scholarly journals Identification of Gm15441, a Txnip antisense lncRNA, as a critical regulator in liver metabolic homeostasis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mingyang Xin ◽  
Qian Guo ◽  
Qingchun Lu ◽  
Juan Lu ◽  
Po-shun Wang ◽  
...  
Keyword(s):  
Mouse Liver ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Underlying Mechanism ◽  
Liver Metabolism ◽  
Similar Response ◽  
Metabolic Homeostasis ◽  
Specific Regulation

Abstract Background The majority of mammalian genome is composed of non-coding regions, where numerous long non-coding RNAs (lncRNAs) are transcribed. Although lncRNAs have been identified to regulate fundamental biological processes, most of their functions remain unknown, especially in metabolic homeostasis. Analysis of our recent genome-wide screen reveals that Gm15441, a thioredoxin-interacting protein (Txnip) antisense lncRNA, is the most robustly induced lncRNA in the fasting mouse liver. Antisense lncRNAs are known to regulate their sense gene expression. Given that Txnip is a critical metabolic regulator of the liver, we aimed to investigate the role of Gm15441 in the regulation of Txnip and liver metabolism. Methods We examined the response of Gm15441 and Txnip under in vivo metabolic signals such as fasting and refeeding, and in vitro signals such as insulin and key metabolic transcription factors. We investigated the regulation of Txnip expression by Gm15441 and the underlying mechanism in mouse hepatocytes. Using adenovirus-mediated liver-specific overexpression, we determined whether Gm15441 regulates Txnip in the mouse liver and modulates key aspects of liver metabolism. Results We found that the expression levels of Gm15441 and Txnip showed a similar response pattern to metabolic signals in vivo and in vitro, but that their functions were predicted to be opposite. Furthermore, we found that Gm15441 robustly reduced Txnip protein expression in vitro through sequence-specific regulation and translational inhibition. Lastly, we confirmed the Txnip inhibition by Gm15441 in vivo (mice) and found that Gm15441 liver-specific overexpression lowered plasma triglyceride and blood glucose levels and elevated plasma ketone body levels. Conclusions Our data demonstrate that Gm15441 is a potent Txnip inhibitor and a critical metabolic regulator in the liver. This study reveals the therapeutic potential of Gm15441 in treating metabolic diseases.

scholarly journals Andrographolide Ameliorates Diabetic Cardiomyopathy in Mice by Blockage of Oxidative Damage and NF-κB-Mediated Inflammation

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Ershun Liang ◽  
Xue Liu ◽  
Zhanhui Du ◽  
Ruixue Yang ◽  
Yuxia Zhao
Keyword(s):  
Oxidative Stress ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Therapeutic Potential ◽  
Myocardial Dysfunction ◽  
Underlying Mechanism ◽  
Ros Generation ◽  
Related Factor

Andrographolide (Andro), a major bioactive component obtained from Andrographis paniculata Nees, has exerted wide antioxidant as well as cytoprotective properties. However, whether Andro treatment could retard the progress of diabetic cardiomyopathy (DCM) remains unknown. In this study, we evaluated the effects of Andro against diabetes-induced myocardial dysfunction and explored the underlying mechanism in STZ-induced diabetic mice. As a result, treatment with Andro dose dependently suppressed cardiac inflammation and oxidative stress, accompanied by decreasing cardiac apoptosis, which subsequently ameliorated cardiac fibrosis and cardiac hypertrophy. Further, Andro blocked hyperglycemia-triggered reactive oxygen species (ROS) generation by suppressing NADPH oxidase (NOX) activation and augmenting nuclear factor erythroid 2-related factor 2 (Nrf2) expression both in vitro and in vivo. Our results suggest that the cardioprotective effects afforded by Andro treatment involve the modulation of NOX/Nrf2-mediated oxidative stress and NF-κB-mediated inflammation. The present study unravels the therapeutic potential of Andro in the treatment of DCM by attenuating oxidative stress, inflammation, and apoptosis.

Bioinformatic analysis of RHO family of GTPases identifies RAC1 pharmacological inhibition as a new therapeutic strategy for hepatocellular carcinoma

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321454
Author(s):  
Juan Bayo ◽  
Esteban J Fiore ◽  
Luciana María Dominguez ◽  
María Jose Cantero ◽  
Matias S Ciarlantini ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Stellate Cell ◽  
Underlying Mechanism ◽  
Intrahepatic Metastasis ◽  
Clinical Prognosis ◽  
Rho Family

ObjectiveThe RHO family of GTPases, particularly RAC1, has been linked with hepatocarcinogenesis, suggesting that their inhibition might be a rational therapeutic approach. We aimed to identify and target deregulated RHO family members in human hepatocellular carcinoma (HCC).DesignWe studied expression deregulation, clinical prognosis and transcription programmes relevant to HCC using public datasets. The therapeutic potential of RAC1 inhibitors in HCC was study in vitro and in vivo. RNA-Seq analysis and their correlation with the three different HCC datasets were used to characterise the underlying mechanism on RAC1 inhibition. The therapeutic effect of RAC1 inhibition on liver fibrosis was evaluated.ResultsAmong the RHO family of GTPases we observed that RAC1 is upregulated, correlates with poor patient survival, and is strongly linked with a prooncogenic transcriptional programme. From a panel of novel RAC1 inhibitors studied, 1D-142 was able to induce apoptosis and cell cycle arrest in HCC cells, displaying a stronger effect in highly proliferative cells. Partial rescue of the RAC1-related oncogenic transcriptional programme was obtained on RAC1 inhibition by 1D-142 in HCC. Most importantly, the RAC1 inhibitor 1D-142 strongly reduce tumour growth and intrahepatic metastasis in HCC mice models. Additionally, 1D-142 decreases hepatic stellate cell activation and exerts an anti-fibrotic effect in vivo.ConclusionsThe bioinformatics analysis of the HCC datasets, allows identifying RAC1 as a new therapeutic target for HCC. The targeted inhibition of RAC1 by 1D-142 resulted in a potent antitumoural effect in highly proliferative HCC established in fibrotic livers.

The Impact of Polyphenolic in The Management of Breast Cancer: Mechanistic Aspects and Recent Patents

2021 ◽  
Vol 16 ◽  
Author(s):  
Heba A.S. El-Nashar ◽  
Shaza H. Aly ◽  
Amirhossein Ahmadi ◽  
Mohamed El-Shazly
Keyword(s):  
Breast Cancer ◽  
Therapeutic Potential ◽  
Treatment Strategies ◽  
Underlying Mechanism ◽  
In Vivo Studies ◽  
Molecular Characteristics ◽  
Anticancer Properties ◽  
The Impact

Background: Breast cancer is the most frequently diagnosed type of cancer in women (2.1 million) and stands as the fifth leading cause of death. Several treatment strategies are available such as surgical resection, radiation, hormonal therapy, and conventional chemotherapy that are associated with severe adverse effects on the patients. Objective: This review aims to summarize the different studies (in vitro, in vivo, and new patents) concerning the therapeutic potential of plant polyphenolics in the management of breast cancer published in the period from January 2016 to January 2021. Moreover, this review will focus on the underlying mechanism of action and molecular characteristics of these compounds. Methods: The data of this review were collected from different scientific databases such as PubMed, Science Direct, Google Scholarship, sci-finder, and Egyptian Knowledge bank (EKB). Results: During the last period (2016-2021), the in vitro studies investigated about 52 natural compounds of polyphenolic nature with promising anti-breast cancer, while fourteen compounds were reported via in vivo studies. Besides, there were about fifteen compounds registered as patent drugs. Different mechanisms of action and molecular targets were reported to provide a great clarified base and precise reflection for the anticancer properties of these compounds against breast cancer. Conclusion: Polyphenolics represent a plentiful sources of anticancer lead compounds that stand against the progression of breast cancer invasion and metastasis.

scholarly journals Transcription Factor Runx1 Activates Opn to Promote Tumor Progression in Head and Neck Cancer

2020 ◽  
Author(s):  
Kai Liu ◽  
Huiying Hu ◽  
Huanyu Jiang ◽  
Haidong Zhang ◽  
Shanchun Gong ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Head And Neck ◽  
Therapeutic Potential ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Luciferase Reporter ◽  
Metastatic Progression ◽  
Related Transcription Factor

Abstract Background:Metastatic progression remains a major burden for head and neck squamous cell carcinoma (HNSCC). Runt-related transcription factor 1 (RUNX1)has been reported to be associated with an aggressive phenotype in several cancers. However, the precise roles of RUNX1 underlying the metastaticprogression of HNSCC remain largely unknown.Methods:RUNX1 expression levels in HNSCC cells and tissues were detected by quantitative real-time PCR (qPCR), Western blottingand immunohistochemistry (IHC). In vitro and in vivo assays were performed to investigate the function of RUNX1 in the metastatic phenotype and the tumorigenic capability of HNSCC cells. Luciferase reporter and chromatin immunoprecipitation (ChIP)-qPCR assays were performed to determine the underlying mechanism of RUNX1-mediated HNSCC aggressiveness.Results:RUNX1 was increased with disease progression in patients withHNSCC.Furthermore, we found that silencing ofRUNX1 significantly decelerated the malignant progression of HNSCC cells and reduced Osteopontin (OPN) expression in vitro, and weakened the tumorigenicityof HNSCC cells in vivo. Mechanistically, we demonstrated that RUNX1 played an important role in activating MAPK signaling by directly binding to the promoter of OPN.Conclusions: Our results provide new insight into the mechanisms underlying the facilitate metastasisability of RUNX1and reveal the therapeutic potential of targeting RUNX1 in HNSCC.

scholarly journals The crude ethanol extract of Periplaneta americana L. stimulates wound healing in vitro & in vivo

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Long-Jian Li ◽  
Mao-Ze Wang ◽  
Tie-Jun Yuan ◽  
Xue-Han Xu ◽  
Haseeb Anwar Dad ◽  
...  
Keyword(s):  
Wound Healing ◽  
Periplaneta Americana ◽  
Therapeutic Potential ◽  
Ethanol Extract ◽  
Underlying Mechanism ◽  
Skin Wound ◽  
Wound Therapy ◽  
Skin Cells

Abstract Periplaneta americana L. is a Traditional Chinese Medicine that has been used in clinic treatment of various diseases for a long history. However, the therapeutic potential and the underlying mechanism of Periplaneta americana L. in the skin wound therapy was not investigated comprehensively yet. This study aims to investigate the influence of the crude ethanol extract of PAL in the different wound stages including: (1) the migration and chemotaxis to skin cells in the first stage; (2) proliferation and cells cycle of skin cells in the second stage; (3) remodeling effect and secretion of growth factors, collagens in the third stage; (4) as well as the influence in the blood vessels regeneration in the late stage. The crude ethanol extract of PAL was shown to (1) promote the keratinocytes proliferation and regulate the cells cycle of fibroblasts significantly; (2) stimulate the migration of keratinocytes and fibroblasts obviously; (3) enhance the EGF and VEGF secretion both in vitro & in vivo; (4) accelerate the wound healing, collagen synthesis and angiogenesis. The crude ethanol extract of KFX was shown a promising therapeutic agent for the wound therapy with great efficacy to accelerate the wound healing with improved quality.

scholarly journals Ethyl Caffeate Ameliorates Collagen-Induced Arthritis by Suppressing Th1 Immune Response

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Shikui Xu ◽  
Aixue Zuo ◽  
Zengjun Guo ◽  
Chunping Wan
Keyword(s):  
Immune Response ◽  
Therapeutic Potential ◽  
Underlying Mechanism ◽  
Pcr Analysis ◽  
Collagen Induced Arthritis ◽  
Th1 Cell ◽  
Intracellular Cytokines ◽  
Th1 Immune Response

The present study was designed to assess the antiarthritic potential of ECF in collagen-induced arthritis (CIA) and explore its underlying mechanism. Methods. In vitro, lymphocyte proliferation assay was measured by CCK-8 kit. In vivo, the therapeutic potential of ECF on CIA was investigated; surface marker, Treg cell, and intracellular cytokines (IL-17A and IFN-γ) were detected by flow cytometry. Th1 cell differentiation assay was performed, and mRNA expression in interferon-γ-related signaling was examined by q-PCR analysis. Results. In vitro, ECF markedly inhibited the proliferation of splenocytes in response to ConA and anti-CD3. In vivo, ECF treatment reduced the severity of CIA, inhibited IFN-γ and IL-6 secretion, and decreased the proportion of CD11b+Gr-1+ splenic neutrophil. Meanwhile, ECF treatment significantly inhibited the IFN-γ expression in CD4+T cell without obviously influencing the development of Th17 cells and T regulatory cells. In vitro, ECF suppressed the differentiation of naive CD4+ T cells into Th1. Furthermore, ECF intensely blocked the transcriptional expression in interferon-γ-related signaling, including IFN-γ, T-bet, STAT1, and STAT4. Conclusion. Our results indicated that ECF exerted antiarthritic potential in collagen-induced arthritis by suppressing Th1 immune response and interferon-γ-related signaling.

Phytosomal Curcumin Elicits Anti-tumor Properties Through Suppression of Angiogenesis, Cell Proliferation and Induction of Oxidative Stress in Colorectal Cancer

2019 ◽  
Vol 24 (39) ◽  
pp. 4626-4638 ◽  
Author(s):  
Reyhaneh Moradi-Marjaneh ◽  
Seyed M. Hassanian ◽  
Farzad Rahmani ◽  
Seyed H. Aghaee-Bakhtiari ◽  
Amir Avan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Therapeutic Potential ◽  
Vegf Signaling ◽  
Anticancer Effects ◽  
Inhibition Of Angiogenesis ◽  
Underlying Mechanisms ◽  
Apoptotic Activity

Background: Colorectal cancer (CRC) is one of the most common causes of cancer-associated mortality in the world. Anti-tumor effect of curcumin has been shown in different cancers; however, the therapeutic potential of novel phytosomal curcumin, as well as the underlying molecular mechanism in CRC, has not yet been explored. Methods: The anti-proliferative, anti-migratory and apoptotic activity of phytosomal curcumin in CT26 cells was assessed by MTT assay, wound healing assay and Flow cytometry, respectively. Phytosomal curcumin was also tested for its in-vivo activity in a xenograft mouse model of CRC. In addition, oxidant/antioxidant activity was examined by DCFH-DA assay in vitro, measurement of malondialdehyde (MDA), Thiol and superoxidedismutase (SOD) and catalase (CAT) activity and also evaluation of expression levels of Nrf2 and GCLM by qRT-PCR in tumor tissues. In addition, the effect of phytosomal curcumin on angiogenesis was assessed by the measurement of VEGF-A and VEGFR-1 and VEGF signaling regulatory microRNAs (miRNAs) in tumor tissue. Results: Phytosomal curcumin exerts anti-proliferative, anti-migratory and apoptotic activity in-vitro. It also decreases tumor growth and augmented 5-fluorouracil (5-FU) anti-tumor effect in-vivo. In addition, our data showed that induction of oxidative stress and inhibition of angiogenesis through modulation of VEGF signaling regulatory miRNAs might be underlying mechanisms by which phytosomal curcumin exerted its antitumor effect. Conclusion: Our data confirmed this notion that phytosomal curcumin administrates anticancer effects and can be used as a complementary treatment in clinical settings.

Medicinal Plants and Bioactive Compounds for Diabetes Management: Important Advances for Drug Discovery

2020 ◽  
Vol 26 ◽  
Author(s):  
Kondeti Ramudu Shanmugam ◽  
Bhasha Shanmugam ◽  
Gangigunta Venkatasubbaiah ◽  
Sahukari Ravi ◽  
Kesireddy Sathyavelu Reddy
Keyword(s):  
Herbal Medicine ◽  
Medicinal Plants ◽  
Bioactive Compounds ◽  
Diabetes Management ◽  
Therapeutic Potential ◽  
Public Health Problem ◽  
In Vivo Studies ◽  
Major Public Health Problem

Background : Diabetes is a major public health problem in the world. It affects each and every part of the human body and also leads to organ failure. Hence, great progress made in the field of herbal medicine and diabetic research. Objectives: Our review will focus on the effect of bioactive compounds of medicinal plants which are used to treat diabetes in India and other countries. Methods: Information regarding diabetes, oxidative stress, medicinal plants and bioactive compounds were collected from different search engines like Science direct, Springer, Wiley online library, Taylor and francis, Bentham Science, Pubmed and Google scholar. Data was analyzed and summarized in the review. Results and Conclusion: Anti-diabetic drugs that are in use have many side effects on vital organs like heart, liver, kidney and brain. There is an urgent need for alternative medicine to treat diabetes and their disorders. In India and other countries herbal medicine was used to treat diabetes. Many herbal plants have antidiabetic effects. The plants like ginger, phyllanthus, curcumin, aswagandha, aloe, hibiscus and curcuma showed significant anti-hyperglycemic activities in experimental models and humans. The bioactive compounds like Allicin, azadirachtin, cajanin, curcumin, querceitin, gingerol possesses anti-diabetic, antioxidant and other pharmacological properties. This review focuses on the role of bioactive compounds of medicinal plants in prevention and management of diabetes. Conclusion: Moreover, our review suggests that bioactive compounds have the potential therapeutic potential against diabetes. However, further in vitro and in vivo studies are needed to validate these findings.

scholarly journals GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 610
Author(s):  
Robin Park ◽  
Andrew L. Coveler ◽  
Ludimila Cavalcante ◽  
Anwaar Saeed
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Potential ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
In Vivo Models ◽  
Gsk 3Β ◽  
Early Phase Clinical Trials

Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

scholarly journals GCH1 induces immunosuppression through metabolic reprogramming and IDO1 upregulation in triple-negative breast cancer

2021 ◽  
Vol 9 (7) ◽  
pp. e002383
Author(s):  
Jin-Li Wei ◽  
Si-Yu Wu ◽  
Yun-Song Yang ◽  
Yi Xiao ◽  
Xi Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Taxonomy ◽  
Underlying Mechanism ◽  
Metabolic Reprogramming ◽  
Sequencing Data ◽  
Aryl Hydrocarbon

PurposeRegulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC.Experimental designUsing the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism.ResultsWe revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy.ConclusionsTumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.

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