the growth of non-small cell lung cancer (NSCLC) cells, but also remarkably alleviated the injury induced by nicotine in liver function. Conclusions NF has the remarkable effect to inhibit nicotine-induced NSCLC progression, which was due to its ability to reduce the activity of Wnt/β-catenin signaling. Thus, the work stated here emphasizes the importance of this traditional medicine and presents a potential novel alternative to NSCLC prevention and therapy. [ABSTRACT FROM AUTHOR]

Male infertility induced by heat stress has been attracting more and more attention. Heat stress not only causes apoptosis of spermatocytes but also has adverse effects on Sertoli cells, further damaging spermatogenesis. Lycium barbarum polysaccharide (LBP) is the main bioactive component of Lycium barbarum, which has a protective effect on male reproduction, but its mechanism is still unclear. In this study, our results proved that LBP blocked the inhibitory effect on the proliferation activity of Sertoli cells after heat stress, reversed the dedifferentiation of Sertoli cells induced by heat stress, and ameliorated the structural integrity of the blood-testis barrier. In addition, it increased the expression of the androgen receptor and activated Akt signaling pathway to resist heat-stress-induced injury of Sertoli cells. [ABSTRACT FROM AUTHOR]

Male infertility induced by heat stress has been attracting more and more attention. Heat stress not only causes apoptosis of spermatocytes but also has adverse effects on Sertoli cells, further damaging spermatogenesis. Lycium barbarum polysaccharide (LBP) is the main bioactive component of Lycium barbarum, which has a protective effect on male reproduction, but its mechanism is still unclear. In this study, our results proved that LBP blocked the inhibitory effect on the proliferation activity of Sertoli cells after heat stress, reversed the dedifferentiation of Sertoli cells induced by heat stress, and ameliorated the structural integrity of the blood-testis barrier. In addition, it increased the expression of the androgen receptor and activated Akt signaling pathway to resist heat-stress-induced injury of Sertoli cells. [ABSTRACT FROM AUTHOR]

Male infertility induced by heat stress has been attracting more and more attention. Heat stress not only causes apoptosis of spermatocytes but also has adverse effects on Sertoli cells, further damaging spermatogenesis. Lycium barbarum polysaccharide (LBP) is the main bioactive component of Lycium barbarum, which has a protective effect on male reproduction, but its mechanism is still unclear. In this study, our results proved that LBP blocked the inhibitory effect on the proliferation activity of Sertoli cells after heat stress, reversed the dedifferentiation of Sertoli cells induced by heat stress, and ameliorated the structural integrity of the blood-testis barrier. In addition, it increased the expression of the androgen receptor and activated Akt signaling pathway to resist heat-stress-induced injury of Sertoli cells. [ABSTRACT FROM AUTHOR]

Male infertility induced by heat stress has been attracting more and more attention. Heat stress not only causes apoptosis of spermatocytes but also has adverse effects on Sertoli cells, further damaging spermatogenesis. Lycium barbarum polysaccharide (LBP) is the main bioactive component of Lycium barbarum, which has a protective effect on male reproduction, but its mechanism is still unclear. In this study, our results proved that LBP blocked the inhibitory effect on the proliferation activity of Sertoli cells after heat stress, reversed the dedifferentiation of Sertoli cells induced by heat stress, and ameliorated the structural integrity of the blood-testis barrier. In addition, it increased the expression of the androgen receptor and activated Akt signaling pathway to resist heat-stress-induced injury of Sertoli cells. [ABSTRACT FROM AUTHOR]

Male infertility induced by heat stress has been attracting more and more attention. Heat stress not only causes apoptosis of spermatocytes but also has adverse effects on Sertoli cells, further damaging spermatogenesis. Lycium barbarum polysaccharide (LBP) is the main bioactive component of Lycium barbarum, which has a protective effect on male reproduction, but its mechanism is still unclear. In this study, our results proved that LBP blocked the inhibitory effect on the proliferation activity of Sertoli cells after heat stress, reversed the dedifferentiation of Sertoli cells induced by heat stress, and ameliorated the structural integrity of the blood-testis barrier. In addition, it increased the expression of the androgen receptor and activated Akt signaling pathway to resist heat-stress-induced injury of Sertoli cells. [ABSTRACT FROM AUTHOR]

In traditional Chinese medicine, propolis has been used for treating oral diseases for centuries, widely. Flavonoid extract is the main active ingredient in propolis, which has attracted extensive attention in recent years. The objective and novelty of the current study aims to identify the mechanism of total flavonoid extract of propolis (TFP) for the treatment of periodontitis, and evaluate the therapeutic effect of TFP-loaded liquid crystal hydrogel (TFP-LLC) in rats with periodontitis. In this study, we used lipopolysaccharide-stimulated periodontal ligament stem cells (PDLSCs) to construct in vitro inflammation model, and investigated the anti-inflammatory effect of TFP by expression levels of inflammatory factors. Osteogenic differentiation was assessed using alkaline phosphatase activity and alizarin red staining. Meanwhile, the expression of toll like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor-kappa B (NF- κ B), receptor activator of NF- κ B (RANK) etc, were quantitated to investigate the therapeutic mechanism of TFP. Finally, we constructed TFP-LLC using a self-emulsification method and administered it to rats with periodontitis via periodontal pocket injection to evaluate the therapeutic effects. The therapeutic index, microcomputed tomography (Micro-CT), H&E staining, TRAP staining, and Masson staining were used for this evaluation. TFP reduced the expression of TLR4, MyD88, NF- κ B and inflammatory factor in lipopolysaccharide-stimulated PDLSCs. Meanwhile, TFP simultaneously regulating alkaline phosphatase, RANK, runt-associated transcription factor-2 and matrix metalloproteinase production to accelerate osteogenic differentiation and collagen secretion. In addition, TFP-LLC can stably anchor to the periodontal lesion site and sustainably release TFP. After four weeks of treatment with TFP-LLC, we observed a decrease in the levels of NF- κ B and interleukin-1 β (IL-1β) in the periodontal tissues of rats, as well as a significant reduction in inflammation in HE staining. Similarly, Micro CT results showed that TFP-LLC could significantly inhibit alveolar bone resorption, increase bone mineral density (BMD) and reduce trabecular bone space (Tb.Sp) in rats with periodontitis. Collectively, we have firstly verified the therapeutic effects and mechanisms of TFP in PDLSCs for periodontitis treatment. Our results indicate that TFP perform anti-inflammatory and tissue repair activities through TLR4/MyD88/NF-κB and RANK/NF- κ B pathways in PDLSCs. Meanwhile, for the first time, we employed LLC delivery system to load TFP for periodontitis treatment. The results showed that TFP-LLC could be effectively retained in the periodontal pocket and exerted a crucial role in inflammation resolution and periodontal tissue regeneration. Scheme 1. Schematic diagram of TFP-LLC alleviating periodontitis via PDLSCs-dependent anti-inflammatory and periodontium regeneration mechanism. TFP–LLC was in situ injected into the periodontal pocket to ensure the sustained release of the active TFP ingredients at the periodontal lesion. TFP–LLC suppresses the expression of inflammatory factors and osteoclastogenesis by interfering with TLR4/MyD88/NF-κB and RANK/NF-κB signaling. In addition, TFP–LLC promotes osteogenic differentiation and collagen regeneration in PDLSCs, as demonstrated by the upregulation of ALP and RUNX2 and downregulation of MMP. The TFP–LLC-induced periodontal homeostasis alleviates acute periodontal inflammation and assists in the long-term tissue regeneration of the gingiva, cementum, periodontal ligament, and alveolar bone, thereby demonstrating comprehensive treatment efficacy in periodontitis. [Display omitted] • We demonstrated that TFP exerts an anti-inflammatory pathway through TLR4/MyD88/NF-κB pathway in PDLSCs. • We proved TFP boosting periodontium regeneration via RANK/NF- κ B pathway in PDLSCs. • We prepared lyotropic liquid crystals containing total flavonoid extract of propolis (TFP-LLC). • TFP-LLC was stably anchored to the periodontal lesion site to form a drug reservoir. • TFP-LLC demonstrated excellent periodontal protection in rats with periodontitis. [ABSTRACT FROM AUTHOR]

Herb-pairs are the basic units of composition in Chinese herbal formulae, where the bridge linking Chinese medicine and prescription consists of two Chinese medicine herbs. The Suanzaoren-Wuweizi herb-pair (SWHP) is commonly used as a sedative or tranquilizer. SWHP has been demonstrated to exert an antianxiety effect in animal models of anxiety. However, little information about its mechanism is available and the effects of SWHP have not been investigated. This study examined the effects of SWHP on ameliorating anxiety-like behaviors by regulating endocannabinoids system (ECS)—brain-derived neurotrophic factor (BDNF)—extracellular regulated protein kinases (ERK) signaling pathway expression, induced by restraint stress (RS) procedures. The antianxiety effects of SWHP on RS rats were then examined through the open-field test (OF) and the elevated plus maze test (EPM). The concentration of BNDF, ERK1/2, p-ERK1/2, cAMP-response element binding protein (CREB), and p-CREB expression in the prefrontal cortex and hippocampus of the rats was then measured by western blot. The number of positive cells of CB1 and CB2 in the rats' hippocampus CA1 region was measured by immunohistochemistry. These results gave compelling evidence that SWHP could modify anxiety-like behaviors of RS rats through regulation of the ECS-BDNF-ERK signaling pathway. Our study demonstrated that SWHP improved anxiety-like behaviors in RS rat models by regulating the ECS-BDNF-ERK signaling pathway. The findings indicate that SWHP may have a therapeutic application in the RS model of anxiety disorder, which proposes a potential new direction for research into anxiety disorders regarding mechanisms and the development of novel antianxiety drugs. [ABSTRACT FROM AUTHOR]

Background: Tension homology deleted on chromosome ten (PTEN) is important in liver fibrosis.Aims: The purpose of this study was to evaluate the PTEN gene effects and mechanism of action on hepatic stellate cells (HSCs).Methods: The rat primary HSCs and human LX-2 cells were transfected by an adenovirus containing cDNA constructs encoding the wild-type PTEN (Ad-PTEN), the PTEN mutant G129E gene (Ad-G129E) and RNA interference targeting the PTEN sequence PTEN short hairpin RNA (PTEN shRNA), to up-regulate and down-regulate PTEN expression, respectively. The HSCs were assayed with a fluorescent microscope, real time PCR, Western blot, MTT, flow cytometry and Terminal-deoxynucleoitidyl transferase mediated nick end labeling. In addition, the CCl4 induced rat hepatic fibrosis model was also established to check the in vivo effects of the recombinant adenovirus with various levels of PTEN expression.Results: The data have shown that the over-expressed PTEN gene led to reduced HSCs activation and viability, caspase-3 activity and cell cycle arrest in the G0/G1 and G2/M phases, as well as negative regulation of the PI3K/Akt and FAK/ERK signaling pathways in vitro. The over-expressed PTEN gene improved liver function, inhibited proliferation and promoted apoptosis of HSCs both in vitro and in vivo.Conclusions: These data have shown that gene therapy using the recombinant adenovirus encoding wild-type PTEN inhibits proliferation and induces apoptosis of HSCs, which is a potential treatment option for hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Zhizhu Xiang (ZZX for short) is the root and rhizome of Valeriana jatamansi Jones, which is a Traditional Chinese Medicine (TCM) used to treat various mood disorders for more than 2000 years, especially anxiety. However, there have been few investigations to clarify the compounds in ZZX for the treatment of anxiety. Our previous study has identified five anti-anxiety components, including hesperidin, isochlorogenic acid A, isochlorogenic acid B and isochlorogenic acid C and chlorogenic acid, from extract of ZZX. In order to find the optimal combination and the underlying mechanism of these five components in the treatment of anxiety disorder, researches were designed based on uniform design method and proteomic technology. The samples with different proportion and content of the five active components were arranged by uniform design method. Then a mathematical model was formulated using partial least square method and stepwise regression analysis. Moreover, the empty bottle stress-induced anxiety rat model was established, and the anti-anxiety effect was recorded by the unconditioned reflex elevated maze test and the open field test. In addition, the isobaric tags for relative and absolute quantitation (iTRAQ) technique, along with the multidimensional liquid chromatography and high-resolution mass spectrometry were applied in proteomic study. At last, the result of proteomic analysis was further confirmed by Western blot. The optimal combination of the components from the extract of ZZX was 1.153 mg/kg hesperidin, 2.197 mg/kg Isochlorogenic acid A, 0.699 mg/kg Isochlorogenic acid B and 1.249 mg/kg Chlorogenic acid. Total 6818 proteins were identified using proteomic analysis and 80 differentially expressed proteins were used for further bioinformatic analysis. These proteins were involved in the neuroactive ligand-receptor interaction, protein digestion and absorption, cholesterol metabolism, Chagas disease, and AGE/RAGE signaling pathway. The composition and proportion of anti-anxiety components in extract of ZZX was disclosed, and there was an anti-anxiety effect for the combined components of flavonoids and phenolic acids. Through proteomic analysis and Western blot, it was found that the effective components of extract of ZZX can exert synergistic anti-anxiety effects via the regulation of multi-signaling pathways. These findings could provide a preliminary research basis for the development of new low-toxic, efficient, stable and controllable anti-anxiety drugs. Image 1 • The optimal combination of the antianxiety components in ZZX (the root and rhizome of Valeriana jatamansi Jones) was 1.153 mg/kg hesperidin, 2.197 mg/kg Isochlorogenic acid A, 0.699 mg/kg Isochlorogenic acid B and 1.249 mg/kg Chlorogenic acid. • During the proteomic analysis, 80 proteins in rats were significantly influenced after dosing components mentioned above. • Bioinformatic analyze results showed that the mechanism of ZZX-OS protect EBS rats from anxiety is related with the neuroactive ligand-receptor interaction, protein digestion and absorption, cholesterol metabolism, Chagas disease, and AGE/RAGE signaling pathway. [ABSTRACT FROM AUTHOR]

Salvia miltiorrhiza Bge. as a traditional Asian medicinal plant, roots and rhizomes (Danshen) are used to treat chronic hepatitis and coronary heart disease. In recent years, the medicinal value of S. miltiorrhiza stems and leaves total phenolic acids extract (JF) similar to roots and rhizomes has received increasing attention. S. miltiorrhiza roots and rhizome tanshinone extract (DT) has a good anti-inflammatory effect. To explore the therapeutic effect and possible molecular mechanisms of JF and DT alone or in combination on dextran sulfate sodium (DSS)-induced colitis mice. Colitis was induced by received 2% DSS in drinking water for 7 consecutive days. Then mice were administered orally for 7 days. Disease activity index (DAI) scores and body weight were recorded daily. After the end of the experiment, colon was removed, colon length was measured and histopathological analysis was performed. Inflammatory factors expression was determined by ELISA, its mRNA expression was detected by real-time quantitative PCR, and the expression of related proteins on TLR4/PI3K/AKT/mTOR signal was analyzed by Western blot. Treatment with JF and DT alone or in combination reduced DAI scores, increase body weight, improved colon shortening, and decreased colon histology scores. In addition, the expression level of inflammatory factors was inhibited. The combination of JF and DT had a better inhibitory effect on inflammatory factors compared to JF alone. We also found that DT alone and JF combined with DT inhibited TLR4/PI3K/AKT/mTOR signaling-related proteins expression levels (including TLR4, p-PI3K p110α/PI3K p110α, p-AKT (ser473)/AKT, mTOR, p-mTOR, NF-κB p65), showing an effective anti-inflammatory effect. We demonstrated for the first time that, JF and DT alone or in combination effectively ameliorated DSS-induced ulcerative colitis in mice, possibly by inhibiting the TLR4/PI3K/AKT/mTOR signaling pathway. Image 1 [ABSTRACT FROM AUTHOR]