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BACKGROUND: In the immunocompromised conditions following renal transplantation, BK virus can reactivate and cause BK virus associated nephropathy (BKVN). Increased BK viral loads and extended duration of infection have been linked to development of BKVN. The aim of this study was to observe the incidence of BKV infection and BKVN, and kinetics of infection and disease in renal transplantation recipients. METHODS: From 2014 to 2018, we conducted a longitudinal cohort observational study of 139 renal transplantation patients treated at a single clinic. Quantitative PCR assay was conducted to assess longitudinal BK viral loads. Analysis of patient clinical characteristics was performed to determine risk factors for BKV infection and associated disease. RESULTS: Of our cohort, 29 (20.9%) patients developed high BK viremia, and 7 (5.0%) developed biopsy-confirmed BKVN. Clinical parameters associated with diabetes (FBS, HbA1c) and hyperlipidemia (TG, TC, LDL-C) were found to be correlated with development of high BK viremia or BKVN. In 3 of 4 patients receiving intravenous immunoglobulin (IVIG) treatment, BK viral loads were reduced by at least 1 log within 2-3 months of administration. Significant differences were measured in BK viral loads and kidney function between BK viremic patients and BKVN patients by 3-9 months post-transplantation. CONCLUSIONS: We identified diabetes and hyperlipidemia as potential risk factors for development of high BK viremia and/or BKVN. IVIG was seen to be effective in reducing viral titers. The period 3-9 months post-transplantation was identified as important for development of BKVN from high BK viremia.
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Exosomes are a subset of extracellular vesicles released by all cell types and involved in local and systemic intercellular communication. In the past decade, research into exosomes has swelled as their important role in the mediation of health and disease has been increasingly established and acknowledged. Exosomes carry a diverse range of cargo including proteins, nucleic acids, and lipids derived from their parental cell that, when delivered to the recipient cell, can confer pathogenic or therapeutic effects through modulation of immunity and inflammation. In this review, the role of exosomes on mediation of immune and inflammatory responses, and their participation in diseases with a significant inflammatory component is discussed. The considerable potential for exosomes in therapy and diagnosis of inflammatory diseases is also highlighted.
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Exossomos/metabolismo , Inflamação/metabolismo , Aminoácidos/metabolismo , Animais , Proliferação de Células/fisiologia , Fibroblastos/metabolismo , Glicogênio/metabolismo , Humanos , Inflamação/imunologia , Ácido Láctico/metabolismoRESUMO
Neolaxiflorin L (NL) is a low-abundant Isodon 7,20-epoxy- ent-kuarenoid and was found to be a promising anticancer drug candidate in our previous study. In order to study its structure-activity relationship (SAR), a diversity-oriented synthetic route toward two libraries of (±)-NL analogs, including analogs containing different functionalities in the same 7,20-epoxy- ent-kuarene skeleton and analogs with skeletal changes, has been developed. The results of this total synthesis-enabled SAR successfully led to a bioactive alkyne-tagged NL derivative, which could be a useful probe for proteomics studies.
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Alcinos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Diterpenos/química , Isodon/química , Alcinos/síntese química , Alcinos/química , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Macrophages are essential for the maintenance of intestinal homeostasis, and their activation has been proposed to be critical to the pathogenesis of inflammatory bowel disease (IBD). Although there are many recognized mediators of macrophage activation, increasing evidence suggests that macrophages respond to exosome stimulation. Exosomes are 40-150 nm microvesicles released from different cell types and are found in a variety of physiological fluids, including serum. As studies have shown that circulating exosomes participate in intercellular communication and can mediate the immune response, we hypothesized that exosomes may play a role in the pathogenesis of IBD though modulation of macrophage activity. In this study, we used the dextran sulfate sodium (DSS) induced acute colitis mice model to investigate the effect of serum exosomes on macrophages and identify exosome proteins potentially involved in macrophage activation. We treated RAW264.7 macrophages with serum exosomes isolated from dextran sulfate sodium induced mice and found that treatment induced phosphorylation of p38 and ERK and production of tumor necrosis factor α when compared to treatment with exosomes isolated from control mice. Subsequent proteomic analysis identified 56 differentially expressed proteins, a majority of which were acute-phase proteins and immunoglobulins. Bioinformatics analysis suggested these proteins were mainly involved in the complement and coagulation cascade, which has been implicated in macrophage activation. Our findings provide new insight into the role of circulating serum exosomes in acute colitis and contribute to the understanding of macrophage activation in the pathogenesis of IBD.
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Colite Ulcerativa/metabolismo , Sulfato de Dextrana/efeitos adversos , Exossomos/efeitos dos fármacos , Exossomos/imunologia , Macrófagos/metabolismo , Proteoma , Animais , Linhagem Celular , Colite Ulcerativa/induzido quimicamente , Ativação do Complemento , Modelos Animais de Doenças , Eletroforese em Gel Bidimensional , Exossomos/química , Exossomos/metabolismo , Feminino , Macrófagos/química , Masculino , Camundongos , Mapas de Interação de Proteínas , Proteoma/análise , Proteoma/imunologia , Proteoma/metabolismo , ProteômicaRESUMO
Gynostemma pentaphyllum saponins (GpS) have been shown to have anti-cancer activity. However, the underlying mechanisms remain unclear. In this study, we used the Apc(Min) (/+) colorectal cancer (CRC) mouse model to investigate the anti-cancer effect of GpS and we demonstrated that GpS treatment could significantly reduce the number and size of intestinal polyps in Apc(Min) (/+) mice. In order to identify the potential targets and mechanisms involved, a comparative proteomics analysis was performed and 40 differentially expressed proteins after GpS treatment were identified. Bioinformatics analyses suggested a majority of these proteins were involved in processes related to cellular redox homeostasis, and predicted Raf-1 as a potential target of GpS. The upregulation of two proteins known to be involved in redox homeostasis, peroxiredoxin-1 (Prdx1) and peroxiredoxin-2 (Prdx2), and the downregulation of Raf-1 were validated using Western blot analysis. After further investigation of the associated signaling networks, we postulated that the anti-cancer effect of GpS was mediated through the upregulation of Prdx1 and Prdx2, suppression of Ras, RAF/MEK/ERK/STAT, PI3K/AKT/mTOR signaling and modulation of JNK/p38 MAPK signaling. We also examined the potential combinatorial effect of GpS with the chemotherapeutic 5-fluorouracil (5-FU) and found that GpS could enhance the anti-cancer efficacy of 5-FU, further suppressing the number of polyps in Apc(Min/+) mice. Our findings highlight the potential of GpS as an anti-cancer agent, the potential mechanisms of its anti-cancer activities, and its effect as an adjuvant of 5-FU in the chemotherapy of CRC.
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Antineoplásicos Fitogênicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/farmacologia , Saponinas/farmacologia , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Colorretais/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Fluoruracila/uso terapêutico , Gynostemma/química , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteoma/metabolismo , Saponinas/uso terapêutico , Transdução de Sinais , Carga TumoralRESUMO
Introduction: Inflammatory bowel disease (IBD) is a globally emergent chronic inflammatory disease which commonly requires lifelong care. To date, there remains a pressing need for the discovery of novel anti-inflammatory therapeutic agents against this disease. Sheng Mai San (SMS) is a traditional Chinese medicine prescription with a long history of use for treating Qi and Yin deficiency and recent studies have shown that SMS exhibits anti-inflammatory potential. However, the effects of SMS on the gastrointestinal system remain poorly studied, and its therapeutic potential and underlying molecular mechanisms in IBD have yet to be discovered. In this study, we examined the therapeutic efficacy of SMS in IBD and its anti-inflammatory activity and underlying molecular mechanism, in vivo and in vitro. Methods: The therapeutic efficacy of SMS in IBD was assessed in the DSS-induced acute colitis mouse model. Body weight, stool consistency, rectal bleeding, colon length, organ coefficient, cytokine levels in colon tissues, infiltration of immune cells, and colon pathology were evaluated. The anti-inflammatory activity of SMS and related molecular mechanisms were further examined in lipopolysaccharide (LPS)-induced macrophages via assessment of pro-inflammatory cytokine secretion and NF-κB, MAPK, STAT3, and NLRP3 signalling. Results: SMS significantly ameliorated the severity of disease in acute colitis mice, as evidenced by an improvement in disease activity index, colon morphology, and histological damage. Additionally, SMS reduced pro-inflammatory cytokine production and infiltration of immune cells in colon tissues. Furthermore, in LPS-induced macrophages, we demonstrated that SMS significantly inhibited the production of cytokines and suppressed the activation of multiple pro-inflammatory signalling pathways, including NF-κB, MAPK, and STAT3. SMS also abolished NLRP3 inflammasome activation and inhibited subsequent caspase-1 activation and IL-1ß secretion, suggesting a new therapeutic target for the treatment of IBD. These mechanistic findings were also confirmed in in vivo assays. Conclusion: This study presents the anti-inflammatory activity and detailed molecular mechanism of SMS, in vitro and in vivo. Importantly, we highlight for the first time the potential of SMS as an effective therapeutic agent against IBD.
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Introduction: Pathological angiogenesis, the abnormal or excessive generation of blood vessels, plays an important role in many diseases including cancer, diabetic retinopathy, psoriasis, and arthritis. Additionally, increasing evidence supports the close linkage between angiogenesis and inflammation. Snake venoms are a rich natural source of biologically active molecules and carry rich potential for the discovery of anti-angiogenic and anti-inflammatory modulators. Methods: Here, we isolated and purified a novel protein, ZK002, from the venom of the snake Deinagkistrodon acutus, and investigated its anti-angiogenic and anti-inflammatory activities and mechanisms. Results: ZK002 was identified as a 30 kDa heterodimeric protein of α and ß chains, which exhibited anti-angiogenic activity in various in vitro assays. Mechanistically, ZK002 inhibited activation of VEGF signaling and related mediators including eNOS, p38, LIMK, and HSP27. ZK002 also upregulated the metalloproteinase inhibitor TIMP3 and inhibited components of the VEGF-induced signaling cascade, PPP3R2 and SH2D2A. The anti-angiogenic activity of ZK002 was confirmed in multiple in vivo models. ZK002 could also inhibit the in vitro expression of pro-inflammatory cytokines, as well as in vivo inflammation in the carrageenin-induced edema rat model. Conclusion: Our findings highlight the potential for further development of ZK002 as a dual function therapeutic against diseases with involvement of pathogenic angiogenesis and chronic inflammation.
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Inflammatory bowel disease (IBD) is a chronic progressive intestinal inflammatory disease, characterized by an altered gut microbiota composition and accompanying alterations in circulatory bile acids. Increasing evidence supports the beneficial effect of probiotics intake on health. Introduction of probiotics to the intestines can modulate gut microbiota composition and in turn regulate the host immune system and modify the inflammatory response. Probiotics can also improve intestinal barrier function and exhibit a positive impact on host physiological and pathological conditions via gut microbiota-derived metabolites. Previous studies have demonstrated that Lactobacillus casei strain Shirota (LcS) treatment could inhibit clinical manifestation of colitis in dextran sulfate sodium (DSS)-induced mice, however, the underlying mechanisms remain unknown. In this study, we employed the DSS-induced acute colitis mouse model to investigate the anti-inflammatory effects of LcS and related mechanisms. Administration of LcS ameliorated the severity of DSS-induced colitis and enhanced intestinal integrity via induction of mucin-2 and occludin expression in colons. Fecal microbiota analysis showed that LcS increased the relative abundance of beneficial bacterial species in colitic mice, whereas the relative abundance of pathobionts was reduced. Additionally, LcS treatment modulated circulating bile acid profiles in colitic mice. In mice treated with LcS, we identified increased levels of primary taurine-conjugated bile acids, including taurocholic acid (TCA) and taurochenodeoxycholic acid (TCDCA). LcS treatment also increased the levels of secondary taurine-conjugated bile acids, including taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA). Moreover, LcS treatment exhibited a suppressive effect on the hydroxylated primary bile acids α-muricholic acid (α-MCA) and ß-muricholic acid (ß-MCA). We further demonstrated that LcS treatment suppressed the expression of pro-inflammatory mediators interferon-gamma (IFN-γ) and nitric oxide (NO), and increased the expression of the anti-inflammatory mediator interleukin-10 (IL-10) in colon tissues, potentially as a result of altered bile acid profiles. Mechanistically, we showed that LcS treatment suppressed the activation of nuclear factor-kappa B (NF-κB) signaling via stabilization of inhibitor of NF-κB alpha (IκBα). Altogether, we have demonstrated the therapeutic effects of LcS in DSS-induced colitis, providing new insights into its effect on bile acid metabolism and the related anti-inflammatory mechanisms. Our findings provide support for the application of LcS in the treatment of IBD.
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Inflammatory bowel disease (IBD) is an idiopathic inflammatory disease affecting the gastrointestinal tract. IBD is characterized by courses of relapse and remission, and remains incurable. Although multiple factors are related to the pathogenesis of IBD, disruption of intestinal mucosa homeostasis has been proposed to be a major contributor to IBD, and abnormal activation of immune cells is key for initiation of the inflammatory response. Macrophages are the most abundant immune cells in the intestine. Once activated, they are responsible for secretion of pro-inflammatory cytokines and chemokines to attract circulating monocytes to inflammatory sites, exacerbating the inflammatory response, and leading to tissue damage. Therefore, the suppression of activated macrophages, cytokine/chemokine production, and subsequent monocyte chemotaxis possesses great potential for the treatment of IBD. In our study, we have demonstrated the inhibitory effect of Centipeda minima total extract (CME) on the activation of NF-κB, STAT3, and MAPK signaling in LPS-stimulated RAW264.7 macrophages. In addition, we identified the significant suppressive effect of CME on CCL8 expression in activated macrophages, which potentially contributed to inhibition of monocyte chemotaxis. In the DSS-induced acute colitis mouse model, we have demonstrated the suppressive effect of CME on intestinal macrophage infiltration and its ameliorative effect in IBD. Altogether, we have provided evidence of the therapeutic effect of CME in IBD and the potential of CME for the treatment of IBD.
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Cancer is the second leading cause of death globally, responsible for an estimated 9.6 million deaths in 2018, and this burden continues to increase. Therefore, there is a clear and urgent need for novel drugs with increased efficacy for the treatment of different cancers. Previous research has demonstrated that brevilin A (BA) exerts anticancer activity in various cancers, including human multiple myeloma, breast cancer, lung cancer, and colon carcinoma, suggesting the anticancer potential present in the chemical scaffold of BA. Here, we designed and synthesized a small library of 12 novel BA derivatives and evaluated the biological anticancer effects of the compounds in various cancer cell lines. The results of this structure-activity relationship study demonstrated that BA derivatives BA-9 and BA-10 possessed significantly improved anticancer activity toward lung, colon, and breast cancer cell lines. BA-9 and BA-10 could more effectively reduce cancer cell viability and induce DNA damage, cell-cycle arrest, and apoptosis when compared with BA. Our findings represent a significant step forward in the development of novel anticancer entities.
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Breast cancer is the most commonly diagnosed cancer in females worldwide. Estimates from the World Health Organization (WHO) International Agency for Research on Cancer, suggest that globally, there were around 2.1 million new breast cancer cases and 627,000 deaths due to breast cancer in 2018. Among the subtypes of breast cancer, triple negative breast cancer (TNBC) is the most aggressive and carries the poorest prognosis, largest recurrence, and lowest survival rate. Major treatment options for TNBC patients are mainly constrained to chemotherapy, which can be accompanied by severe side effects. Therefore, development of novel and effective anti-cancer drugs for the treatment of TNBC are urgently required. Centipeda minima is a well-known traditional Chinese herbal medicine that has historically been used to treat rhinitis, sinusitis, relieve pain, and reduce swelling. Recent studies have shown that Centipeda minima exhibited efficacy against certain cancers, however, to date, no studies have been conducted on its effects in breast cancer. Here, we aimed to investigate the anti-cancer activity of the total extract of Centipeda minima (CME), and its underlying mechanism, in TNBC. In MDA-MB-231, we found that CME could significantly reduce cell viability and proliferation, induce apoptosis and inhibit cancer cell migration and invasion, in a dose and time-dependent manner. We showed that CME may potentially act via inhibition of multiple signaling pathways, including the EGFR, PI3K/AKT/mTOR, NF-κB, and STAT3 pathways. Treatment with CME also led to in vitro downregulation of MMP-9 activity and inhibition of metastasis. Further, we demonstrated that CME could significantly reduce tumor burden in MDA-MB-231 xenograft mice, without any appreciable side effects. Based on our findings, CME is a promising candidate for development as a therapeutic with high efficacy against TNBC.
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Challenges in the development of anti-cancer chemotherapeutics continue to exist, particularly with respect to adverse effects and development of resistance, underlining the need for novel drugs with good safety profiles. Natural products have proven to be a fertile ground for exploitation, and development of anti-cancer drugs from structurally complex natural products holds promise. Unfortunately, this approach is often hindered by low isolation yields and limited information from preliminary cell-based assays. Here we report a concise and scalable synthesis of a series of low-abundance Isodon diterpenoids (a large class of natural products with over 1000 members isolated from the herbs of genus Isodon, which are well-known folk medicines for the treatment of inflammation and cancer), including eriocalyxin B, neolaxiflorin L and xerophilusin I. These scalable syntheses enable multilevel bio-evaluation of the natural products, in which we identify neolaxiflorin L as a promising anti-cancer drug candidate.
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Antineoplásicos/síntese química , Produtos Biológicos/síntese química , Diterpenos/síntese química , Descoberta de Drogas/métodos , Isodon/química , Animais , Humanos , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/tratamento farmacológicoRESUMO
Recent advances in the development of anti-inflammatory agents have improved their therapeutic outcome in inflammatory bowel disease (IBD), however, the presence of side effects and limited effectiveness hinder their widespread use. Therefore, novel compounds with strong anti-inflammatory efficacy are still required. In this study, we investigated the anti-inflammatory effect and potential mechanisms of Gynostemma pentaphyllum (Thunb.) Makino saponins (GpS), a major component of the herbal medicine widely used in Asian countries. In in vitro studies, we demonstrated that GpS dose dependently suppressed activation of macrophages, one of the main effectors in IBD. GpS also suppressed cytokine production and the activation of NF-κB and STAT3 signaling in lipopolysaccharide-induced macrophages, without affecting their viability. Further in vivo studies demonstrated that GpS could ameliorate the weight loss, increased disease activity index, colon shortening and histological damage associated with dextran sulfate sodium (DSS)-induced colitis in mice. In agreement with results from our in vitro experiments, GpS suppressed cytokine production and activation of NF-κB and STAT3 signaling in the colons of DSS-induced mice. In this study, we present for the first time, evidence of the therapeutic effect of GpS in IBD, highlighting its potential as an effective therapeutic against the disease.
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A unique, dual-function, photoactivatable anticancer prodrug, RuEuL, has been tailored that features a ruthenium(II) complex linked to a cyclen-europium chelate via a π-conjugated bridge. Under irradiation at 488 nm, the dark-inactive prodrug undergoes photodissociation, releasing the DNA-damaging ruthenium species. Under evaluation-window irradiation (λirr = one-photon 350 nm or two-photon 700 nm), the drug delivery process can be quantitatively monitored in real-time because of the long-lived red europium emission. Linear relationships between released drug concentration and ESI-MS or luminescence responses are established. Finally, the efficiency of the new prodrug is demonstrated both in vitro RuEuL anticancer prodrug over some existing ones and open the way for decisive improvements in multipurpose prodrugs.