Comparative study of curcumin and curcumin formulated in a solid dispersion: Evaluation of their antigenotoxic effects

Mendonça, Leonardo Meneghin; Machado, Carla da Silva; Teixeira, Cristiane Cardoso Correia; Freitas, Luís Alexandre Pedro de; Bianchi, Marcelo; Antunes, Lusânia Maria Greggi

doi:10.1590/s1415-475738420150046

Cited by 19 publications

(16 citation statements)

References 48 publications

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“…Meanwhile, curcumin was not toxic but less effective. A poor aqueous solubility, low bioavailability, and intense staining color of curcumin have been reported as problems 48 . Therefore, we selected temsirolimus as a candidate of the optimal mTORC1 inhibitor for human disc disease [ Fig.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of mTORC1 but not mTORC2 protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism through Akt and autophagy induction

Kakiuchi

Yurube

Kakutani

et al. 2019

Osteoarthritis and Cartilage

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Objective: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates nutrients to execute cell growth. We hypothesized that mTOR is influential in the intervertebral discdlargest avascular, low-nutrient organ. Our objective was to identify the optimal mTOR inhibitor for treating human degenerative disc disease. Design: mTOR complex 1 (mTORC1) regulates p70/ribosomal S6 kinase (p70/S6K), negatively regulates autophagy, and is controlled by Akt. Akt is controlled by phosphatidylinositol 3-kinase (PI3K) and mTOR complex 2 (mTORC2). mTORC1 inhibitorsdrapamycin, temsirolimus, everolimus, and curcumin, mTORC1&mTORC2 inhibitordINK-128, PI3K&mTOR inhibitordNVP-BEZ235, and Akt inhibitordMK-2206dwere applied to human disc nucleus pulposus (NP) cells. mTOR signaling, autophagy, apoptosis, senescence, and matrix metabolism were evaluated. Results: mTORC1 inhibitors decreased p70/S6K but increased Akt phosphorylation, promoted autophagy with light chain 3 (LC3)-II increases and p62/sequestosome 1 (p62/SQSTM1) decreases, and suppressed pro-inflammatory interleukin-1 beta (IL-1b)-induced apoptotic terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positivity (versus rapamycin, 95% confidence interval (CI) À0.431 to À0.194; temsirolimus, 95% CI À0.529 to À0.292; everolimus, 95% CI À0.477 to À0.241; curcumin, 95% CI À0.248 to À0.011) and poly (ADP-ribose) polymerase (PARP) and caspase-9 cleavage, senescent senescence-associated beta-galactosidase (SA-b-gal) positivity (versus rapamycin, 95% CI À0.437 to À0.230; temsirolimus, 95% CI À0.534 to À0.327; everolimus, 95% CI À0.485 to À0.278; curcumin, 95% CI À0.210 to À0.003) and p16/INK4A expression, and catabolic matrix metalloproteinase (MMP) release and activation. Meanwhile, dual mTOR inhibitors decreased p70/S6K and Akt phosphorylation without enhanced autophagy and suppressed apoptosis, senescence, and matrix catabolism. MK-2206 counteracted protective effects of temsirolimus. Additional disc-tissue analysis found relevance of mTOR signaling to degeneration grades. Conclusion: mTORC1 inhibitorsdnotably temsirolimus with an improved water solubilitydbut not dual mTOR inhibitors protect against inflammation-induced apoptosis, senescence, and matrix catabolism in human disc cells, which depends on Akt and autophagy induction.

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Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of mTORC1 but not mTORC2 protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism through Akt and autophagy induction

Kakiuchi

Yurube

Kakutani

et al. 2019

Osteoarthritis and Cartilage

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“…Rapamycin, temsirolimus, and everolimus showed similar mTORC1 inhibition effects; however, temsirolimus appeared to be the most effective, possibly as a result of improved water solubility, which also enables intravenous administration, whereas the other inhibitors are limited to oral administration . In contrast, curcumin was not toxic but was less effective, and poor aqueous solubility, low bioavailability, and intense color‐staining are limitations associated with curcumin …”

Section: Pharmacological Mtor Signaling Modulation In Human Disc Cellsmentioning

confidence: 99%

“…105,106 In contrast, curcumin was not toxic but was less effective, and poor aqueous solubility, low bioavailability, and intense color-staining are limitations associated with curcumin. 108…”

mentioning

confidence: 99%

Autophagy and mTOR signaling during intervertebral disc aging and degeneration

et al. 2020

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Degenerative disc disease is a highly prevalent, global health problem that represents the primary cause of back pain and is associated with neurological disorders, including radiculopathy, myelopathy, and paralysis, resulting in worker disability and socioeconomic burdens. The intervertebral disc is the largest avascular organ in the body, and degeneration is suspected to be linked to nutritional deficiencies. Autophagy, the process through which cells self‐digest and recycle damaged components, is an important cell survival mechanism under stress conditions, especially nutrient deprivation. Autophagy is negatively controlled by the mammalian target of rapamycin (mTOR) signaling pathway. mTOR is a serine/threonine kinase that detects nutrient availability to trigger the activation of cell growth and protein synthesis pathways. Thus, resident disc cells may utilize autophagy and mTOR signaling to cope with harsh low‐nutrient conditions, such as low glucose, low oxygen, and low pH. We performed rabbit and human disc cell and tissue studies to elucidate the involvement and roles played by autophagy and mTOR signaling in the intervertebral disc. In vitro serum and nutrient deprivation studies resulted in decreased disc cell proliferation and metabolic activity and increased apoptosis and senescence, in addition to increased autophagy. The selective RNA interference‐mediated and pharmacological inhibition of mTOR complex 1 (mTORC1) was protective against inflammation‐induced disc cellular apoptosis, senescence, and extracellular matrix catabolism, through the induction of autophagy and the activation of the Akt‐signaling network. Although temsirolimus, a rapamycin derivative with improved water solubility, was the most effective mTORC1 inhibitor tested, dual mTOR inhibitors, capable of blocking multiple mTOR complexes, did not rescue disc cells. In vivo, high levels of mTOR‐signaling molecule expression and phosphorylation were observed in human intermediately degenerated discs and decreased with age. A mechanistic understanding of autophagy and mTOR signaling can provide a basis for the development of biological therapies to treat degenerative disc disease.

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“… 2013 ) and to have antigenotoxic and anti-inflammatory activities in rats (Mendonca et al. 2015 ; Teixeira et al. 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Curcumin suppresses inflammatory cytokines and heat shock protein 70 release and improves metabolic parameters during experimental sepsis

Silva

Catalão

Felippotti

et al. 2016

Pharmaceutical Biology

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Context: Curcumin has been reported to have anti-inflammatory, antioxidant and hypoglycaemic properties, besides reducing mortality in sepsis.Objective: This study evaluates the biological activities of a curcumin dispersion formulated by spray-drying in experimental sepsis.Materials and methods: Male Wistar rats were subjected to sepsis by caecal ligation and puncture (CLP), controls were sham operated. The animals were treated with curcumin dispersion (100 mg/kg, p.o.) or water for 7 days prior to CLP and at 2 h after surgery. One group was used to analyze curcumin absorption through HPLC; another had the survival rate assessed during 48 h; and from a third group, blood was collected by decapitation to analyze metabolic and inflammatory parameters.Results: The plasma curcumin levels reached 2.5 ng/mL at 4 h, dropped significantly (p < 0.001) at 6 h (1.2 ng/mL), and were undetectable at 24 h in both groups. Curcumin temporarily increased the survival rate of the septic rats by 20%. Moreover, it attenuated glycaemia (p < 0.05) and volemia (p < 0.05) alterations typically observed during sepsis, and decreased the levels of the proinflammatory cytokines IL-1β and IL-6 in plasma (p < 0.001) and peritoneal lavage fluid (p < 0.05) of septic rats. Serum HSP70 levels were decreased (p < 0.01) at 24 h after CLP.Discussion and conclusion: Our results show that the curcumin dispersion dose employed was not detrimental to the septic rats. In fact, it temporarily increased their survival rate, improved important metabolic parameters, reduced proinflammatory cytokines and HSP70 production.

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Comparative study of curcumin and curcumin formulated in a solid dispersion: Evaluation of their antigenotoxic effects

Cited by 19 publications

References 48 publications

Pharmacological inhibition of mTORC1 but not mTORC2 protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism through Akt and autophagy induction

Pharmacological inhibition of mTORC1 but not mTORC2 protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism through Akt and autophagy induction

Autophagy and mTOR signaling during intervertebral disc aging and degeneration

Curcumin suppresses inflammatory cytokines and heat shock protein 70 release and improves metabolic parameters during experimental sepsis

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