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Tetrahydrocurcumin (THC) is one of the major metabolites of curcumin (CUR), an ancient bioactive natural polyphenolic compound. This research article describes both the solid and liquid state characterization of THC using advanced spectroscopic and thermo-analytical techniques. Anti-inflammatory, anti-oxidant, and neuroprotective activities of THC were investigated using in vitro cell lines. Liquid chromatography-mass spectrometry analysis revealed that our sample comprised 95.15% THC, 0.51% tetrahydrodemethoxycurcumin (THDC), 3.40% hexahydrocurcumin, and 0.94% octahydrocurcumin. Gas chromatography-mass spectrometry analysis indicated the presence of 96.68% THC and 3.32% THDC. THC in solution existed as keto-enol tautomers in three different forms at different retention time, but the enol form was found to be dominant, which was also supported by nuclear magnetic resonance analysis. THC was thermally stable up to 335.55 °C. THC exhibited more suppression of cytokines (TNF-α, IL-1β, and MIP-1α) than CUR in a concentration-dependent manner in mouse splenocytes, while NK-cell and phagocytosis activity was increased in macrophages. THC showed a significant reduction of free radicals (LPO) along with improved antioxidant enzymes (SOD and catalase) and increased free radical scavenging activity against ABTS+ radicals in HepG2 cells. THC displayed higher protection capability than CUR from oxidative stress and neuronal damage by improving cell viability against H 2 O 2 induced HepG2 cells and MPP+ induced SH-SY5Y cells, respectively, in a concentration-dependent manner. Thus, a variation of the biological activities of THC might rely on its keto-enol form and the presence of other THC analogs as impurities. The present study could be advantageous for further research on THC for better understanding its physicochemical properties and biological variation. Image 1 • Solid and liquid state characterization of THC using advanced analytical techniques. • THC existed in 3 different forms viz. one keto form, two enol forms in solution. • THC was found to be thermally more stable than curcumin. • THC exhibited significant suppression of proinflammatory cytokines, increased NK cells and phagocytosis activities. • THC showed higher total anti-oxidant activity and neuroprotective activity than curcumin. [ABSTRACT FROM AUTHOR]

The present study utilized molecular docking and density functional theory (DFT) approaches, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties to investigate the binding interactions, reactivity, stability, and drug-likeness of curcumin (1), tetrahydrocurcumin (2), and tetrahydrocurcumin derivatives (3–6) as potential anti-cancer agents. MGL (Molecular Graphic Laboratory) and Discovery Studio Visualizer (DSV) software employed for docking studies. Pharmacokinetic and pharmacodynamic (ADME-Tox) analyses were conducted using SwissADME and pKCSM web servers. Total Electron Density (TED) measurements identified molecular adsorption sites, considering various factors, including quantum chemical characteristics, to assess compound effectiveness using DFT method implanted in the Gaussian software. The binding energy (Eb) from docking simulations was used to evaluate inhibitory potential. ADMET analysis suggested favorable oral bioavailability and pharmacokinetics for all studied substances, excluding compound 4. DFT and docking investigations highlighted compounds 1, 2, and 6 as optimal scaffolds for drug design based on in silico screening tests. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • High fat/fructose diet (HFFD) damages liver via CYP450-induced oxidative stress. • Increases in oxidative events correlated well with CYP2E1 and CYP3A11 induction. • Tetrahydrocurcumin (THC) attenuated oxidative stress via suppression of CYP450s. • THC has hepatoprotective potential to prevent oxidative stress resulting from HFFD. Abstract Excessive consumption of a fat- and/or fructose-rich hypercaloric diet leads to metabolic syndromes. This study aimed to investigate the hepatoprotective effects of tetrahydrocurcumin (THC), an anti-oxidant metabolite of curcumin, in a hypercaloric diet-induced oxidative stress mouse model. Male ICR mice were fed a high-fat and high-fructose diet (HFFD) containing hydrogenated soybean oil (44.1% saturated fat and 0.2% trans-fatty acids) and a 20% fructose solution for 8 weeks. The HFFD induced hepatic injury through cytochrome P450 (CYP450)-induced oxidative stress, increased glucose tolerance, and increased CYP450 expression. THC attenuated oxidative stress in the HFFD mice by decreasing glucose tolerance, alanine aminotransferase and aspartate aminotransferase levels. In addition, THC suppressed HFFD-induced NADPH-CYP450 reductase activity, restored expression of anti-oxidative stress response related genes, and reduced ROS production by CYP2E1 and CYP3A11. Thus, THC is an excellent candidate for protection against HFFD-induced liver injury related to phase I biotransformation and anti-oxidation pathway. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) often leads to sudden cardiac death. Persistent myocardial ischemia increases oxidative stress and impairs mitochondrial function, contributing significantly to postinfarction cardiac dysfunction and remodeling, and the subsequent progression to heart failure (HF). Tetrahydrocurcumin (THC), isolated from the rhizome of turmeric, has antioxidant properties and has been shown to protect against cardiovascular diseases. However, its effects on HF after MI are poorly understood. The objective was the investigation of the pharmacological effects of THC and its associated mechanisms in the pathogenesis of HF after MI. A total of 120 mice (C57BL/6, male) were used for the in vivo experiments. An MI mouse model was created by permanent ligation of the left anterior descending coronary artery. The mice received oral dose of THC at 120 mg/kg/d and the effects on MI-induced myocardial injury were evaluated by assessment of cardiac function, histopathology, myocardial oxidative levels, and mitochondrial function. Molecular mechanisms were investigated by intraperitoneal injection of 50 mg/kg of the SIRT3 selective inhibitor 3-TYP. Meanwhile, mouse neonatal cardiomyocytes were isolated and cultured in a hypoxic incubator to verify the effects of THC in vitro. Lastly, SIRT3 and Nrf2 were silenced using siRNAs to further explore the regulatory mechanism of key molecules in this process. The mouse hearts showed significant impairment in systolic function after MI, together with enlarged infarct size, increased myocardial fibrosis, cardiac hypertrophy, and apoptosis of cardiomyocytes. A significant reversal of these changes was seen after treatment with THC. Moreover, THC markedly reduced reactive oxygen species generation and protected mitochondrial function, thus mitigating oxidative stress in the post-MI myocardium. Mechanistically, THC counteracted reduced Nrf2 nuclear accumulation and SIRT3 signaling in the MI mice while inhibition of Nrf2 or SIRT3 reversed the effects of THC. Cell experiments showed that Nrf2 silencing markedly reduced SIRT3 levels and deacetylation activity while inhibition of SIRT3 signaling had little impact on Nrf2 expression. This is the first demonstration that THC protects against the effects of MI. THC reduced both oxidative stress and mitochondrial damage by regulating Nrf2-SIRT3 signaling. The results suggest the potential of THC in treating myocardial ischemic diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

In the past, curcumin was the go-to medication for diabetes, but recent studies have shown that tetrahydrocurcumin is more effective. The problem is that it's not very soluble in water or very bioavailable. So, our research aims to increase the bioavailability and anti-diabetic efficacy of tetrahydrocurcumin in streptozotocin-induced diabetic rats by synthesizing tetrahydrocurcumin-loaded solid lipid nanoparticles. Box Behnken Design was employed for the optimization of tetrahydrocurcumin-loaded solid lipid nanoparticles (THC-SLNs). The optimal formulation was determined by doing an ANOVA to examine the relationship between the independent variables (drug-to-lipid ratio, surfactant concentration, and co-surfactant concentration) and the dependent variables (particle size, percent entrapment efficiency, and PDI). Particle size, PDI, and entrapment efficiency all showed statistical significance based on F-values and p-values. The optimized batch was prepared using a drug-to-lipid ratio (1:4.16), 1.21% concentration of surfactant, and 0.4775% co-surfactant (observed with a particle size of 147.1 nm, 83.58 ± 0.838 % entrapment efficiency, and 0.265 PDI, and the values were found very close with the predicted ones. As the THC peak vanishes from the DSC thermogram of the improved formulation, this indicates that the drug has been transformed from its crystalline form into its amorphous state. TEM analysis of optimized formulation demonstrated mono-dispersed particles with an average particle size of 145 nm which are closely related to zetasizer's results. In-vitro release study of optimized formulation demonstrated burst release followed by sustained release up to 71.04% throughout 24 hrs. Increased bioavailability of the adjusted THC-SLN was found in an in vivo pharmacokinetics research with 9.47 folds higher AUC (0-t) compared to plain THC-suspension. Additionally, pharmacodynamic experiments of optimized formulation demonstrated a marked decrease in blood glucose level to 63.7% and increased body weight from 195.8 ± 7.223 to 231.2 ± 7.653 on the 28th day of the study and showed a better anti-diabetic effect than plain drug suspension. Results of stability studies revealed that formulation can be stored for longer periods at room temperature. Tetrahydrocurcumin can be effectively administered by SLN for the treatment of diabetes. [ABSTRACT FROM AUTHOR]

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 CCl 4 twice per week for 8 weeks. Daily oral administration of THC at 10 mg/kg and 50 mg/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. [ABSTRACT FROM AUTHOR]

Tetrahydrocurcumin (THCu) is one of the major reduction metabolites of curcumin (CUR), which is a well-known yellow food pigment from turmeric with strong antioxidant, anti-inflammatory, and antibacterial properties. THCu exhibits better solubility, stability, bioavailability than CUR and similar pharmacological activities. In recent years, the market demand for the colorless THCu has a large growth for its application in the field of functional foods and cosmetics due to its strong antioxidant and skin-whitening function. Current industrial production mainly relies on chemical synthesis. The environmental-friendly and good-selectivity synthesis methods like microbial/enzymatic transformation might be better alternative. Several microorganisms have been reported with the capability of CUR reduction. Good-selectivity enzymes also have been characterized like alcohol dehydrogenase from equine liver and curcumin reductase from gut bacteria. This review focuses on the production technology of THCu and summarizes researches on its new chemical synthesis strategies, possible bioconversion methods, detection methods and potential applications. [Display omitted] • Tetrahydrocurcumin displays better stability, absorption and biological activity. • New synthesis materials and routes were disclosed with high yield and purity. • Microbial biotransformation methods generally produce various byproducts. • Enzymatic biotransformation displayed high regioselectivity but low yield. • The application includes skin whitening and anti-aging, chemopreventation, etc. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a non-essential heavy metal with high toxicity potential. Humans are exposed to Cd present in diet, polluted air, and cigarette smoke. Cd exposure has been associated with increased risk of chronic diseases, including hypertension, atherosclerosis, diabetes, and nephropathy, all of which could be attributable to dysfunctional endothelial and smooth muscle cells. Cd toxicity is correlated with increased reactive oxygen formation and depletion of antioxidants, resulting in an oxidative stress. Chelation of Cd has proved useful in the removal of the Cd burden. However, several chelating agents cause side effects in clinical usage. Recent studies have shown that the antioxidant compounds curcumin and tetrahydrocurcumin can alleviate vascular dysfunction and high blood pressure caused by Cd toxicity. In chronic Cd exposure, these antioxidants protect vascular endothelium by increasing nitric oxide (NO?) bioavailability and improving vascular function. Antioxidant activity against Cd intoxication results directly and/or indirectly through free radical scavenging, metal chelation, enhanced expression of the antioxidant defense system, regulation of inflammatory enzymes, increase in NO? bioavailability, and reduction of gastrointestinal absorption and tissue Cd accumulation. This review summarizes current knowledge of Cd-induced oxidative stress and cardiovascular dysfunction and a possible protective effect conferred by the antioxidants curcumin and tetrahydrocurcumin. [ABSTRACT FROM AUTHOR]

Background: Acute myocardial dysfunction in patients with sepsis is attributed to oxidative stress, inflammation, and cardiomyocyte loss; however, specific drugs for its prevention are still lacking. Tetrahydrocurcumin (THC) has been proven to contribute to the prevention of various cardiovascular diseases by decreasing oxidative stress and inflammation. This study was performed to investigate the functions and mechanism of action of THC in septic cardiomyopathy.Methods: After the oral administration of THC (120 mg/kg) for 5 consecutive days, a mouse model of sepsis was established via intraperitoneal lipopolysaccharide (LPS, 10 mg/kg) injection. Following this, cardiac function was assessed, pathological section staining was performed, and inflammatory markers were detected.Results: Myocardial systolic function was severely compromised in parallel with the accumulation of reactive oxygen species and enhanced cardiomyocyte apoptosis in mice with sepsis. These adverse changes were markedly reversed in response to THC treatment in septic mice as well as in LPS-treated H9c2 cells. Mechanistically, THC inhibited the release of pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin (IL)-1β, and IL-6, by upregulating mitogen-activated protein kinase phosphatase 1, to block the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK). Additionally, THC enhanced the levels of antioxidant proteins, including nuclear factor-erythroid 2-related factor 2, superoxide dismutase 2, and NAD(P)H quinone oxidoreductase 1, while decreasing gp91phox expression. Furthermore, upon THC treatment, Bcl-2 expression was significantly increased, along with a decline in Bax and cleaved caspase-3 expression, which reduced cardiomyocyte loss.Conclusion: Our findings indicate that THC exhibited protective potential against septic cardiomyopathy by reducing oxidative stress and inflammation through the regulation of JNK/ERK signaling. The findings of this study provide a basis for the further evaluation of THC as a therapeutic agent against septic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Abstract: The present study was undertaken to investigate the protective effect of tetrahydrocurcumin (THC) and chlorogenic acid (CGA) against streptozotocin (STZ)–nicotinamide (NA)-induced type 2 diabetes in adult Wistar rats. Diabetes was induced in experimental rats weighing 180–220g, by a single intraperitoneal (i.p.) injection of STZ (45mg/kg BW), 15min after the (i.p.) administration of NA (110mg/kg BW). THC (80mg/kg BW) and CGA (5mg/kg BW) were orally administered to diabetic rats for a period of 45days. Fasting plasma glucose, glycosylated haemoglobin (HbA1C), thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides (LOOH) were significantly increased, whereas insulin, total haemoglobin (Hb), non-enzymic antioxidants (reduced glutathione (GSH), vitamin C, vitamin E and ceruloplasmin) were decreased significantly in diabetic rats. Though the diabetic rats treated with THC and CGA individual exerts beneficial effects in all the biochemical parameters in (STZ)-induced diabetic rats. The combined treatment with THC and CGA normalized all the above-mentioned biochemical parameters in STZ-induced diabetic rats. Normal pancreatic histological architecture in THC and CGA treated diabetic rats revealed that these phytochemical exert higher degree of protection when administered in combination than single treatment of individual compounds. [Copyright &y& Elsevier]

[Display omitted] • 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. [ABSTRACT FROM AUTHOR]

[Display omitted] • Tetrahydrocurcumin (THC) improves glucose and lipid metabolism disorders in nonalcoholic fatty liver disease (NAFLD) in mice. • THC regulates the expression of oxidoreductase genes and lipid-metabolizing enzyme genes in the liver of NAFLD mice. • THC increases the antioxidant capacity and inhibits lipid deposition in HepG2 cells by activating the NRF2 signaling pathway. Nonalcoholic fatty liver disease (NAFLD) is the most common liver metabolic disease in the world. In this study we investigated the effect of tetrahydrocurcumin (THC), a potent antioxidant, on NAFLD. We found that THC significantly reduced the body weight, serum and liver lipids, serum malondialdehyde (MDA) and fasting blood glucose (FBG) of male NAFLD mice induced by feeding a high-fat diet (HFD) for 8 weeks. A RNA-seq analysis revealed that THC also affected the expression of many genes involved in lipid metabolism in the liver of NAFLD mice, including increasing the mRNA expression of CYP51 and FOXQ1. Moreover, THC significantly reduced sodium oleate-induced lipid accumulation, activated the NRF2 pathway, and up-regulated the mRNA expression of FGF21 in HepG2 cells. Overall, our study showed that THC can improve the antioxidant capacity of liver, which suggests that dietary THC may be used to treat NAFLD. [ABSTRACT FROM AUTHOR]

[Display omitted] • γ-cyclodextrin and bile acids synergistically increase the solubility of curcumin. • γ-cyclodextrin complexed curcumin enhances the metbolic bioavailability of tetrahydrocurucmin in humans. • γ-cyclodextrin complexed curcumin yields higher serum levels of tetrahydrocurcumin than curcumin. • Long-term supplementation of γ-cyclodextrin complexed curcumin is well tolerated. Tetrahydrocurcumin, curcumin's main metabolite, exhibits properties similar to curcumin with superior effectiveness in certain categories. However, as curcumin's bioavailabilty and in vivo conversion are low, formulations yielding appreciable tetrahydrocurcumin concentrations are required to convey potential health benefits either through tetrahydrocurucmin itself, complementary or synergistic to curcumin. Here, we conducted a study with humans orally receiving γ-cyclodextrin complexed curcumin for 12 weeks daily and analyzed the metabolic bioavailability of tetrahydrocurcumin. Notably, supplementation yielded threefold higher serum tetrahydrocurcumin compared to curcumin already after 4 weeks. In fact, this is in line with previously unpublished data demonstrated here revealing an increased metabolic bioavailability (BA = 39.8) of tetrahydrocurcumin. Foremost we show that γ-cyclodextrin enhances the oral and metabolic bioavailability of curcumin and tetrahydrocurcumin, respectively. This is likely related to an improved uptake of cyclodextrin complexed curcumin corroborated by enclosed in vitro studies, its metabolic turnover and the prolonged plasma half-life of tetrahydrocurcumin. [ABSTRACT FROM AUTHOR]