Tetrahydrocurcumin Research Articles

Tetrahydrocurcumin, a major metabolite of curcumin, ameliorates allergic airway inflammation by attenuating Th2 response and suppressing the IL-4Rα-Jak1-STAT6 and Jagged1/Jagged2 -Notch1/Notch2 pathways in asthmatic mice.

Curcumin (Cur), derived from Curcuma species, exhibits anti-inflammatory, antioxidant, and anticancer effects. Although Cur has some beneficial effects on asthma, its clinical application is limited by its low bioavailability. Tetrahydrocurcumin (THC), the major active metabolite of Cur, has multiple biological functions, similarly to Cur, and importantly, it showed enhanced bioavailability in tissues and plasma. However, the effect of THC on asthma has not been reported. The current study sought to investigate the efficacy of dietary THC on allergic asthma compared to that of Cur in an animal model. The anti-inflammatory effects of Cur and THC were evaluated in an ovalbumin-induced asthmatic mouse model. The nasal symptoms, pathological alterations of the lung tissues, oxidants and antioxidants, cytokine production, T cell subsets, and Th2-related signalling pathway activity were assessed. Both THC and Cur had beneficial effects on asthmatic mice with regard to nasal symptoms, pathological changes (eosinophils and mucus hyper-production), oxidative stress (malondialdehyde), cytokine production (IL-13), Th17 and cytotoxic T cell subsets, and Th2 signalling pathway (IL-4Rα-Jak1-STAT6 and Jagged1/Jagged2-Notch1/Notch2 axis) activity. THC was more effective than Cur in suppressing tissue eosinophilia, mucus production, and IL-4Rα/Jak1/STAT6 pathway activity. Furthermore, only THC inhibited peripheral eosinophil levels, Th2 cytokines (IL-4 and IL-5), and Th2 cell subsets and enhanced an antioxidant enzyme (glutathione). The above results demonstrated for the first time that THC was superior to Cur in modulating allergic asthmatic phenotypes, especially attenuating the Th2 response. THC might be a potentially effective agent for asthma treatment.

Fabrication of Buccal Dissolving Tetrahydro Curcumin Loaded Polyvidone Fiber Mat: Synthesis, Characterization, and In Vitro Evaluations

Fabrication of Buccal Dissolving Tetrahydro Curcumin Loaded Polyvidone Fiber Mat: Synthesis, Characterization, and In Vitro Evaluations

Preparation and Characterization of Tetrahydrocurcumin-Loaded Cellulose Acetate Phthalate/Polyethylene Glycol Electrospun Nanofibers.

A simple composite electrospun nanofiber of cellulose acetate phthalate (CAP)-polyethylene glycol (PEG) loaded with tetrahydrocurcumin (THC) was developed in this study, and the in vitro diffusion of THC was evaluated. The nanofibers were characterized by scanning electron microscopy, powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FT-IR), and differential scanning calorimetry (DSC). The formulated nanofiber (NF) with THC has smooth morphology with diameter of around 300-500nm. The complete entrapment and dispersion of THC was observed from the results of PXRD and DSC due to the loss of THC crystalline property. Further, FT-IR demonstrated that the vibration bands for the polymers used were dominant over the THC, and the vibrational bands of THC were not observed from the final formulation. The drug entrapment by the final CAP + PEG NF was found to be 95.5% with the high swelling index. From the in vitro release study, it was found that the formulated THC-loaded CAP + PEG NF has followed anomalous mechanism, demonstrating both diffusion and swelling controlled modes. The drug release extended up to 12h with a final cumulative release of 94.24%.

Topical delivery of tetrahydrocurcumin lipid nanoparticles effectively inhibits skin inflammation: in vitro and in vivo study

Tetrahydrocurcumin (THC) also referred to as ‘white curcumin’, is a stable colorless hydrogenated product of curcumin with superior antioxidant and anti-inflammatory properties. The present study is an attempt to elevate the topical bioavailability of THC, post-incorporation into a nano-carrier system with its final dosage as a hydrogel. Lipid nanoparticles of THC (THC-SLNs) prepared by microemulsification technique were ellipsoidal in shape (revealed in transmission electron microscopy) with a mean particle size of 96.6 nm and zeta potential of −22 mV. Total drug content and entrapment efficiency of THC-SLNs was 94.51% ± 2.15% and 69.56% ± 1.35%, respectively. Differential scanning calorimetry and X-ray diffraction studies confirmed the formation of THC-SLNs. In vitro drug release studies showed the drug release from THC-SLNs gel to follow Higuchi’s equation revealing a Fickian diffusion. Ex vivo permeation studies indicated a 17 times (approximately) higher skin permeation of THC-SLNs gel as compared with the free THC gel. Skin irritation, occlusion, and stability studies indicated the formulation to be nonirritating, and stable with a desired occlusivity. Pharmacodynamic evaluation in an excision wound mice model clearly revealed the enhanced anti-inflammatory activity of THC-SLNs gel and was further confirmed using biochemical and histopathological studies. It is noteworthy to report here that THC-SLNs gel showed significantly better (p ≤ 0.001) activity than free THC in gel. As inflammation is innate to all the skin disorders, the developed product opens up new therapeutic avenues for several skin diseases. To the best of our knowledge, this is the first paper elaborating the therapeutic usefulness of white curcumin-loaded lipidic nanoparticles for skin inflammation.

Lactose-crosslinked fish gelatin-based porous scaffolds embedded with tetrahydrocurcumin for cartilage regeneration

Tetrahydrocurcumin (THC) is one of the major colourless metabolites of curcumin and shows even greater pharmacological and physiological benefits. The aim of this work was the manufacturing of porous scaffolds as a carrier of THC under physiological conditions. Fish-derived gelatin scaffolds were prepared by freeze-drying by two solutions concentrations (2.5% and 4% w/v), cross-linked via addition of lactose and heat-treated at 105 °C. This cross-linking reaction resulted in more water resistant scaffolds with a water uptake capacity higher than 800%. Along with the cross-linking reaction, the gelatin concentration affected the scaffold morphology, as observed by scanning electron microscopy images, by obtaining a reduced porosity but larger pores sizes when the initial gelatin concentration was increased. These morphological changes led to a scaffold's strength enhancement from 0.92 ± 0.22 MPa to 2.04 ± 0.18 MPa when gelatin concentration was increased. THC release slowed down when gelatin concentration increased from 2.5 to 4% w/v, showing a controlled profile within 96 h. Preliminary in vitro test with chondrocytes on scaffolds with 4% w/v gelatin offered higher metabolic activities and cell survival up to 14 days of incubation. Finally the addition of THC did not influence significantly the cytocompatibility and potential antibacterial properties were demonstrated successfully against Staphylococcus aureus.

The pharmacokinetics and tissue distribution of curcumin and its metabolites in mice.

Curcumin (CUR) is the major active component of turmeric and plays an important role in the prevention and treatment of many chronic diseases such as respiratory and neurodegenerative disease. In the present work, a rapid and simple LC-MS/MS method was developed to investigate the pharmacokinetics and tissue distribution of CUR and its metabolites in mice after intravenous administration of CUR (20 mg/kg). The results showed that the values of AUC0-∞ were 107.0 ± 18.3, 6.0 ± 1.2 and 12.0 ± 4.0 (mg/L) min, and those for t1/2z were 32.4 ± 10.8, 6.4 ± 2.4 and 5.6 ± 1.8 min for CUR, dihydrocurcumin (DHC) and tetrahydrocurcumin (THC) in plasma, respectively. CUR and THC could be detected in liver while CUR and DHC were detected in kidney. Only CUR was detected in brain. These findings indicated that THC was the main metabolite of CUR in plasma. The exposure of CUR in plasma was 6-fold greater than that in liver, kidney and brain.

Tetrahydrocurcumin Provides Neuroprotection in Experimental Traumatic Brain Injury and the Nrf2 Signaling Pathway as a Potential Mechanism

The protective effect of tetrahydrocurcumin (THC) after experimental traumatic brain injury (TBI) has been demonstrated, as demonstrated by the inhibition of oxidative stress, mitochondrial dysfunction, and apoptosis. However, the mechanisms underlying this effect are still not well understood. This study was to investigate the neuroprotective effects of THC, and its potential mechanisms, in a rat model of TBI. To this end, rats were divided into 4 groups: the sham group, the TBI group, the TBI + vehicle (V) group, and the TBI + THC group. THC or V was administered via intraperitoneal injection to rats in the TBI + V and TBI + THC groups 30 min after TBI. After euthanasia (24 h after TBI), neurological scores, brain water content, and neuronal cell death in the cerebral cortex were recorded. Brain samples were collected after neurological scoring for further analysis. THC treatment alleviated brain edema, attenuated TBI-induced neuronal cell apoptosis, and improved neurobehavioral function. In addition, NFE2-related factor 2 (Nrf2) expression was upregulated following TBI. These results suggest that THC improves neurological outcome after TBI, possibly by activating the Nrf2 signaling pathway.

Mechanism of Mitochondrial Dysfunction in Brain Vasculature during Ischemic Stroke: Role of Tetrahydrocurcumin

Cerebral ischemic/reperfusion (I/R) injury is a major cause of stroke and is associated with the formation of leaky mitochondria leading to mitochondrial dysfunction. Tetrahydrocurcumin (THC), a major herbal antioxidant and anti‐inflammatory compound, has shown to protect the brain against injury. The objectives of this study are to identify the mechanism of mitochondrial dysfunction during I/R and the therapeutic potential of THC to mitigate mitophagy in an experimental stroke model. In our study, 8–10 weeks old male C57BL/6 wild‐type mice were subjected to middle cerebral artery occlusion (MCAO) for 40 min, followed by reperfusion for 72 hours. THC (25 mg/kg‐BW/day) was injected intraperitoneally (I.P.) once daily for 3 days after 40 minutes of ischemia. The experimental groups were: (i) sham (control), (ii) I/R (stroke) and (iii) I/R+THC. We found that infarct size, brain edema, and permeability were increased in ischemic mice as compared to sham‐operated control group; however THC treatment in I/R mice almost normalized these changes. Plasma levels of tHcy were significantly increased in the I/R mice compared to the sham group, but THC treatment restored the tHcy to control level in I/R+THC group. Western blot analysis also revealed that the protein levels of CBS, CSE, and MTHFR were significantly increased while the level of SAHH was significantly decreased in I/R mice compared to sham. THC treatment ameliorates these changes to control levels. The levels of mitochondrial p47phox, gp91phox (oxidants) were increased, and levels of Trx‐2, SOD‐2 (anti‐oxidants) were decreased, respectively, in the ischemic mitochondrial fraction. Treatment with THC mitigated these levels. Interestingly, matrix extracted from isolated mitochondria of the ischemic brain also showed an increase in MMP‐9 activity in gelatin‐gel zympography. We also observed an increase in TIMP‐1 and a decrease in TIMP‐2 protein expression in the ischemic brain as compared to sham. THC treatments reversed all these changes to normal levels. Further, we identified that the activation of MMP‐9 is associated with reduced expression of mitochondrial tight junction proteins and collagen IV/elastion degradation leading to mitophagy. To determine whether occludin and zona occluden‐1 (ZO1) are MMP target, we determined TJP protein expression by Western analysis. The results showed downregulation of occludin and ZO1 in the mitochondria from the ischemic brain, which was mitigated by THC treatment. Experimental data also revealed a robust degradation of elastin and accumulation of collagen IV in the ischemic brain as compared to sham. To further support the claim of mitophagy occurrence in ischemic brains, the levels of mitophagy markers (conversion of LC3‐I to LC3‐II in mitochondria) Mfn‐1(fusion protein) and DRP‐1 (fission protein) were measured by Western Blot. The LC3‐II was increased, whereas Mfn‐1 and DRP‐1 protein expression were decreased in ischemic mitochondria. THC treatment inhibited the conversion of LC3‐Ito LC‐3‐II and enhanced the expression of MFN‐1 and DRP‐1. In conclusion, this study suggests a potential therapeutic role of dietary THC to repair mitochondrial damage during ischemia stroke.Support or Funding InformationThis work is financially supported by National Institute of health grant AR‐067667 and HL‐107640‐NT are greatly acknowledgedThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Tetrahydrocurcumin Ameliorates Tacrolimus-Induced Nephrotoxicity Via Inhibiting Apoptosis

BackgroundCalcineurin inhibitors are effective immunosuppressive agents, but associated adverse effects such as nephrotoxicity may limit efficacy. Tacrolimus (FK506) is an immunosuppressive drug used mainly to lower the risk of organ rejection after allogeneic organ transplant. Adverse effects of FK-506 can prompt patients to end treatment despite the efficacy. In the present study, we investigated the protective effect and mechanism of tetrahydrocurcumin (THC) on FK506-induced renal damage, apoptosis, and oxidative stress to evaluate its possible use for kidney protection. Materials and MethodsThe effect of THC on FK506-induced kidney cell damage was investigated in LLC-PK1 cells. LLC-PK1 cells were pretreated with THC at concentrations of dose for 2 hours followed by addition of FK506 for 24 hours. LLC-PK1 cells were treated with FK506 and THC, and cell viability and glutathione was measured. The number of apoptotic cells was measured using an annexin V/propidium iodide staining with flow cytometry. The effect of apoptosis by THC in LLC-PK1 cells was determined by measuring the caspase-9, caspase-3, B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X protein levels using Western blotting analyses. ResultsFK506-induced LLC-PK1 renal cell damage was markedly ameliorated by THC treatment. THC protected LLC-PK1 cells by preventing FK506-induced glutathione decrease. THC protects against FK506-induced apoptosis in LLC-PK1 cells. Apoptosis was significantly decreased, and Bcl-2 was elevated in the THC-treated group. Bcl-2-associated X protein, caspase-3, and caspase-9 were decreased in the THC-treated group. ConclusionThese results collectively provide therapeutic evidence that THC ameliorates the FK506-induced renal damage via antioxidant effect and apoptosis inhibition.

Tetrahydrocurcumin Enhances Islet Cell Function and Attenuates Apoptosis in Mouse Islets

BackgroundThe transplantation of isolated pancreatic islets is a promising treatment for diabetes. Curcumin has been used for its pharmacologic effects, such as antidiabetic and anti-inflammatory activities. Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, has been reported to have antioxidant and anti-inflammatory activities. This study examines the hypothesis that preoperative THC treatment can attenuate ischemic damage and apoptosis before islet transplantation. MethodsIslets isolated from Balb/c mice were randomly divided into 2 groups and cultured in medium supplemented with or without THC. In vitro islet viability and function were assessed. After treatment with a cytokine cocktail consisting of tumor necrosis factor-α, interferon-β, and interleukin-1β, islet cell viability, function, and apoptotic status were determined. Proteins related to apoptosis were analyzed using INS-1 cell after streptozocin treatment. ResultsThere was no difference in cell viability between the 2 groups. Islets cultured in the medium supplemented with THC showed 1.3-fold higher glucose-induced insulin secretion than the islets cultured in the medium without THC. After treatment with a cytokine cocktail, glucose-induced insulin release, and NO of the islets were significantly improved in THC-treated islets compared with islets not treated with THC. Apoptosis was significantly decreased, and B-cell lymphoma-2 was elevated in the THC-treated group. The streptozocin-treated INS-1 cell produced significantly higher levels of and B-cell lymphoma-2-associated X protein, caspase-3, and caspase-9 than INS-1 treated with THC. ConclusionsThese results suggest that preoperative THC administration enhances islet function before transplantation and attenuates the cytokine-induced damage associated with apoptosis.

The enhanced effect of tetrahydrocurcumin on radiosensitivity of glioma cells.

To evaluate the effects of tetrahydrocurcumin (THC) on the radiosensitivity of glioma cells and the possible molecular mechanism. MTT assay, colony forming and wound healing assays were performed to detect the proliferation, radiosensitivity and migration of cells with various treatments. Cell apoptosis, cell cycle and GHS level were determined for exploring potent sensitization mechanism of THC. Meanwhile, protein expressions of cyclin D1 and PCNA were also measured. Furthermore, both orthotopic C6 mouse models and C6 subcutaneously grafted mouse models were established to test the tumour inhibitory effects of combined treatment in vivo. Cells treated with combined THC and radiation demonstrated lower cell viability and higher apoptosis rate as compared to radiation group. Moreover, the intracellular GSH was also decreased in the THC co-treated C6 cells. More importantly, combinatorial treatment group significantly induced G0/G1 cell cycle arrest and a decrease in the S phase cell through the down-regulation of cyclin D1 and PCNA. The in-vivo therapeutic efficacy assay indicated that the growth of tumour was greatly inhibited in combinatorial group. Tetrahydrocurcumin can synergistically enhance the radiosensitivity of glioma cells by inhibiting the expressions of cyclin D1 and PCNA.

Dietary tetrahydrocurcumin reduces renal fibrosis and cardiac hypertrophy in 5/6 nephrectomized rats.

Tetrahydrocurcumin (THC) is the principal metabolite of curcumin and has antioxidant properties. In the present investigation, the effect of THC on renal and cardiovascular outcomes was studied in rats with chronic kidney disease (CKD). CKD rats were randomized following 5/6 nephrectomy to a special diet for 9 weeks which contained 1% THC (CKD+THC group). Low‐dose polyenylphosphatidylcholine was used as a lipid carrier to increase bioavailability. Endpoints included tail blood pressure, normalized heart weight, plasma and urine biochemical data, and kidney tissue analyses. CKD animals demonstrated increased proteinuria, decreased creatinine clearance, hypertension, and cardiac hypertrophy. The antioxidant proteins CuZn SOD and glutathione peroxidase were decreased in the remnant kidney, while apoptosis (caspase‐3) and fibrosis (alpha‐SM actin) were increased. Renal fibrosis was confirmed histologically on trichrome staining. These pathologic changes were ameliorated in the CKD+THC group with significant decrease in proteinuria, hypertension, and kidney fibrosis. THC therapy restored levels of CuZn SOD and glutathione peroxidase. Consistent with prior reports, dietary THC did not improve nuclear Nrf2 levels. In summary, dietary THC therapy improved expression of antioxidant proteins in the remnant kidney, decreased renal fibrosis and proteinuria, and ameliorated hypertension in 5/6 nephrectomized rats.

Tetrahydrocurcumin‑induced autophagy via suppression of PI3K/Akt/mTOR in non‑small cell lung carcinoma cells.

Lung carcinoma is the leading cause of mortality due to cancer worldwide. Autophagy has a significant role in the development and progression of non‑small cell lung carcinoma (NSCLC). A previous study has revealed that tetrahydrocurcumin (THC), a traditional Chinese medicine isolated from Curcumawenyujin (Chen & Ling, 1981), induces autophagy in human A549 NSCLC cells. The present study evaluated THC‑induced autophagy in A549 cells using various assays, including the Cell Counting Kit‑8, acridine orange staining, flow cytometry, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), and western blot analysis of the markers of autophagy. THC inhibited the growth and proliferation of A549 cells (P<0.05). Acridine orange staining and flow cytometry revealed that THC treatment significantly enhanced autophagic cell proliferation inhibition (P<0.05). The RT‑qPCR analysis revealed that THC treatment increased Beclin‑1 expression level and compared with the control group (P<0.05). The light chain 3 (LC3)‑II/LC3‑I ratio was reduced in THC‑treated cells when compared with the control group (P<0.05). Protein expression of various markers of autophagy, including p62, phosphorylated (p)‑mechanistic target of rapamycin (mTOR), phosphoinositide 3‑kinase (PI3K), p‑PI3K, protein kinase B (Akt), and p‑Akt was significantly reduced in THC‑treated cells (P<0.05). In conclusion, the present study revealed the underlying mechanisms associated with THC‑induced autophagy. A promising method of enhancing the therapeutic efficacy of THC against NSCLC cells may include inducing autophagy via inhibition of the PI3K/Akt/mTOR signaling pathway.

Tetrahydrocurcumin ameliorates free fatty acid-induced hepatic steatosis and improves insulin resistance in HepG2 cells

Elevated levels of free fatty acids (FFAs) in the liver, resulting from either increased lipolysis or imbalanced FFAs flux, is a key pathogenic factor of hepatic steatosis. This study was conducted to examine the therapeutic effect of tetrahydrocurcumin (THC), a naturally occurring curcuminoid and a metabolite of curcumin, on oleic acid (OA)-induced steatosis in human hepatocellular carcinoma cells and to elucidate the underlying mechanism. HepG2 cells were incubated with OA to induce steatosis, and then treated with various concentrations of THC. The results showed that THC treatment significantly decreased lipid accumulation in OA-treated HepG2 cells, possibly, by inhibiting the expression of the lipogenic proteins, sterol regulatory element-binding protein 1 (SREBP-1c), peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FAS), and fatty acid-binding protein 4 (FABP4). Moreover, THC attenuated OA-induced hepatic lipogenesis in an adenosine monophosphate–activated protein kinase (AMPK)-dependent manner, which was reversed by pretreatment with an AMPK inhibitor. THC promoted lipolysis and upregulated the expression of genes involved in β-oxidation. Glucose uptake and insulin signaling impaired in HepG2 cells incubated with OA were abated by THC treatment, including phosphorylation of the insulin receptor substrate 1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt and downstream signaling pathways, forkhead box protein O1 (FOXO1) and glycogen synthase kinase 3 β (GSK3β), which are involved in gluconeogenesis and glycogen synthesis, respectively. Altogether, these results demonstrated the novel therapeutic benefit of THC against hepatic steatosis and, consequently, a potential treatment for non-alcoholic fatty liver disease (NAFLD).

Tetrahydro curcumin loaded PCL-PEG electrospun transdermal nanofiber patch: Preparation, characterization, and in vitro diffusion evaluations

Tetrahydro curcumin (THC) loaded polycaprolactone (PCL)-polyethylene glycol (PEG) composite electrospun nanofiber (NF) was developed, and hybridized as a transdermal patch. The nanofiber was prepared with 2:1 ratio of 10% w/v PCL and 5% w/v PEG and loaded with 8.7 % wt THC. The prepared NF was characterized by scanning electron microscopy (SEM), fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermo gravimetric analysis (TGA), X-ray diffraction (XRD), and ultraviolet–visible spectroscopy. The NF mat was hybridized in to transdermal patches then its physical-chemical parameters and in vitro diffusion of THC were also evaluated. The prepared formulation ideally followed the Higuchi's model (r2 = 0.975) of diffusion mechanism with case II relaxation behavior and anomalous transport of THC for 24 h.

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 ameliorates homocysteine-mediated mitochondrial remodeling in brain endothelial cells.

Homocysteine (Hcy) causes endothelial dysfunction by inducing oxidative stress in most neurodegenerative disorders. This dysfunction is highly correlated with mitochondrial dynamics such as fusion and fission. However, there are no strategies to prevent Hcy-induced mitochondrial remodeling. Tetrahydrocurcumin (THC) is an anti-inflammatory and anti-oxidant compound. We hypothesized that THC may ameliorates Hcy-induced mitochondria remodeling in mouse brain endothelial cells (bEnd3) cells. bEnd3 cells were exposed to Hcy treatment in the presence or absence of THC. Cell viability and autophagic cell death were measured with MTT and MDC staining assay. Reactive oxygen species (ROS) production was determined using DCFH-DA staining by confocal microscopy. Autophagy flux was assessed using a conventional GFP-microtubule-associated protein 1 light chain 3 (LC3) dot assay. Interaction of phagophore marker LC-3 with mitochondrial receptor NIX was observed by confocal imaging. Mitochondrial fusion and fission were evaluated by western blot and RT-PCR. Our results demonstrated that Hcy resulted in cell toxicity in a dose-dependent manner and supplementation of THC prevented the detrimental effects of Hcy on cell survival. Furthermore, Hcy also upregulated fission marker (DRP-1), fusion marker (Mfn2), and autophagy marker (LC-3). Finally, we observed that Hcy activated mitochondrial specific phagophore marker (LC-3) and co-localized with the mitochondrial receptor NIX, as viewed by confocal microscopy. Pretreatment of bEnd3 with THC (15 μM) ameliorated Hcy-induced oxidative damage, mitochondrial fission/fusion, and mitophagy. Our studies strongly suggest that THC has beneficial effects on mitochondrial remodeling and could be developed as a potential therapeutic agent against hyperhomocysteinemia (HHcy) induced mitochondrial dysfunction.

Disposition, Metabolism and Histone Deacetylase and Acetyltransferase Inhibition Activity of Tetrahydrocurcumin and Other Curcuminoids

Tetrahydrocurcumin (THC), curcumin and calebin-A are curcuminoids found in turmeric (Curcuma longa). Curcuminoids have been established to have a variety of pharmacological activities and are used as natural health supplements. The purpose of this study was to identify the metabolism, excretion, antioxidant, anti-inflammatory and anticancer properties of these curcuminoids and to determine disposition of THC in rats after oral administration. We developed a UHPLC–MS/MS assay for THC in rat serum and urine. THC shows multiple redistribution phases with corresponding increases in urinary excretion rate. In-vitro antioxidant activity, histone deacetylase (HDAC) activity, histone acetyltransferase (HAT) activity and anti-inflammatory inhibitory activity were examined using commercial assay kits. Anticancer activity was determined in Sup-T1 lymphoma cells. Our results indicate THC was poorly absorbed after oral administration and primarily excreted via non-renal routes. All curcuminoids exhibited multiple pharmacological effects in vitro, including potent antioxidant activity as well as inhibition of CYP2C9, CYP3A4 and lipoxygenase activity without affecting the release of TNF-α. Unlike curcumin and calebin-A, THC did not inhibit HDAC1 and PCAF and displayed a weaker growth inhibition activity against Sup-T1 cells. We show evidence for the first time that curcumin and calebin-A inhibit HAT and PCAF, possibly through a Michael-addition mechanism.

Curcuminoids in Multi‐Component Synthesis

The introduction of a 1,3‐dicarbonyl unit in curcuminoid derivatives for multi‐component reactions (MCRs) to furnish six‐membered heterocyclic compounds has been reviewed. Attention has focused on the assembly of the three‐component Biginelli reactions relating to curcumin or tetrahydrocurcumin (THC), aromatic aldehydes and urea as substrates. The hybrid molecules of two bioactive agents were designed and synthesized by using these MCRs concepts. The four‐component modified Hantzsch condensation was the latest development of this synthetic route. The possible mechanism of the MCRs of both curcumin and THC were also summarized.

Curcumin and its allied analogues: epigenetic and health perspectives - a review

Curcumin (diferuoyl methane) is a yellow active ingredient present in turmeric. It is a homodimer of feruloylmethane that comprises a hydroxyl and methoxy group (heptadiene with two Michael acceptors), and α-, β-diketone. It contains various metabolites, i.e. hexahydrocurcumin (HHC), tetrahydrocurcumin (THC), octahydrocurcumin (OHC), dihydrocurcumin (DHC), curcumin sulphate, and curcumin glucuronide. Curcumin has been proven the most effective histone deacetylase (HDAC) inhibitor in HeLa nuclear extracts. It has the ability to affect the Akt, growth factors, NF-kB, and metastatic and angiogenic pathways. Curcumin has a strong therapeutic or preventive potential against several major human ailments, i.e. suppression of inflammation, cardiovascular, diabetes, tumorigenesis, chronic fatigue, antidepressant and neurological activities, depression, loss of muscle and bone, and neuropathic pain. In future, higher utilisation of curcumin as an active agent in food based products is required to curtail the human health disorders.