scholarly journals Implications on the Therapeutic Potential of Statins via Modulation of Autophagy

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Armita Mahdavi Gorabi ◽  
Nasim Kiaie ◽  
Saeed Aslani ◽  
Thozhukat Sathyapalan ◽  
Tannaz Jamialahmadi ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tumor Metastasis ◽  
Inflammatory Cell ◽  
Therapeutic Potential ◽  
Lipid Lowering ◽  
Anticancer Effects ◽  
Autophagy Pathway ◽  
The One ◽  
Anti Inflammation

Statins, which are functionally known as 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) inhibitors, are lipid-lowering compounds widely prescribed in patients with cardiovascular diseases (CVD). Several biological and therapeutic functions have been attributed to statins, including neuroprotection, antioxidation, anti-inflammation, and anticancer effects. Pharmacological characteristics of statins have been attributed to their involvement in the modulation of several cellular signaling pathways. Over the past few years, the therapeutic role of statins has partially been attributed to the induction of autophagy, which is critical in maintaining cellular homeostasis and accounts for the removal of unfavorable cells or specific organelles within cells. Dysregulated mechanisms of the autophagy pathway have been attributed to the etiopathogenesis of various disorders, including neurodegenerative disorders, malignancies, infections, and even aging. Autophagy functions as a double-edged sword during tumor metastasis. On the one hand, it plays a role in inhibiting metastasis through restricting necrosis of tumor cells, suppressing the infiltration of the inflammatory cell to the tumor niche, and generating the release of mediators that induce potent immune responses against tumor cells. On the other hand, autophagy has also been associated with promoting tumor metastasis. Several anticancer medications which are aimed at inducing autophagy in the tumor cells are related to statins. This review article discusses the implications of statins in the induction of autophagy and, hence, the treatment of various disorders.

scholarly journals Metformin Ameliorates Ethanol-Induced Liver Triglyceride Accumulation by LKB1/AMPK/ACC Pathway

2021 ◽  
Author(s):  
Fotian Xie ◽  
Dongmei Wang ◽  
Kwok Fai So ◽  
Jia Xiao ◽  
Yi Lv
Keyword(s):  
Lipid Accumulation ◽  
Therapeutic Potential ◽  
Lipid Lowering ◽  
Liver Triglyceride ◽  
Hepatic Lipid Accumulation ◽  
Triglyceride Accumulation ◽  
Lipid Formation

Abstract Background: Hepatic lipid accumulation is one of the main pathological features of alcoholic liver disease. Metformin is an AMPK activator that has been shown to have lipid lowering effects. The purpose of this study was to investigate whether metformin had a beneficial effect on lipid accumulation in the pathogenesis of ALD.Methods: AML12 cells and male C57BL/6 mice were used to establish ALD models in vitro and in vivo, respectively. The effects of metformin on hepatocyte lipid accumulation and ALD progression in mice were detected. The role of LKB1/AMPK/ACC axis in metformin against ethanol-induced lipid accumulation was evaluated by siRNA and AAV-shRNA interference.Results: Metformin reduced the ethanol-induced lipid accumulation in AML12 cells through activating AMPK/ACC and SREBP1c and inhibiting PPARα. In addition, compared with control mice, metformin treatment inhibited ethanol-induced liver adipose accumulation and the increase of ALT and AST in serum. Interference with LKB1 attenuated the effect of metformin on ethanol-induced lipid accumulation both in vitro and in vivo.Conclusion: Metformin protects against lipid formation in ALD by activating LKB1/AMPK/ACC axis. Thus, metformin has therapeutic potential for the prevention of ALD.

Therapeutic Potential of Melatonin in the Regulation of MiR-148a-3p and Angiogenic Factors in Breast Cancer

MicroRNA ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 237-247 ◽  
Author(s):  
Jéssica Zani Lacerda ◽  
Lívia Carvalho Ferreira ◽  
Beatriz Camargo Lopes ◽  
Andrés Felipe Aristizábal-Pachón ◽  
Marcio Chaim Bajgelman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Real Time ◽  
Tumor Cells ◽  
Therapeutic Potential ◽  
Xenograft Model ◽  
Angiogenic Factors ◽  
Migration And Invasion ◽  
Gene And Protein Expression

Background: The high mortality rate of breast cancer is related to the occurrence of metastasis, a process that is promoted by tumor angiogenesis. MicroRNAs are small molecules of noncoding mRNA that play a key role in gene regulation and are directly involved in the progression and angiogenesis of various tumor types, including breast cancer. Several miRNAs have been described as promoters or suppressors angiogenesis and may be associated with tumor growth and metastasis. Melatonin is an oncostatic agent with a capacity of modifying the expression of innumerable genes and miRNAs related to cancer. Objective: The aim of this study was to evaluate the role of melatonin and the tumor suppressor miR- 148a-3p on angiogenesis of breast cancer. Method: MDA-MB-231 cells were treated with melatonin and modified with the overexpression of miR-148a-3p. The relative quantification in real-time of miR-148a-3p, IGF-IR and VEGF was performed by real-time PCR. The protein expression of these targets was performed by immunocytochemistry and immunohistochemistry. Survival, migration and invasion rates of tumor cells were evaluated. Finally, the xenograft model of breast cancer was performed to confirm the role of melatonin in the tumor. Results: The melatonin was able to increase the gene level of miR-148a-3p and decreased the gene and protein expression of IGF-1R and VEGF, both in vitro and in vivo. In addition, it also had an inhibitory effect on the survival, migration and invasion of breast tumor cells. Conclusion: Our results confirm the role of melatonin in the regulation of miR-148a-3p and decrease of angiogenic factors.

scholarly journals Schisantherin A Attenuates Neuroinflammation in Activated Microglia: Role of Nrf2 Activation Through ERK Phosphorylation

2018 ◽  
Vol 47 (5) ◽  
pp. 1769-1784 ◽  
Author(s):  
Chuwen Li ◽  
Tongkai Chen ◽  
Hefeng Zhou ◽  
Chao Zhang ◽  
Yu Feng ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Therapeutic Potential ◽  
Erk Phosphorylation ◽  
Nrf2 Activation ◽  
Antioxidative Effects ◽  
Underlying Mechanisms ◽  
Oxidative Effects ◽  
Anti Inflammation ◽  
Schisantherin A

Background/Aims: In the present study, we investigated whether schisantherin A (StA) had anti-inflammatory effects under neuroinflammatory conditions. Methods: The effects of StA and its underlying mechanisms were examined in lipopolysaccharide (LPS)-activated BV-2 microglial cells by ELISA, qPCR, EMSA, Western blot, and IHC. Results: Firstly, we found that StA inhibited the inflammatory response in LPS-activated BV-2 microglia. Secondly, we found that StA suppressed LPS-induced activation of NF-κB via interfering with degradation of IκB and phosphorylation of IκB, IKK, PI3K/Akt, JNK, and p38 MAPK. Thirdly, StA conferred indirect antioxidative effects via quenching ROS and promoted expression of antioxidant enzymes, including HO-1 and NQO-1, via stimulating activation of Nrf2 pathways. Finally, we demonstrated that anti-neuroinflammatory actions of StA were dependent on ERK phosphorylation-mediated Nrf2 activation. Conclusion: StA induced ERK phosphorylation-mediated Nrf2 activation, which contributed to its anti-inflammation and anti-oxidation. The anti-neuroinflammatory and anti-oxidative effects of StA may show preventive therapeutic potential for various neuroinflammatory disorders.

scholarly journals Fatty acid oxidation: driver of lymph node metastasis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mao Li ◽  
Hong-chun Xian ◽  
Ya-Jie Tang ◽  
Xin-hua Liang ◽  
Ya-ling Tang
Keyword(s):  
Lymph Node ◽  
Fatty Acid ◽  
Lymph Node Metastasis ◽  
Tumor Cells ◽  
Fatty Acid Oxidation ◽  
Tumor Metastasis ◽  
Cancer Metabolism ◽  
Acid Oxidation ◽  
Node Metastasis

AbstractFatty acid oxidation (FAO) is the emerging hallmark of cancer metabolism because certain tumor cells preferentially utilize fatty acids for energy. Lymph node metastasis, the most common way of tumor metastasis, is much indispensable for grasping tumor progression, formulating therapy measure and evaluating tumor prognosis. There is a plethora of studies showing different ways how tumor cells metastasize to the lymph nodes, but the role of FAO in lymph node metastasis remains largely unknown. Here, we summarize recent findings and update the current understanding that FAO may enable lymph node metastasis formation. Afterward, it will open innovative possibilities to present a distinct therapy of targeting FAO, the metabolic rewiring of cancer to terminal cancer patients.

scholarly journals The essential role of PRAK in tumor metastasis and its therapeutic potential

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuqing Wang ◽  
Wei Wang ◽  
Haoming Wu ◽  
Yu Zhou ◽  
Xiaodan Qin ◽  
...  
Keyword(s):  
Tumor Metastasis ◽  
Essential Role ◽  
Therapeutic Potential ◽  
Lung Metastases ◽  
Breast Cancers ◽  
Loss Of Function ◽  
Apparent Effect ◽  
Metastatic Risk ◽  
Pronounced Inhibition

AbstractMetastasis is the leading cause of cancer-related death. Despite the recent advancements in cancer treatment, there is currently no approved therapy for metastasis. The present study reveals a potent and selective activity of PRAK in the regulation of tumor metastasis. While showing no apparent effect on the growth of primary breast cancers or subcutaneously inoculated tumor lines, Prak deficiency abrogates lung metastases in PyMT mice or mice receiving intravenous injection of tumor cells. Consistently, PRAK expression is closely associated with metastatic risk in human cancers. Further analysis indicates that loss of function of PRAK leads to a pronounced inhibition of HIF-1α protein synthesis, possibly due to reduced mTORC1 activities. Notably, pharmacological inactivation of PRAK with a clinically relevant inhibitor recapitulates the anti-metastatic effect of Prak depletion, highlighting the therapeutic potential of targeting PRAK in the control of metastasis.

Tumor metastasis in an orthotopic murine model of head and neck cancer: Possible role of TGF-beta 1 secreted by the tumor cells

2006 ◽  
Vol 97 (5) ◽  
pp. 1036-1051 ◽  
Author(s):  
Santanu Dasgupta ◽  
Malaya Bhattacharya-Chatterjee ◽  
Bert W. O'Malley ◽  
Sunil K. Chatterjee
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Tumor Cells ◽  
Neck Cancer ◽  
Murine Model ◽  
Tumor Metastasis ◽  
Tgf Beta

scholarly journals Fluid Shear Stress Induces EMT of Circulating Tumor Cells via JNK Signaling in Favor of Their Survival during Hematogenous Dissemination

2020 ◽  
Vol 21 (21) ◽  
pp. 8115
Author(s):  
Ying Xin ◽  
Keming Li ◽  
Mo Yang ◽  
Youhua Tan
Keyword(s):  
Shear Stress ◽  
Shear Flow ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Tumor Metastasis ◽  
Fluid Shear Stress ◽  
Fluid Shear ◽  
Jnk Signaling ◽  
Hematogenous Dissemination

Tumor cells metastasize to distal organs mainly through hematogenous dissemination, where they experience considerable levels of fluid shear stress. Epithelial–mesenchymal transition (EMT) plays a critical role in tumor metastasis. However, how fluid shear stress influences the EMT phenotype of circulating tumor cells (CTCs) in suspension has not been fully understood. The role of shear-induced EMT in cell survival under blood shear flow remains unclear. This study shows that the majority of breast CTCs underwent apoptosis under shear flow and the surviving cells exhibited mesenchymal phenotype, suggesting that fluid shear stress induces EMT. Mechanistically, fluid shear stress-activated Jun N-terminal kinase (JNK) signaling, inhibition/activation of which suppressed/promoted the EMT phenotype. In particular, shear flow facilitated the JNK-dependent transition of epithelial CTCs into the mesenchymal status and maintained the pre-existing mesenchymal cells. Importantly, the induction of EMT suppressed the pro-apoptosis gene p53 upregulated modulator of apoptosis (PUMA) and enhanced the survival of suspended CTCs in fluid shear stress, which was rescued by overexpressing PUMA or silencing JNK signaling, suggesting that shear-induced EMT promotes CTC survival through PUMA downregulation and JNK activation. Further, the expressions of EMT markers and JUN were correlated with poor patient survival. In summary, our findings have demonstrated that fluid shear stress induces EMT in suspended CTCs via JNK signaling that promotes their survival in shear flow. This study thus unveils a new role of blood shear stress in CTC survival and facilitates the development of novel therapeutics against tumor metastasis.

Role of chemokines in proteinuric kidney disorders

2014 ◽  
Vol 16 ◽  
Author(s):  
Juan Antonio Moreno ◽  
Sara Moreno ◽  
Alfonso Rubio-Navarro ◽  
Carmen Gómez-Guerrero ◽  
Alberto Ortiz ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Recent Progress ◽  
Inflammatory Cell ◽  
Therapeutic Potential ◽  
Clinical Implications ◽  
Tubular Epithelial Cells ◽  
Cell Recruitment ◽  
Inflammatory Cell Recruitment ◽  
Progression Of Renal Disease

Experimental and human studies have shown that proteinuria contributes to the progression of renal disease. Overexposure to filtered proteins promotes the expression and release of chemokines by tubular epithelial cells, thus leading to inflammatory cell recruitment and renal impairment. This review focuses on recent progress in cellular and molecular understanding of the role of chemokines in the pathogenesis of proteinuria-induced renal injury, as well as their clinical implications and therapeutic potential.

Role of Melatonin in the Inflammatory Process and its Therapeutic Potential

2018 ◽  
Vol 24 (14) ◽  
pp. 1563-1588 ◽  
Author(s):  
Livia Carrascal ◽  
Pedro Nunez-Abades ◽  
Antonio Ayala ◽  
Mercedes Cano
Keyword(s):  
Inflammatory Process ◽  
Therapeutic Agent ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Mitochondrial Homeostasis ◽  
Therapeutic Value ◽  
Bowel Diseases ◽  
The One ◽  
The Brain

Melatonin is an indolamine synthesized and secreted by the pineal gland along with other extrapineal sources including immune system cells, the brain, skin and the gastrointestinal tract. Growing interest in this compound as a potential therapeutic agent in several diseases stems from its pleiotropic effects. Thus, melatonin plays a key role in various physiological activities that include regulation of circadian rhythms, immune responses, the oxidative process, apoptosis or mitochondrial homeostasis. Most of these processes are altered during inflammatory pathologies, among which neurodegenerative and bowel diseases stand out. Therapeutic assays with melatonin indicate that it has a beneficial therapeutic value in the treatment of several inflammatory diseases, such as Alzheimer, Amiotrophic Lateral, Multiple Sclerosis and Huntigton´s disease as well as ulcerative colitis. However, contradictory effects have been demonstrated in Parkinson´s and Chron´s diseases, which, in some cases, the reported effects were beneficial while in others the pathology was exacerbated. These various results may be related to several factors. In the first place, it should be taken into account that at the beginning of the inflammation phase there is a production of reactive oxygen species (ROS) that should not be blocked by exclusively antioxidant molecules, since, on the one hand, it would be interfering with the action of neutrophils and macrophages and, on the other, with the apoptotic signals activated by ROS. It is also important to keep in mind that the end result of an anti-inflammatory molecule will depend on the degree of inflammation or whether or not it has been resolved and has therefore become chronic. In this review we present the use of melatonin in the control of inflammation underlying the above mentioned diseases. These actions are mediated through their receptors but also with their direct antioxidant action and melatonin's ability to break the vicious cycle of ROSinflammation. This review is aimed at evaluating the effect of melatonin on activity of the inflammatory process and at its immunomodulator effects.

scholarly journals Targets (Metabolic Mediators) of Therapeutic Importance in Pancreatic Ductal Adenocarcinoma

2020 ◽  
Vol 21 (22) ◽  
pp. 8502
Author(s):  
Vikrant Rai ◽  
Swati Agrawal
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Cells ◽  
Therapeutic Potential ◽  
Therapeutic Targets ◽  
The United States ◽  
Metabolic Reprogramming ◽  
Ductal Adenocarcinoma ◽  
Advanced Stages ◽  
Novel Therapeutic

Pancreatic ductal adenocarcinoma (PDAC), an extremely aggressive invasive cancer, is the fourth most common cause of cancer-related death in the United States. The higher mortality in PDAC is often attributed to the inability to detect it until it has reached advanced stages. The major challenge in tackling PDAC is due to its elusive pathology, minimal effectiveness, and resistance to existing therapeutics. The aggressiveness of PDAC is due to the capacity of tumor cells to alter their metabolism, utilize the diverse available fuel sources to adapt and grow in a hypoxic and harsh environment. Therapeutic resistance is due to the presence of thick stroma with poor angiogenesis, thus making drug delivery to tumor cells difficult. Investigating the metabolic mediators and enzymes involved in metabolic reprogramming may lead to the identification of novel therapeutic targets. The metabolic mediators of glucose, glutamine, lipids, nucleotides, amino acids and mitochondrial metabolism have emerged as novel therapeutic targets. Additionally, the role of autophagy, macropinocytosis, lysosomal transport, recycling, amino acid transport, lipid transport, and the role of reactive oxygen species has also been discussed. The role of various pro-inflammatory cytokines and immune cells in the pathogenesis of PDAC and the metabolites involved in the signaling pathways as therapeutic targets have been previously discussed. This review focuses on the therapeutic potential of metabolic mediators in PDAC along with stemness due to metabolic alterations and their therapeutic importance.

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