scholarly journals The Synergistic Effects of 5-Aminosalicylic Acid and Vorinostat in the Treatment of Ulcerative Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Long He ◽  
Shuting Wen ◽  
Zhuotai Zhong ◽  
Senhui Weng ◽  
Qilong Jiang ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Side Effects ◽  
Interaction Analysis ◽  
Synergistic Effects ◽  
Pathway Enrichment Analysis ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Aminosalicylic Acid

Background: The drug 5-aminosalicylic acid (5-ASA) is the first-line therapy for the treatment of patients with mild-to-moderate ulcerative colitis (UC). However, in some cases, 5-ASA cannot achieve the desired therapeutic effects. Therefore, patients have to undergo therapies that include corticosteroids, monoclonal antibodies or immunosuppressants, which are expensive and may be accompanied by significant side effects. Synergistic drug combinations can achieve greater therapeutic effects than individual drugs while contributing to combating drug resistance and lessening toxic side effects. Thus, in this study, we sought to identify synergistic drugs that can act synergistically with 5-ASA.Methods: We started our study with protein-metabolite analysis based on peroxisome proliferator-activated receptor gamma (PPARG), the therapeutic target of 5-ASA, to identify more additional potential drug targets. Then, we further evaluated the possibility of their synergy with PPARG by integrating Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis, pathway-pathway interaction analysis, and semantic similarity analysis. Finally, we validated the synergistic effects with in vitro and in vivo experiments.Results: The combination of 5-ASA and vorinostat (SAHA) showed lower toxicity and mRNA expression of p65 in human colonic epithelial cell lines (Caco-2 and HCT-116), and more efficiently alleviated the symptoms of dextran sulfate sodium (DSS)-induced colitis than treatment with 5-ASA and SAHA alone.Conclusion: SAHA can exert effective synergistic effects with 5-ASA in the treatment of UC. One possible mechanism of synergism may be synergistic inhibition of the nuclear factor kappa B (NF-kB) signaling pathway. Moreover, the metabolite-butyric acid may be involved.

scholarly journals Targeting the EZH2-PPAR Axis Is a Potential Therapeutic Pathway for Pancreatic Cancer

PPAR Research ◽  
2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Jilong Hu ◽  
Zhinan Zheng ◽  
Jia Lei ◽  
Yuxin Cao ◽  
Qiyun Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cyclin D1 ◽  
Caspase 3 ◽  
Synergistic Effects ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Agonist ◽  
Combined Use

Enhancer of zeste homolog 2 (EZH2) is abnormally highly expressed in pancreatic cancer (PC). However, it is not ideal to treat PC by inhibiting EZH2. This study reported that the combined use of pan-peroxisome proliferator-activated receptor (PPAR) agonist could significantly improve the anti-PC effect of EZH2 inhibitor. In vitro, PC cell lines PANC-1 and AsPC-1 were cultured, and MTT and flow cytometry were performed to observe the effects of pan-PPAR agonist bezafibrate and EZH2 selective inhibitor GSK126 on cell viability and apoptosis. In vivo, CDXs of PANC-1 and AsPC-1 were established to observe the effects of bezafibrate and GSK126 on bearing tumors. Western blotting was performed to detect the protein expressions of H3K27me3, β-catenin, p-β-catenin, cyclin D1, c-Myc, and cleaved caspase 3 in vitro and in vivo. The results showed that bezafibrate significantly improved the effects of GSK126 on proliferation inhibition and apoptosis promotion in vitro and the growth suppression of CDX tumors in vivo. It also significantly enhanced the effects of GSK126 on upregulating the expression level of p-β-catenin and that of cleaved caspase 3 in vitro and in vivo. In parallel, downregulation of the expression levels of H3K27me3, β-catenin, cyclin D1, and c-Myc was also observed in vitro or in vivo. These results suggest that the combination of bezafibrate and GSK126 has synergistic effects on PC, and the molecular mechanism may be related to the enhanced inhibition of the Wnt/β-catenin signaling pathway. We believe that targeting the EZH2-PPAR axis is a potential therapeutic pathway for PC.

scholarly journals The PPARγ ligand rosiglitazone attenuates hypoxia-induced endothelin signaling in vitro and in vivo

2011 ◽  
Vol 301 (6) ◽  
pp. L881-L891 ◽  
Author(s):  
Bum-Yong Kang ◽  
Jennifer M. Kleinhenz ◽  
Tamara C. Murphy ◽  
C. Michael Hart
Keyword(s):  
Transcription Factors ◽  
Hypoxia Inducible Factor ◽  
Cell Counting ◽  
Mouse Lung ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels

Peroxisome proliferator-activated receptor (PPAR) γ activation attenuates hypoxia-induced pulmonary hypertension (PH) in mice. The current study examined the hypothesis that PPARγ attenuates hypoxia-induced endothelin-1 (ET-1) signaling to mediate these therapeutic effects. To test this hypothesis, human pulmonary artery endothelial cells (HPAECs) were exposed to normoxia or hypoxia (1% O2) for 72 h and treated with or without the PPARγ ligand rosiglitazone (RSG, 10 μM) during the final 24 h of exposure. HPAEC proliferation was measured with MTT assays or cell counting, and mRNA and protein levels of ET-1 signaling components were determined. To explore the role of hypoxia-activated transcription factors, selected HPAECs were treated with inhibitors of hypoxia-inducible factor (HIF)-1α (chetomin) or nuclear factor (NF)-κB (caffeic acid phenethyl ester, CAPE). In parallel studies, male C57BL/6 mice were exposed to normoxia (21% O2) or hypoxia (10% O2) for 3 wk with or without gavage with RSG (10 mg·kg−1·day−1) for the final 10 days of exposure. Hypoxia increased ET-1, endothelin-converting enzyme-1, and endothelin receptor A and B levels in mouse lung and in HPAECs and increased HPAEC proliferation. Treatment with RSG attenuated hypoxia-induced activation of HIF-1α, NF-κB activation, and ET-1 signaling pathway components. Similarly, treatment with chetomin or CAPE prevented hypoxia-induced increases in HPAEC ET-1 mRNA and protein levels. These findings indicate that PPARγ activation attenuates a program of hypoxia-induced ET-1 signaling by inhibiting activation of hypoxia-responsive transcription factors. Targeting PPARγ represents a novel therapeutic strategy to inhibit enhanced ET-1 signaling in PH pathogenesis.

scholarly journals Curcumin: Phytochemical Therapy in the Treatment of Hyperlipidemia

2019 ◽  
Keyword(s):  
Side Effects ◽  
Curcuma Longa ◽  
Experimental Studies ◽  
Lipid Lowering ◽  
Modern World ◽  
Therapeutic Effects ◽  
Synthetic Drugs ◽  
Wide Range

In modern world, hyperlipidemia is the most common disorder mainly caused by lifestyle habits and the major cause of cardiovascular, coronary and atherosclerotic changes. Such disorder is characterized by abnormally elevated levels of any or all lipids or lipoproteins in the blood. A wide range of drugs are available for the treatment of hyperlipidemia, class of antihyperlipidemic drugs, but such drug-therapies are carried out with presence of various side effects. In the last decades, different in vitro and in vivo research have been conducted to confirm the therapeutic effects of various phytochemical agents that overcome the side effects caused by synthetic drugs. According to Ayurvedic recommendations and experimental studies, numerous phytochemical agents have been reported to possess different antihyperlipidemic properties. One of the most studied phytochemical agent - curcumin, herbal polyphenol and active ingredient which can be extracted from the powder rhizome of the plant Curcuma longa, has been reported to possess a wide range of pharmacological properties such as antimicrobial, antioxidative, antiinflammatory and anticancer property. Recent studies also suggests curcumin as potential lipid lowering candidate in treatment of hyperlipidemia. The aim of this review is to present and discuss phytochemistry, molecular mechanism of hypolipidemic activity of curcumin, demonstrating its importance as potential therapy for the treatment of hyperlipidemia.

scholarly journals Efficacy of Linezolid and Fosfomycin in Catheter-Related Biofilm Infection Caused by Methicillin-ResistantStaphylococcus aureus

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Dong Chai ◽  
Xu Liu ◽  
Rui Wang ◽  
Yan Bai ◽  
Yun Cai
Keyword(s):  
Synergistic Effects ◽  
Antibacterial Activities ◽  
Therapeutic Effects ◽  
Viable Bacteria ◽  
Mrsa Infection ◽  
New Treatments ◽  
Time Kill ◽  
Important Basis

As long-standing clinical problems, catheter-related infections and other chronic biofilm infections are more difficult to treat due to the high antibiotic resistance of biofilm. Therefore, new treatments are needed for more effective bacteria clearance. In this study, we evaluated the antibacterial activities of several common antibiotics alone and their combinations against biofilm-embedded methicillin-resistantstaphylococcus aureus(MRSA) infections, bothin vitroandin vivo. In brief, fosfomycin, levofloxacin, and rifampin alone or in combination with linezolid were testedin vitroagainst planktonic and biofilm-embedded MRSA infection in three MRSA stains. The synergistic effects between linezolid and the other three antibiotics were assessed by fractional inhibitory concentration index (FICI) and time-kill curves, where the combination of linezolid plus fosfomycin showed the best synergistic effect in all strains. For further evaluationin vivo, we applied the combination of linezolid and fosfomycin in a catheter-related biofilm rat model and found that viable bacteria counts in biofilm were significantly reduced after treatment (P<0.05). In summary, we have shown here that the combination of linezolid and fosfomycin treatment had improved therapeutic effects on biofilm-embedded MRSA infection bothin vitroandin vivo, which provided important basis for new clinical therapy development.

scholarly journals Synergistic effects of exosomal crocin or curcumin compounds and HPV L1-E7 polypeptide vaccine construct on tumor eradication in C57BL/6 mouse model

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258599
Author(s):  
Elnaz Abbasifarid ◽  
Azam Bolhassani ◽  
Shiva Irani ◽  
Fattah Sotoodehnejadnematalahi
Keyword(s):  
Cervical Cancer ◽  
Mouse Model ◽  
Tumor Cells ◽  
Synergistic Effects ◽  
Low Cost ◽  
Hpv Infection ◽  
Therapeutic Effects ◽  
T Cell Immune Responses

Cervical cancer is the most common malignant tumor in females worldwide. Human papillomavirus (HPV) infection is associated with the occurrence of cervical cancer. Thus, developing an effective and low-cost vaccine against HPV infection, especially in developing countries is an important issue. In this study, a novel HPV L1-E7 fusion multiepitope construct designed by immunoinformatics tools was expressed in bacterial system. HEK-293T cells-derived exosomes were generated and characterized to use as a carrier for crocin and curcumin compounds. The exosomes loaded with crocin and curcumin compounds as a chemotherapeutic agent (ExoCrocin and ExoCurcumin) were used along with the L1-E7 polypeptide for evaluation of immunological and anti-tumor effects in C57BL/6 mouse model. In vitro studies showed that ExoCrocin and ExoCurcumin were not cytotoxic at a certain dose, and they could enter tumor cells. In vivo studies indicated that combination of the L1-E7 polypeptide with ExoCrocin or ExoCurcumin could produce a significant level of immunity directed toward Th1 response and CTL activity. These regimens showed the protective and therapeutic effects against tumor cells (the percentage of tumor-free mice: ~100%). In addition, both ExoCrocin and ExoCurcumin represented similar immunological and anti-tumor effects. Generally, the use of exosomal crocin or curcumin forms along with the L1-E7 polypeptide could significantly induce T-cell immune responses and eradicate tumor cells.

scholarly journals Insight into Gentisic Acid Antidiabetic Potential Using In Vitro and In Silico Approaches

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1932
Author(s):  
Hamza Mechchate ◽  
Imane Es-safi ◽  
Omkulthom Mohamed Al kamaly ◽  
Dalila Bousta
Keyword(s):  
In Silico ◽  
Tyrosine Phosphatase ◽  
Health Benefit ◽  
In Vivo Studies ◽  
In Vitro Tests ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Gentisic Acid

Numerous scientific studies have confirmed the beneficial therapeutic effects of phenolic acids. Among them gentisic acid (GA), a phenolic acid extensively found in many fruit and vegetables has been associated with an enormous confirmed health benefit. The present study aims to evaluate the antidiabetic potential of gentisic acid and highlight its mechanisms of action following in silico and in vitro approaches. The in silico study was intended to predict the interaction of GA with eight different receptors highly involved in the management and complications of diabetes (dipeptidyl-peptidase 4 (DPP4), protein tyrosine phosphatase 1B (PTP1B), free fatty acid receptor 1 (FFAR1), aldose reductase (AldR), glycogen phosphorylase (GP), α-amylase, peroxisome proliferator-activated receptor gamma (PPAR-γ) and α-glucosidase), while the in vitro study studied the potential inhibitory effect of GA against α-amylase and α-glucosidase. The results indicate that GA interacted moderately with most of the receptors and had a moderate inhibitory activity during the in vitro tests. The study therefore encourages further in vivo studies to confirm the given results.

scholarly journals Therapeutically targeting head and neck squamous cell carcinoma through synergistic inhibition of LSD1 and JMJD3 by TCP and GSK-J1

2019 ◽  
Vol 122 (4) ◽  
pp. 528-538 ◽  
Author(s):  
Wei Zhang ◽  
Jie Cheng ◽  
Pengfei Diao ◽  
Dongmiao Wang ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Synergistic Effects ◽  
Therapeutic Effects ◽  
Rna Seq ◽  
Promising Therapeutic Target ◽  
Combinational Treatment ◽  
Induced Apoptosis ◽  
Preclinical Animal Models

Abstract Background The histone demethylase LSD1 is a key mediator driving tumorigenesis, which holds potential as a promising therapeutic target. However, treatment with LSD1 inhibitors alone failed to result in complete cancer regression. Methods The synergistic effects of TCP (a LSD1 inhibitor) and GSK-J1 (a JMJD3 inhibitor) against HNSCC were determined in vitro and in preclinical animal models. Genes modulated by chemical agents or siRNAs in HNSCC cells were identified by RNA-seq and further functionally interrogated by bioinformatics approach. Integrative siRNA-mediated gene knockdown, rescue experiment and ChIP-qPCR assays were utilised to characterise the mediators underlying the therapeutic effects conferred by TCP and GSK-J1. Results Treatment with TCP and GSK-J1 impaired cell proliferation, induced apoptosis and senescence in vitro, which were largely recapitulated by simultaneous LSD1 and JMJD3 knockdown. Combinational treatment inhibited tumour growth and progression in vivo. Differentially expressed genes modulated by TCP and GSK-J1 were significantly enriched in cell proliferation, apoptosis and cancer-related pathways. SPP1 was identified as the mediator of synergy underlying the pro-apoptosis effects conferred by TCP and GSK-J1. Co-upregulation of LSD1 and JMJD3 associated with worse prognosis in patients with HNSCC. Conclusions Our findings revealed a novel therapeutic strategy of simultaneous LSD1 and JMJD3 inhibition against HNSCC.

scholarly journals Autologous Exosome Transfer: A New Personalised Treatment Concept to Prevent Colitis in a Murine Model

2019 ◽  
Vol 14 (6) ◽  
pp. 841-855 ◽  
Author(s):  
Chunhua Yang ◽  
Mingzhen Zhang ◽  
Junsik Sung ◽  
Lixin Wang ◽  
Yunjin Jung ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Wound Healing ◽  
Intestinal Inflammation ◽  
Personalised Medicine ◽  
Hydrodynamic Diameter ◽  
Therapeutic Effects ◽  
Healing Phase ◽  
Anti Inflammatory

Abstract Background and Aims Epigenetic information delivered by intestinal exosomes can be useful for diagnosing intestinal diseases, such as ulcerative colitis, but the therapeutic effects of intestinal exosomes have not been fully exploited. We herein developed an autologous exosome therapy that could treat intestinal disease without any risk of inducing a systemic immunological reaction. Methods Intestinal exosomes were isolated and purified from faeces by our newly developed multi-step sucrose gradient ultracentrifugation method. Lipopolysaccharide [LPS]-activated macrophages were employed to test the in vitro anti-inflammatory ability of intestinal exosomes. To evaluate the in vivo anti-inflammatory activity of our system, we gavaged dextran sulphate sodium [DSS]-induced colitic mice with their own healing phase intestinal exosomes. Results Mouse intestinal exosomes are round extracellular vesicles with a hydrodynamic diameter of ~140 [±20] nm and a surface charge of ~-12 [±3] mV. Among the exosomes obtained at four different stages of DSS-induced ulcerative colitis [1, before treatment; 2, DSS-treated; 3, healing phase; and 4, back to normal], the healing phase exosomes showed the best in vitro anti-inflammatory effects and promotion of wound healing. Moreover, oral co-administration of autologous healing phase exosomes with DSS was found to significantly reduce the risk of a second round of DSS-induced ulcerative colitis in mice. Conclusions Intestinal exosomes obtained during the healing phase that follows induced intestinal inflammation could strongly promote wound healing in the host. Oral administration of autologous exosomes from the healing phase could be a safe and effective approach for treating the ulcerative colitis of a given patient in the context of personalised medicine.

scholarly journals Baicalein Restores the Balance of Th17/Treg Cells via Aryl Hydrocarbon Receptor to Attenuate Colitis

2020 ◽  
Vol 2020 ◽  
pp. 1-19
Author(s):  
Chang Liu ◽  
Yanyang Li ◽  
Yanping Chen ◽  
Shaowei Huang ◽  
Xiaojing Wang ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Cell Differentiation ◽  
Aryl Hydrocarbon Receptor ◽  
Treg Cell ◽  
Treg Cells ◽  
Therapeutic Effects ◽  
Scutellaria Baicalensis Georgi ◽  
Aryl Hydrocarbon

As one of the ligands of aryl hydrocarbon receptor (AhR), baicalein, isolated from Scutellaria baicalensis Georgi, has been proved to exert potential therapeutic effects on ulcerative colitis (UC), but its therapeutic mechanism remains obscure. Authentically, ulcerative colitis can be alleviated by regulating the differentiation of naïve CD4+ T cells via AhR activation. So, our study planned to prove the hypothesis that baicalein protected mice against UC by regulating the balance of Th17/Treg cells via AhR activation. Immunofluorescence and western blot results showed that baicalein could promote AhR activation and induce it to transfer to the nucleus. We further determined the effect of baicalein on naïve CD4+ T cell differentiation in vitro by magnetic cell separation and drug intervention. The results showed that baicalein could promote Treg cell differentiation by activating AhR. In vivo study, UC mice were established by free drinking of dextran sulfate sodium (DSS) for 7 days and then were orally administrated by baicalein (10, 20, and 40 mg/kg), TCDD (AhR agonist), and CH223191 (antagonist). The results demonstrated that baicalein improved the symptoms of UC mice, regulated the balance of Th17/Treg cells, and restored the balance of proinflammatory cytokines such as IL-17, IL-6, and TNF-α; anti-inflammatory cytokines such as IL-10 and TGF-β; and epithelial protective cytokine IL-22 in UC mice, and these effects were related to AhR. Taken together, our research found that baicalein might be a potential drug for UC via regulating Treg cell differentiation and maintaining immune homeostasis and attempted to shed a light on the pivotal role of AhR in these effects.

scholarly journals Therapeutic Effects of Polyphenols on the Treatment of Colorectal Cancer by Regulating Wnt β-Catenin Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Mehran Pashirzad ◽  
Thomas P. Johnston ◽  
Amirhossein Sahebkar
Keyword(s):  
Colorectal Cancer ◽  
Natural Products ◽  
Side Effects ◽  
Signaling Pathway ◽  
Target Genes ◽  
Treatment Options ◽  
Therapeutic Effects ◽  
Incidence And Mortality

Colorectal cancer (CRC) is the third most common cause of cancer-related death worldwide in terms of both its rates of incidence and mortality. Due to serious side effects associated with conventional chemotherapeutic treatments, many natural products with fewer adverse side effects have been considered as potential treatment options. In fact, many natural products have widely been used in various phases of clinical trials for CRC, as well as in in vitro and in vivo preclinical studies. Curcumin (CUR) and resveratrol (RES) are classified as natural polyphenolic compounds that have been demonstrated to have anticancer activity against CRC and are associated with minimal side effects. By regulating select target genes involved in several key signaling pathways in CRC, in particular, the Wnt β-catenin signaling cascade, the course of CRC may be positively altered. In the current review, we focused on the therapeutic effects of CUR and RES in CRC as they pertain to modulation of the Wnt β-catenin signaling pathway.

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