scholarly journals Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-32 ◽  
Author(s):  
Marco Malavolta ◽  
Massimo Bracci ◽  
Lory Santarelli ◽  
Md Abu Sayeed ◽  
Elisa Pierpaoli ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Therapeutic Potential ◽  
Epigallocatechin Gallate ◽  
Natural Compounds ◽  
Related Factor ◽  
Phenethyl Isothiocyanate ◽  
Toxic Compounds ◽  
In Vivo Effects

The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms) that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.

scholarly journals Discrete Role for Cytosolic Phospholipase A2α in Platelets

2002 ◽  
Vol 196 (3) ◽  
pp. 349-357 ◽  
Author(s):  
Dennis A. Wong ◽  
Yoshihiro Kita ◽  
Naonori Uozumi ◽  
Takao Shimizu
Keyword(s):  
Therapeutic Potential ◽  
Genetically Engineered ◽  
Collagen Receptors ◽  
Cytosolic Phospholipase ◽  
Genetically Engineered Mice ◽  
Cytosolic Pla2 ◽  
In Vivo Effects ◽  
Deficient Mice

Among several different types of phospholipase A2 (PLA2), cytosolic PLA2 (cPLA2)α and group IIA (IIA) secretory PLA2 (sPLA2) have been studied intensively. To determine the discrete roles of cPLA2α in platelets, we generated two sets of genetically engineered mice (cPLA2α−/−/sPLA2-IIA−/− and cPLA2α−/−/sPLA2-IIA+/+) and compared their platelet function with their respective wild-type C57BL/6J mice (cPLA2α+/+/sPLA2-IIA−/−) and C3H/HeN (cPLA2α+/+/sPLA2-IIA+/+). We found that cPLA2α is needed for the production of the vast majority of thromboxane (TX)A2 with collagen stimulation of platelets. In cPLA2α-deficient mice, however, platelet aggregation in vitro is only fractionally decreased because small amounts of TX produced by redundant phospholipase enzymes sufficiently preserve aggregation. In comparison, adenosine triphosphate activation of platelets appears wholly independent of cPLA2α and sPLA2-IIA for aggregation or the production of TX, indicating that these phospholipases are specifically linked to collagen receptors. However, the lack of high levels of TX limiting vasoconstriction explains the in vivo effects seen: increased bleeding times and protection from thromboembolism. Thus, cPLA2α plays a discrete role in the collagen-stimulated production of TX and its inhibition has a therapeutic potential against thromboembolism, with potentially limited bleeding expected.

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.

Nanoencapsulated dietary polyphenols for cancer prevention and treatment: successes and challenges

Nanomedicine ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. 1147-1162 ◽  
Author(s):  
Shams Tabrez ◽  
Nasimudeen R Jabir ◽  
Vaqar Mustafa Adhami ◽  
Mohammad Imran Khan ◽  
Mohammed Moulay ◽  
...  
Keyword(s):  
Cancer Prevention ◽  
Therapeutic Potential ◽  
Epigallocatechin Gallate ◽  
Systemic Delivery ◽  
Dietary Polyphenols ◽  
Prevention And Treatment ◽  
In Vivo Animal Models ◽  
Successes And Challenges

Many dietary polyphenols have been investigated for their therapeutic potential either as single agents or in combinations. Despite the significant anticancer potential of these polyphenols in in vitro cell culture and in vivo animal models, their clinical applications have been limited because of challenges such as ineffective systemic delivery, stability and low bioavailability. Nanoencapsulation of these polyphenols could prolong circulation, improve localization, enhance efficacy and reduce the chances of multidrug resistance. This review summarized the use of various polyphenols especially epigallocatechin gallate, quercetin, curcumin and resveratrol as nanoformulations for cancer prevention and treatment. Despite some success, more research is warranted to design a nanoencapsulated combination of polyphenols, effective in in vitro, in vivo and human systems.

scholarly journals Senolytic Activity of Selected NRF2-Interacting Natural Compounds

2020 ◽  
Author(s):  
Rahagir Salekeen ◽  
Ayesha Ashraf ◽  
Ahsan Habib
Keyword(s):  
Systematic Review ◽  
Cell Cycle ◽  
Related Factor ◽  
Nuclear Factor ◽  
Plant Metabolites ◽  
Cycle Arrest ◽  
Suppressor Mechanism ◽  
In Vivo Effects

Cellular senescence is a process that results in irreversible cell-cycle arrest acting as an autonomous tumor-suppressor mechanism. During senescence, cells develop distinctive metabolic and signaling features, together referred to as the senescence-associated secretory phenotypes (SASPs). The SASPs are implicated in several aging related pathologies, including various disorders and malignancies. Senolytics are rejuvenative compounds that eliminate harmful SASPs, which accumulate by evading immunosurveillance and activate inflammatory pathways. Several senolytic compounds, especially dietary plant metabolites that activate the cytoprotective NRF2 (nuclear factor erythroid derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been shown to target senescent cells that escape immunosurveillance. In this study, we have performed a systematic review of in vitro and in vivo effects of selected NRF2-interacting phytocompounds: quercetin, fisetin, hesperidin, epicatechin, metformin and resveratrol on senescent cells and evaluated their prospective utilization in gerotherapeutics.

scholarly journals Chitosan nanoparticles potentiate the in vitro and in vivo effects of curcumin and other natural compounds

2020 ◽  
Vol 28 ◽  
Author(s):  
Vanessa Falchetti Lopes ◽  
Camila Nascimento Giongo ◽  
Laís de Almeida Campos ◽  
Wolf-Rainer Abraham ◽  
Rubiana Mara Mainardes ◽  
...  
Keyword(s):  
Biological Effects ◽  
Chitosan Nanoparticles ◽  
Natural Compounds ◽  
Biological Properties ◽  
Cellular Transport ◽  
Naturally Occurring ◽  
Nanostructured Systems ◽  
In Vivo Effects

: The development of biodegradable nanoparticles is an important tool for the biological transport of chemical compounds. The nanoencapsulation reduces the biopharmaceutical and pharmacokinetic drawbacks of compounds and enhances their biological properties. Naturally occurring polymers such as proteins and polysaccharides have been widely applied in the development of nanostructured systems of several therapeutic agents. Among them is chitosan, a crustaceancarapace-chitin derived biopolymer. In addition to its biocompatibility and biodegradability, chitosan is known for its mucoadhesion properties. Chitosan-based nanostructured systems potentiate most of aspects of the loaded drugs, including cellular transport and other biological effects. The use of chitosan nanoparticles enhances permeation, stability, and bioactivity of natural compounds. In this review, an overview of the main features of chitosan nanoparticles that improved in vitro and in vivo effects of bioactive natural molecules is given, emphasizing the results obtained with curcumin.

scholarly journals The Protective Roles and Molecular Mechanisms of Troxerutin (Vitamin P4) for the Treatment of Chronic Diseases: A Mechanistic Review

2020 ◽  
Vol 19 (1) ◽  
pp. 97-110
Author(s):  
Mohammad Zamanian ◽  
Gholamreza Bazmandegan ◽  
Antoni Sureda ◽  
Eduardo Sobarzo-Sanchez ◽  
Hasan Yousefi-Manesh ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Therapeutic Potential ◽  
Acetylcholinesterase Activity ◽  
Nuclear Factor Κb ◽  
In Vivo Studies ◽  
Related Factor ◽  
Nuclear Factor

: Troxerutin (TRX), a semi-synthetic bioflavonoid derived from rutin, has been reported to exert several pharmacological effects including antioxidant, anti-inflammatory, antihyperlipidemic, and nephroprotective. However, the related molecular details and its mechanisms remain poorly understood. In the present review, we presented evidences from the diversity in vitro and in vivo studies on the therapeutic potential of TRX against neurodegenerative, diabetes, cancer and cardiovascular diseases with the purpose to find molecular pathways related to the treatment efficacy. TRX has a beneficial role in many diseases through multiple mechanisms including, increasing antioxidant enzymes and reducing oxidative damage, decreasing in proapoptotic proteins (APAF-1, BAX, caspases-9 and-3) and increasing the antiapoptotic BCL-2, increasing the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and downregulating the nuclear factor κB (NFκ). TRX also reduces acetylcholinesterase activity and upregulates phosphoinositide 3- kinase/Akt signaling pathway in Alzheimer’s disease models. Natural products such as TRX may develop numerous and intracellular pathways at several steps in the treatment of many diseases. Molecular mechanisms of action are revealing novel, possible combinational beneficial approaches to treat multiple pathological conditions.

scholarly journals Nuclear factor erythroid 2-related factor 2 activation mediates hyperhomocysteinemia-associated lipolysis suppression in adipocytes

2018 ◽  
Vol 243 (11) ◽  
pp. 926-933 ◽  
Author(s):  
Xin Li ◽  
Yuhong Cheng ◽  
Xiuli Zhong ◽  
Bing Zhang ◽  
Zhiwei Bao ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Epigallocatechin Gallate ◽  
Underlying Mechanism ◽  
Control Group ◽  
Related Factor ◽  
Nuclear Factor ◽  
Glycerol Release ◽  
Nrf2 Activation

Hyperhomocysteinemia (HHcy) is associated with suppressed lipolytic response in adipocytes/adipose tissue, however, the underlying mechanism remains to be extensively studied. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcriptional factor regulating antioxidant generation, has been recently reported to mediate lipid metabolism. Employing both fully differentiated 3T3-L1 adipocytes and male C57BL/6 mice, in the present study, we investigated the potential involvement of Nrf2 activation in HHcy-mediated lipolytic suppression. Our results showed that homocysteine (Hcy) treatment resulted in suppressed lipolysis, evidenced by increased intracellular triglyceride (TG) accumulation, decreased glycerol and free fatty acid (FFA) in fully differentiated 3T3-L1 adipocytes. Interestingly, Hcy exposure was associated with Nrf2 activation in adipocytes. Further studies showed that Nrf2 knockdown via siRNA transfection ameliorated Hcy-induced glycerol release in adipocytes. On the contrary, Nrf2 activators, epigallocatechin gallate (EGCG) and tert-butylhydroquinone (t-BHQ), increased intracellular TG content and decreased glycerol release in adipocytes. Importantly, our in vitro observations were corroborated by our in vivo findings, in which Hcy feeding (0.1% wt/vol) for four weeks induced Nrf2 expression in adipose tissue and lowered circulating FFA and glycerol levels in mice. Furthermore, EGCG injection (5 mg/kg/d) decreased circulating glycerol levels in comparison to the control group in mice. In conclusion, these results indicated that Nrf2 activation in response to HHcy plays an important role in mediating Hcy-suppressed lipolysis in adipocytes.

In vitro and in vivo effects of 17β-N-(4-phenylcarbamoyl) androst-4-en-3-one derivatives as 5a-reductase inhibitors and on androgen-dependent glands

2020 ◽  
Vol 16 ◽  
Author(s):  
Marisa Cabeza ◽  
Lucero Bautista ◽  
Eugene Bratoeff ◽  
Juan Soriano ◽  
Yvonne Heuze
Keyword(s):  
Therapeutic Potential ◽  
Hamster Model ◽  
Toxicological Effects ◽  
Reductase Inhibitors ◽  
Ic50 Values ◽  
Prostate Diseases ◽  
In Vivo Effects ◽  
Vitro Effect

Background: 5α-Reductase inhibitors have proven useful for the treatment of prostate diseases, which can result from the unregulated activity of the 5α-reductase enzyme. This study was focused on determining the activity of four different derivatives of 17β-phenyl carbamoyl-androst-4-en-3-one 1–4 as inhibitors of 5α-reductase (5RD5A), to improve on the effect of current drugs. Methods: In vitro effect of compounds 1-4 on the activity of the human prostate enzyme, 5α-reductase, was determined measuring IC50 values, the concentration of a compound that inhibits the activity of 5RD5A2 by 50%. In vivo, the pharmacological effects of compounds 1-4 were identified in a hamster model of prostate hypertrophy. Results: The steroidal 17β-carboxamides 1, 3, and 4 (IC50 = 5±0.5, 0.112±0.045, 0.167±0.056 nM) significantly inhibited the in vitro activity of the 5RD5A2 enzyme with higher potency than finasteride, which is a drug known as a specific 5RD5A2 inhibitor (IC50 = 8.5±0.3 nM). Compounds 1, 3, and 4 were more potent than finasteride to decrease the size of hamster flank organs in castrated animals treated with testosterone. Also, compounds 1–4 were more effective than finasteride itself to reduce the weight of the prostate in the hamster model, without producing toxicological effects during the six days of treatment. Conclusion: In conclusion, the steroidal 17β-carboxamides 1–4 were suitable inhibitors of human 5RD5A2 activity, in addition to being able to reduce prostate weight without causing toxicity. These steroids could, therefore, have promising therapeutic potential for the treatment of benign prostatic hyperplasia.

scholarly journals Bioactive Compounds in Oxidative Stress-Mediated Diseases: Targeting the NRF2/ARE Signaling Pathway and Epigenetic Regulation

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1859
Author(s):  
Muthu Thiruvengadam ◽  
Baskar Venkidasamy ◽  
Umadevi Subramanian ◽  
Ramkumar Samynathan ◽  
Mohammad Ali Ali Shariati ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pathological Condition ◽  
Epigallocatechin Gallate ◽  
The Body ◽  
Related Factor ◽  
In Vivo Models ◽  
Dietary Phytochemicals ◽  
Antioxidant Defense Systems

Oxidative stress is a pathological condition occurring due to an imbalance between the oxidants and antioxidant defense systems in the body. Nuclear factor E2-related factor 2 (NRF2), encoded by the gene NFE2L2, is the master regulator of phase II antioxidant enzymes that protect against oxidative stress and inflammation. NRF2/ARE signaling has been considered as a promising target against oxidative stress-mediated diseases like diabetes, fibrosis, neurotoxicity, and cancer. The consumption of dietary phytochemicals acts as an effective modulator of NRF2/ARE in various acute and chronic diseases. In the present review, we discussed the role of NRF2 in diabetes, Alzheimer’s disease (AD), Parkinson’s disease (PD), cancer, and atherosclerosis. Additionally, we discussed the phytochemicals like curcumin, quercetin, resveratrol, epigallocatechin gallate, apigenin, sulforaphane, and ursolic acid that have effectively modified NRF2 signaling and prevented various diseases in both in vitro and in vivo models. Based on the literature, it is clear that dietary phytochemicals can prevent diseases by (1) blocking oxidative stress-inhibiting inflammatory mediators through inhibiting Keap1 or activating Nrf2 expression and its downstream targets in the nucleus, including HO-1, SOD, and CAT; (2) regulating NRF2 signaling by various kinases like GSK3beta, PI3/AKT, and MAPK; and (3) modifying epigenetic modulation, such as methylation, at the NRF2 promoter region; however, further investigation into other upstream signaling molecules like NRF2 and the effect of phytochemicals on them still need to be investigated in the near future.

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