Major Metabolite Of Curcumin Research Articles

Tetrahydrocurcumin targets TRIP13 inhibiting the interaction of TRIP13/USP7/c-FLIP to mediate c-FLIP ubiquitination in triple-negative breast cancer

IntroductionTriple-negative breast cancer (TNBC) has a high mortality rate and limited treatment options. Tetrahydrocurcumin (THC), a major metabolite of curcumin, has potential antitumor activities. However, the antitumor effects and mechanism of THC in TNBC remain elusive. ObjectivesTo investigate the mechanism of THC in combating TNBC by targeting TRIP13 to disrupt the interaction of the TRIP13/USP7/c-FLIP complex and mediate c-FLIP ubiquitination both in vitro and in vivo. MethodsApoptosis was measured by TUNEL and flow cytometry. Click chemistry-based target fishing, CETSA, DARTS, and SPR were used to identify direct target of THC. Protein interactions was examined using co-immunoprecipitation. The role of USP7 in THC-mediated c-FLIP ubiquitination was evaluated by in vitro deubiquitination assay. Human breast cancer clinical samples were employed to assess the expression of c-FLIP, TRIP13, and USP7. The impact of THC on USP7/TRIP13/c-FLIP was analyzed using co-immunoprecipitation, confocal microscopy, molecular docking and dynamics simulations. ResultsTHC effectively inhibits TNBC cell proliferation and tumor growth in vitro and in vivo without significant toxicity. Mechanistically, THC induces extrinsic apoptosis in TNBC primarily by promoting degradation of c-FLIP, a key negative regulator in the apoptotic pathway. Furthermore, utilizing click chemistry-based target fishing, we identified TRIP13, a component of the highly conserved AAA ATPase family, as a direct target of THC in combating TNBC. Interestingly, contrary to previous drug-target studies, the knockdown of TRIP13 further amplified the antitumor effects of THC. After in-depth investigation, it was revealed that TRIP13 forms a trimeric complex with USP7 and c-FLIP in TNBC cells. THC specifically targets TRIP13 to disrupt the interaction of TRIP13/USP7/c-FLIP, leading to the ubiquitination of c-FLIP, ultimately inducing extrinsic apoptosis. ConclusionsThese findings offer new insights into the novel molecular mechanisms of anti-TNBC effects of THC and present a promising targeted therapeutic strategy for TNBC.

The interaction mechanisms of tetrahydrocurcumin on alcohol dehydrogenase: Insights from enzymatic activity assays, spectroscopic methods and computational techniques

Tetrahydrocurcumin (THC), a major metabolite of curcumin, is renowned for its potent antioxidant and anti-inflammatory properties, including preventing liver injury from alcohol. Alcohol dehydrogenase (ADH), an essential enzyme in alcohol metabolism, is significant in the development of alcohol-induced diseases. Hence, enzymatic activity assays, spectroscopic methods, and computational techniques were employed in this study to explore their interaction. The results indicated that THC can competitively inhibit ADH activity, as inferred from the kinetic parameter values. Meanwhile, THC spontaneously entered the substrate-binding cavity of ADH to form a binary complex, and surrounded by Thr178, Leu57, Ile318, Leu141, Glu68, Leu116, Phe93, Val294, and Asp49. The Ka value of this binding was 1.724 ± 0.017 × 104 M−1 at 298 K. This binding process was driven by hydrogen bonds and van der Waals forces; additionally, the π electrons in THC were significant for the stability of the ADH-THC complex. The presence of THC led to a decrease in the α-helix content of ADH, resulting in a looser secondary structure. Furthermore, molecular dynamic simulations revealed that Glu68, Leu116, Phe93, Val294, and Asp49 made significant contributions to the binding process. The inhibition of ADH catalytic activity may be primarily attributed to the interaction between THC and the Val294 residue.

Novel tetrahydrocurcumin integrated mucoadhesive nanocomposite κ-carrageenan/xanthan gum sponges: a strategy for effective local treatment of oral cancerous and precancerous lesions

Oral cancer is one of the leading causes of death worldwide. Oral precancerous lesions (OPL) are the precursors of oral cancer, with varying degrees of progression. Tetrahydrocurcumin (THC) is a major metabolite of curcumin with superior anticancer properties against various types of cancer. However, THC’s clinical outcome is limited by its poor aqueous solubility. Herein, we developed novel mucoadhesive biopolymer-based composite sponges for buccal delivery of THC, exploiting nanotechnology and mucoadhesion for efficient prevention and treatment of oral cancer. Firstly, THC-nanocrystals (THC-NC) were formulated and characterized for subsequent loading into mucoadhesive composite sponges. The anticancer activity of THC-NC was assessed on a human tongue squamous carcinoma cell line (SCC-4). Finally, the chemopreventive activity of THC-NC loaded sponges (THC-NC-S) was examined in DMBA-induced hamster OPL. The selected THC-NC exhibited a particle size of 532.68 ± 13.20 nm and a zeta potential of −46.08 ± 1.12 mV. Moreover, THC-NC enhanced the anticancer effect against SCC-4 with an IC50 value of 80 µg/mL. THC-NC-S exhibited good mucoadhesion properties (0.24 ± 0.02 N) with sustained drug release, where 90% of THC was released over 4 days. Furthermore, THC-NC-S had a magnificent potential for maintaining high chemopreventive activity, as demonstrated by significant regression in the dysplasia degree and a decline in cyclin D1 (control: 40.4 ± 12.5, THC-NC-S: 12.07 ± 5.2), culminating in significant amelioration after 25 days of treatment. Conclusively, novel THC-NC-S represent a promising platform for local therapy of OPL, preventing their malignant transformation into cancer.

Oral administration of tetrahydrocurcumin entrapped hybrid colloid as a food additive ameliorates atopic dermatitis

• Tetrahydrocurcumin entrapped hybrid colloid as food additive was assembled and investigated. • The oral administration of TCCHC can alleviate the symptoms of atopic dermatitis in NC/Nga animal model. • TCCHC might be a promising new functional food additive for AD patients. Atopic dermatitis (AD) is a chronic relapsing inflammatory disease that is primarily characterized by pruritus. AD is a multifactorial disease related to epidermal barrier disruption, which mainly occurs during infancy and childhood. Although AD is usually associated with multiple causes, including elevated IgE levels and environmental factors, the pathogenesis and etiology of AD are not fully understood. Tetrahydrocurcumin (THC) is a major metabolite of curcumin, which has antioxidant, anti-inflammatory, chemopreventive, anti-bacterial, anti-dyslipidemic, and anti-aging activities, and is known to be effective against AD symptoms. To improve the efficiency of delivery in vivo , we synthesized a tetrahydrocurcumin-entrapped calcium carbonate hybrid colloid (TCCHC). To elucidate the efficacy of the TCCHC in an AD mouse model, we determined for the first time, whether TCCHC can attenuate AD in an in vivo NC/Nga mouse model. When applied subcutaneously into NC/Nga mice repeatedly treated with house dust mite antigens, TCCHC could reduce symptoms, such as clinical score, serum IgE levels, ear thickness, mast cell infiltration, and thymic stromal lymphopoietin (TSLP) and CD86+ cells in skin lesions. TCCHC also significantly reduced the gene expression of various inflammatory cytokines, such as interleukin (IL)-4, IL-5, and IL-13 in the serum of Nc/Nga mice. Altogether, these results suggest that TCCHC can alleviate the symptoms of AD and is a promising food additive for AD patients.

Hexahydrocurcumin ameliorates hypertensive and vascular remodeling in L-NAME-induced rats

Hexahydrocurcumin (HHC), a major metabolite of curcumin, possesses several biological activities such as antioxidant, anti-inflammation, and cardioprotective properties. This study aimed to investigate the effect of HHC on high blood pressure, vascular dysfunction, and remodeling induced by N-nitro L-arginine methyl ester (L-NAME) in rats. Male Wistar rats (200–250 g) received L-NAME (40 mg/kg) via drinking water for seven weeks. HHC at doses of 20, 40 or 80 mg/kg or enalapril 10 mg/kg was orally administered for the last three weeks. Blood pressure was measured weekly. Rats induced with L-NAME showed the development of hypertension, vascular dysfunction, and remodeling as demonstrated by an increase in wall thickness, cross-sectional area, and collagen deposition in the aorta. The overexpression of nuclear factor kappa B (NF-кB), vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), tumor necrosis factor-alpha (TNF-α), phosphorylated-extracellular-regulated kinase 1/2 (p-ERK1/2), phosphorylated-c-Jun N-terminal kinases (p-JNK), phosphorylated-mitogen activated protein kinase p38 (p-p38), transforming growth factor-beta 1 (TGF-β1), matrix metalloproteinase-9 (MMP-9) and collagen type 1 was observed in L-NAME-induced hypertensive rats. Increased oxidative stress markers, decreased plasma nitric oxide (NO) levels and the down-regulation of endothelial nitric oxide synthase (eNOS) expression in aortic tissues were also found in L-NAME-induced rats. Moreover, L-NAME-induced rats showed enhanced synthetic protein expression in aortic tissues. These alterations were suppressed in hypertensive rats treated with HHC or enalapril. The present study shows that HHC exhibited antihypertensive effects by improving vascular function and ameliorated the development of vascular remodeling. The responsible mechanism may involve antioxidant and anti-inflammation potential.

Curcumin induces apoptosis by inhibiting BCAT1 expression and mTOR signaling in cytarabine‑resistant myeloid leukemia cells.

Cytarabine is a key chemotherapy drug for treating leukemia; however, chemotherapy-induced multidrug resistance is a major cause of therapy failure or tumor recurrence. Current medical treatment strategies still cannot address the issue of multidrug resistance phenotypes in the treatment of leukemia. Curcumin counteracts tumor development by inducing apoptosis in cytarabine-resistant acute myeloid leukemia cells. Branched-chain amino acid transaminase 1 (BCAT1), an aminotransferase enzyme, acts on branched-chain amino acids. Moreover, the aberrant expression of BCAT1 has been observed in numerous cancer cells, and BCAT1 serves a critical role in the progression of myeloid leukemia. BCAT1 can interfere with cancer cell proliferation by regulating mTOR-mediated mitochondrial biogenesis and function. The present study aimed to investigate whether curcumin induces apoptosis by regulating BCAT1 expression and mTOR signaling in cytarabine-resistant myeloid leukemia cells. Four leukemia cell lines and three primary myeloid leukemia cells were treated with curcumin, and the expression and activity of BCAT1 and mTOR were investigated by reverse transcription-quantitative PCR, western blotting and α-KG quantification assay. The results demonstrated that curcumin inhibited BCAT1 expression in Kasumi-1, KG-1, HL60, cytarabine-resistant HL60, and cytarabine-resistant primary myeloid leukemia cells. Notably, tetrahydrocurcumin, a major metabolite of curcumin, and cytarabine had no inhibitory effect on BCAT1 expression. Furthermore, BCAT1 and mTOR signaling may modulate each other in cytarabine-resistant HL60 cells. The present results indicated that curcumin may induce apoptosis by inhibiting the BCAT1 and mTOR pathways. Thus, understanding the mechanism underlying curcumin-induced apoptosis in cytarabine-resistant cells can support the development of novel drugs for leukemia.

Hexahydrocurcumin alleviated blood-brain barrier dysfunction in cerebral ischemia/reperfusion rats.

Hexahydrocurcumin (HHC), a major metabolite of curcumin, has been reported to have protective effects against ischemic and reperfusion damage. The goal of the present research was to examine whether HHC could alleviate brain damage and ameliorate functional outcomes by diminishing the blood-brain barrier (BBB) damage that follows cerebral ischemia/reperfusion. Middle cerebral artery occlusion was induced for 2h in rats followed by reperfusion. The rats were divided into three groups: sham-operated, vehicle-treated, and HHC-treated groups. At the onset of reperfusion, the rats were immediately intraperitoneally injected with 40mg/kg HHC. At 48h after reperfusion, the rats were evaluated for neurological deficits and TTC staining. At 24h and 48h after reperfusion, animals were sacrificed, and their brains were extracted. Treatment with HHC reduced neurological scores, infarct volume, morphological changes, Evans blue leakage and immunoglobulin G extravasation. Moreover, HHC treatment reduced BBB damage and neutrophil infiltration, downregulated myeloperoxidase, ICAM-1, and VCAM-1, upregulated tight junction proteins (TJPs), and reduced aquaporin 4 expression and brain water content. These results revealed that HHC treatment preserved the BBB from cerebral ischemia/reperfusion injury by regulating TJPs, attenuating neutrophil infiltration, and reducing brain edema formation.

Pharmacokinetics and pharmacodynamics of curcumin in regulating antioxidant and epigenetic gene expression in healthy human volunteers

Curcumin is a major component of the spice, turmeric (Curcuma longa) often used in food or as a dietary supplement. Many preclinical studies on curcumin suggests benefit in many diseases due to its antioxidant and epigenetic effects. The few human studies and curcumin's unfavorable pharmacokinetics (PK) have limited its potential, leading researchers to study and develop formulations to improve its PK. The purpose of this clinical study is to describe the pharmacokinetics and pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy human volunteers. Twelve volunteers received 4 g of curcumin capsules with standard breakfast. Plasma samples were collected at specified timepoints and analyzed for curcumin levels. RNA was extracted and analyzed for expression of select antioxidant and epigenetic histone deacetylase (HDAC) genes. Plasma levels of parent curcumin were not detected by HPLC‐ITMS/MS/MS. However, curcumin glucuronide, a major metabolite of curcumin, was detected as soon as 30 min. These observations of little to no curcumin and low levels of metabolite are in line with previous studies. Antioxidant genes Nrf2, HO‐1, NQO1, and HDAC1, HDAC2, HDAC3, and HDAC4 were quantified by qPCR. Curcumin glucuronide pharmacokinetics are well‐described by a one‐compartment model and the PK/PD of curcumin glucuronide and its effect on antioxidant and epigenetic gene expression are explained by indirect response model (IDR). Increasing AUC or exposure to curcumin glucuronide was correlated with overall PD response. Physiologically based pharmacokinetic modeling (PBPK) and simulation using Simcyp correlated well with our observed data in the human volunteers. In vitro experiments on curcumin glucuronide in HepG2C8 cells also show that Nrf2‐ARE luciferase activity increases after 24‐hour treatment. These results show that poor bioavailability of curcumin remains a challenge but that oral administration of curcumin delivers detectable levels of curcumin glucuronide and may mediate the antioxidant and epigenetic effects of curcumin.Support or Funding InformationGrant: This work was supported in part by institutional funds and R01AT007065 from the National Center for Complementary and Alternative Medicines (NCCAM) and the Office of Dietary Supplements (ODS).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers.

Curcumin is a major component of the spice turmeric ( Curcuma longa), often used in food or as a dietary supplement. Many preclinical studies on curcumin suggest health benefits in many diseases due to its antioxidant/anti-inflammatory and epigenetic effects. The few human studies and curcumin's unfavorable pharmacokinetics (PK) have limited its potential, leading researchers to study and develop formulations to improve its PK. The purpose of this clinical study is to describe the acute pharmacokinetics and pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy human volunteers. Twelve volunteers received a 4 g dose of curcumin capsules with a standard breakfast. Plasma samples were collected at specified time points and analyzed for curcumin and its glucuronide levels. RNA was extracted from leukocytes and analyzed for expression of select antioxidant and epigenetic histone deacetylase (HDAC) genes. Plasma levels of parent curcumin were below the detection limit by HPLC-ITMS/MS/MS. However, curcumin-O-glucuronide (COG), a major metabolite of curcumin, was detected as soon as 30 min. These observations of little to no curcumin and some levels of metabolite are in line with previous studies. PD marker antioxidant genes NRF2, HO-1, and NQO1 and epigenetic genes HDAC1, HDAC2, HDAC3, and HDAC4 were quantified by qPCR. COG PK is well-described by a one-compartment model, and the PK/PD of COG and its effect on antioxidant and epigenetic gene expression are captured by an indirect response model (IDR). A structural population PK model was sequentially established using a nonlinear mixed-effect model program (Monolix Lixoft, Orsay, France). Physiologically based pharmacokinetic modeling (PBPK) and simulation using Simcyp correlated well with the observed data. Taken together, these results show that the bioavailability of the parent curcumin compound is low, and oral administration of curcumin can still deliver detectable levels of curcumin glucuronide metabolite. But most importantly, it elicits antioxidant and epigenetic effects which could contribute to the overall health beneficial effects of curcumin.

Subchronic and Reproductive/Developmental Toxicity Studies of Tetrahydrocurcumin in Rats

Tetrahydrocurcumin (THC) is a major metabolite of curcumin, which is obtained from Curcuma longa. THC has various benefits and overcomes the bioavailability issue of curcumin. To establish it as a pharmacologically active molecule, its safety profile has to be determined. Thus, the present study aimed to determine the preclinical safety profile of THC in a 90-day subchronic and reproductive/developmental toxicity study in Wistar rats. THC at oral doses of 100, 200, and 400 mg/kg was administered daily for 90 days. Rats in the recovery group were kept for 14 days after treatment termination. The animals were observed for treatment-related morbidity, mortality, and changes in clinical signs, clinical pathology, and histopathology. In the reproductive/developmental toxicity study, THC at 100, 200, and 400 mg/kg was administered orally to rats and the reproductive/developmental parameters in adult male and female rats and pups were observed. THC at up to 400 mg/kg/day of did not have any significant effect on all parameters in male and female rats in both toxicity studies. Thus, 400 mg/kg/day can be considered as the no-observed-adverse-effect-level of THC in rats.

Tetrahydrocurcumin attenuates carbon tetrachloride-induced hepatic fibrogenesis by inhibiting the activation and autophagy of hepatic stellate cells

Tetrahydrocurcumin (THC) is known to be the major metabolite of curcumin. The present study aimed to investigate the efficacy of THC and curcumin against hepatic fibrogenesis and the underlying responsible molecular mechanisms. Hepatic fibrogenesis was induced by intraperitoneal injection of CCl4 twice per week for 8weeks. Daily oral administration of THC at 10mg/kg and 50mg/kg attenuated liver fibrogenesis more effectively than curcumin, as indicated by histopathological changes and a reduction in serum biochemical markers, collagen deposition, and fibrogenic molecules such as α-SMA and TGF-β1. THC exerted anti-fibrotic effects through the down-regulation of the TGF-β1/Smad and MAPKs signaling pathways. Moreover, IHC double-staining showed that THC diminished the autophagic process in activated HSCs in the liver. These findings suggest that THC alleviated hepatic fibrogenesis via inhibition of multiple signaling and autophagy suppression. THC could be used as a potent dietary supplement for the management of fibrotic liver diseases.

Bioavailability of curcumin and curcumin glucuronide in the central nervous system of mice after oral delivery of nano-curcumin

Curcumin is a bioactive molecule extracted from Turmeric roots that has been recognized to possess a wide variety of important biological activities. Despite its great pharmacological activities, curcumin is highly hydrophobic, which results in poor bioavailability. We have formulated this hydrophobic compound into stable polymeric nanoparticles (nano-curcumin) to enhance its oral absorption. Pharmacokinetic analysis after oral delivery of nano-curcumin in mice demonstrated approximately 20-fold reduction in dose requirement when compared to unformulated curcumin to achieve comparable plasma and central nervous system (CNS) tissue concentrations. This investigation corroborated our previous study of curcumin functionality of attenuating opioid tolerance and dependence, which shows equivalent efficacy of low-dose (20mg/kg) nano-curcumin and high-dose (400mg/kg) pure curcumin in mice. Furthermore, the highly selective and validated liquid chromatography⿿mass spectrometry (LC⿿MS) method was developed to quantify curcumin glucuronide, the major metabolite of curcumin. The results suggest that the presence of curcumin in the CNS is essential for prevention and reversal of opioid tolerance and dependence.

Use of basic mobile phase to improve chromatography and boost sensitivity for quantifying tetrahydrocurcumin in human plasma by LC-MS/MS.

Tetrahydrocurcumin (THC), a major metabolite of curcumin, is often quantified by LC-MS or LC-MS/MS using acidic mobile phases due to the concern of its instability in a basic medium. However, acidic mobile phases often lead to poor chromatography (e.g. split or double peaks) and reduced detection sensitivity in the commonly used negative ionization mode. To overcome these shortcomings, a basic mobile phase was used for the first time in the LC-MS/MS quantification of THC. In comparison with the acidic mobile phases, a single symmetrical chromatographic peak was obtained and the sensitivity increased by 7-fold or more under the equivalent conditions. The new LC-MS/MS method using the basic mobile phase has been successfully validated for the quantification of THC in human EDTA plasma over the concentration range of 5-2500ng/ml. The within-batch accuracy (% nominal concentration) was between 88.7 and 104.9 and the between-batch accuracy ranged from 96.7 to 108.6. The CVs for within- and between-batch precisions were equal to or less than 5.5% and 9.1%, respectively. No significant matrix interference or matrix effect was observed from normal or lipemic and hemolytic plasma matrices. In addition, the common stabilities with adequate durations were established, including up to 5days of post-preparative stability. Furthermore, when the validated method was applied to a clinical study, the passing rate of ISR samples was 83%, indicating the good reproducibility of the method. The success of the unconventional approach presented in this article demonstrates that a mobile phase could be selected based mainly on its merits to facilitate LC separation and/or MS detection. There is no need for excessive concern about the stability of the compound(s) of interest in the selected mobile phase because the run time of modern LC-MS or LC-MS/MS methods is typically only a few minutes.

Effects of curcumin metabolites on human colon adenocarcinoma cells

Stepwise cancer development involves metastatic migration as well as uncontrolled cell growth. Cancer cells undergo migration and invasion which allow them to translocate within tissues. Tetrahydrocurcumin (THC), a major metabolite of curcumin, exhibits anti‐carcinogenesis and antioxidation in vivo. In the present study, we found that THC and two other metabolites of curcumin, tetrahydrodemethoxycurcumin (THDC) and tetrahydrobisdemethoxycurcumin (THBC), could reduce the survival ratio of human colon adenocarcinoma cells, COLO205, HCT116, and HT29, in a dose‐dependent manner. The results also indicated that the fewer the methoxy groups of the curcumim metabolites, the more the inhibitory effects. However, curcumin metabolites did not trigger apoptotic cell death in COLO205 cells significantly, whereas curcumin did. Our data also strongly suggest a role of THBC in inhibiting cellular migration in HCT116 cells. Taken together, these results demonstrated the anticancer efficacy of curcumin metabolites which provides a potential application basis for the prevention of human colon cancer.Support or Funding InformationThis study was supported by NSC102‐2320‐B‐309‐001‐MY3 to M‐F Lee and NSC100‐2313‐B‐309‐003 to A‐C Cheng.

Curcumin and tetrahydrocurcumin both prevent osteoarthritis symptoms and decrease the expressions of pro-inflammatory cytokines in estrogen-deficient rats.

BackgroundMenopausal symptoms are associated with inflammation. Curcumin is a well-known anti-inflammatory bioactive compound from turmeric whereas tetrahydrocurcumin (THC) is a major metabolite of curcumin that may have different efficacies. However, they have not been studied for anti-menopausal symptoms and anti-osteoarthritis effects. We compared the efficacies of curcumin and THC for preventing postmenopausal and osteoarthritis symptoms in ovariectomized (OVX) obese rats with monoiodoacetate (MIA) injections into the right knee to generate a similar pathology as osteoarthritis.MethodsOVX rats were provided a 45 % fat diet containing either (1) 0.4 % curcumin (curcumin), (2) 0.4 % THC, (3) 30 μg/kg body weight 17β-estradiol + 0.4 % dextrin (positive control), (4) 0.4 % dextrin (placebo; control), or (5) 0.4 % dextrin with no MIA injection (normal control) for 4 weeks. At the beginning of the fifth week, OVX rats were given articular injections of MIA or normal-control saline into the right knee and the assigned diets were provided for an additional 3 weeks.ResultsCurcumin and THC had similar efficacies for skin tail temperature in OVX rats whereas THC, but not curcumin, prevented glucose intolerance, which might be involved in exacerbating osteoarthritis. Both protected against osteoarthritis symptoms and pain-related behaviors better than 17β-estradiol treatment in estrogen-deficient rats. Curcumin and THC prevented the deterioration of articular cartilage compared to control. They also maintained lean body mass and lowered fat mass as much as 17β-estradiol treatment. The improvement in osteoarthritis symptoms was associated with decreased gene expressions of matrix metalloproteinase (MMP)3 and MMP13 and tumor necrosis factor-α, interleukin (IL)1β, and IL6 in the articular cartilage.ConclusionsTHC and curcumin are effective for treating postmenopausal and osteoarthritis symptoms in OVX rats with MIA-induced osteoarthritis-like symptoms and may have potential as interventions for menopausal and osteoarthritic symptoms in humans.

Curcumin inhibits lymphangiogenesis in vitro and in vivo.

Curcumin, a dietary compound from turmeric, has potent antimetastatic effects; however, the underlying mechanisms are not well understood. The aim of this study is to investigate the effects and mechanisms of curcumin on lymphangiogenesis (formation of new lymphatic vessels), which plays a critical role in tumor metastasis. Curcumin inhibited vascular endothelial growth factor-C (VEGF-C) induced lymphangiogenesis in a Matrigel plug assay in mice, and VEGF-C induced tube formation in human dermal lymphatic endothelial cells, demonstrating its antilymphangiogenic action in vivo and in vitro. Curcumin inhibited lymphangiogenesis, in part through suppression of proliferation, cell-cycle progression and migration of lymphatic endothelial cells, while it had little effect on matrix metalloproteinase activities. Curcumin inhibited expressions of VEGF receptors (VEGFR2 and VEGFR3), as well as downstream signaling such as phosphorylation of ERK and FAK. Finally, curcumin sulfate and curcumin glucuronide, which are two major metabolites of curcumin in vivo, had little inhibitory effect on proliferation of human dermal lymphatic endothelial cells. Our results demonstrate that curcumin inhibits lymphangiogenesis in vitro and in vivo, which could contribute to the antimetastatic effects of curcumin.

Tetrahydrocurcumin protects against cadmium-induced hypertension, raised arterial stiffness and vascular remodeling in mice.

BackgroundCadmium (Cd) is a nonessential heavy metal, causing oxidative damage to various tissues and associated with hypertension. Tetrahydrocurcumin (THU), a major metabolite of curcumin, has been demonstrated to be an antioxidant, anti-diabetic, anti-hypertensive and anti-inflammatory agent. In this study, we investigated the protective effect of THU against Cd-induced hypertension, raised arterial stiffness and vascular remodeling in mice.MethodsMale ICR mice received CdCl2 (100 mg/l) via drinking water for 8 weeks. THU was administered intragastrically at dose of 50 or 100 mg/kg/day concurrently with Cd treatment.ResultsAdministration of CdCl2 significantly increased arterial blood pressure, blunted vascular responses to vasoactive agents, increased aortic stiffness, and induced hypertrophic aortic wall remodeling by increasing number of smooth muscle cells and collagen deposition, decreasing elastin, and increasing matrix metalloproteinase (MMP)-2 and MMP-9 levels in the aortic medial wall. Supplementation with THU significantly decreased blood pressure, improved vascular responsiveness, and reversed the structural and mechanical alterations of the aortas, including collagen and elastin deposition. The reduction on the adverse response of Cd treatment was associated with upregulated eNOS and downregulated iNOS protein expressions, increased nitrate/nitrite level, alleviated oxidative stress and enhanced antioxidant glutathione. Moreover, THU also reduced the accumulation of Cd in the blood and tissues.ConclusionsOur results suggest that THU ameliorates cadmium-induced hypertension, vascular dysfunction, and arterial stiffness in mice through enhancing NO bioavailability, attenuating oxidative stress, improving vascular remodeling and decreasing Cd accumulation in other tissues. THU has a beneficial effect in moderating the vascular alterations associated with Cd exposure.

Inhibitory effect of tetrahydrocurcumin on dimethylnitrosamine-induced liver fibrosis in rats

Chronic liver disease is characterized by an exacerbated accumulation of deposition of collagen, causing progressive fibrosis, which may lead to cirrhosis. We evaluated the inhibitory effect of tetrahydrocurcumin (THC), a major metabolite of curcumin, on liver fibrogenesis both in vitro, HSC-T6 cell, and in vivo, dimethylnitrosamine (DMN)-induced liver fibrosis in rat. The liver inflammation in HSC-T6 cell was initiated by transforming growth factor-β1 (TGF-β1), and fibrosis in Sprague–Dawley rats was induced by intraperitoneal (i.p.) injection of DMN (10mg/kg) 3days per week for four consecutive weeks. THC (10mg/kg) was administered in rats by oral gavage daily. DMN caused hepatic injury as indicated by analysis of liver function, morphology, histochemistry, and fibrotic parameters. Once-daily dosing with THC alleviated liver damage as signified by histopathological examination of the α-smooth muscle actin (α-SMA) and collagen I, accompanied by the reduction TGF-β1 and serum levels of transaminase (P<0.05). These data revealed that the THC exerts hepatoprotective activity in experimental fibrosis, potentially by inhibiting the TGF-β1/Smad signaling.

Chemopreventative effects of tetrahydrocurcumin on human diseases

Chemoprevention is a relatively new and promising strategy to prevent human degenerative diseases, including cancer, and is defined as the use of natural dietary compounds and/or synthetic substances to block, inhibit, reverse, or retard the progress of human diseases. Tetrahydrocurcumin (THC) is a major metabolite of curcumin (extracted from the roots of the Curcuma longa Linn). THC has been demonstrated to prevent oxidative stress and inflammation, to act against neurodegeneration, and to possess anti-cancer activity. In this review, we summarize the current knowledge and underlying molecular mechanisms of the chemopreventative activities of THC and its potential effects on the development of various human diseases.

Tetrahydrocurcumin, a major metabolite of curcumin, is more effective than curcumin in preventing azoxymethane-induced colon carcinogenesis

Tetrahydrocurcumin, a major metabolite of curcumin, is more effective than curcumin in preventing azoxymethane-induced colon carcinogenesis