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Sepsis-induced acute kidney injury (AKI) continues to be associated with poor outcomes in critical care patients. Previous research has revealed that tetrahydrocurcumin (THC) exerts renoprotective effects in multiple nephritic disorders by modulating inflammation and oxidative stress. However, the effects of THC on sepsis-induced AKI and the underlying mechanisms remain unclear. In this study, a mouse model of sepsis-induced AKI, generated by cecal ligation and puncture operation, was used to investigate the protective effects of THC and the role of SIRT1. Histological manifestation and TUNEL analysis were observed to determine the severity of kidney damage. Levels of BUN, SCr, KIM-1, and UAlb/Cr were calculated to assess the renal function. Expressions of IL-1β, IL-6, and TNF-α were measured to evaluate the inflammatory response. MDA content, SOD, GSH, CAT, and GPx activities and DHE staining were analyzed to estimate the degree of oxidative stress. Protein expressions of SIRT1, Ac-p65, and Ac-foxo1 were detected to explore the underlying mechanisms. We observed that THC not only increased the survival rate, improved the kidney function and ameliorated the renal histological damage of septic mice, but also inhibited inflammatory response, prohibited oxidative stress, and prevented cell apoptosis in renal tissues in septic mice. Mechanistically, THC remarkably increased the expression of SIRT1, accompanied by decreased expressions of downstream molecules Ac-p65 and Ac-foxo1. Meanwhile, the beneficial effects of THC were clearly abolished by the SIRT1-specific inhibitor EX527. These results delineate that THC prevents sepsis-induced AKI by suppressing inflammation and oxidative stress through activating the SIRT1 signaling. Abbreviation: Ac-p65: acetylated p65; Ac-foxo 1: acetylated forkhead box O1; AKI: acute kidney injury; BUN: blood urea nitrogen; CAT: catalase; DHE: dihydroethidium; GPx: glutathione peroxidase; GSH: reduced glutathione; IL-1β: Interleukin-1 beta; IL-6: Interleukin-6; KIM-1: kidney injury molecule 1; MDA: malondialdehyde; SCr: serum creatinine; SIRT1: silent information regulator 1; SOD: superoxide dismutase; THC: tetrahydrocurcumin; TNF-α: tumor necrosis factor-alpha; TUNEL: TdT-mediated dUTP Nick-End Labeling; UAlb/Cr: urine micro albumin/creatinine. [ABSTRACT FROM AUTHOR]

Objectives: The present study aimed to develop and validate a discriminative dissolution method for tetrahydrocurcumin (THC), a Biopharmaceutical Classification System class II drug, by a simple ultraviolet (UV) spectrophotometric analysis. The final dissolution medium composition was selected based on the solubility and stability criteria of the drug. Materials and Methods: As a prerequisite for this, the solubility of the drug was assessed in media of different pH (1.2-7.4), and surfactant concentrations of 0.5-1.5% (w/v) sodium lauryl sulfate (SLS) in water, and pH 7.4 phosphate buffer. The dissolved drug concentration in each medium was quantified by UV analysis at 280 nm wavelength. Results: The drug solubility was found to be high at a pH of 1.2 and 7.4. The media with surfactant enhanced solubility of the drug by approximately 17-fold and exhibited better sink conditions. The discriminative power of the developed dissolution medium (i.e., 1% w/v SLS in pH 7.4) was determined by performing in vitro dissolution studies of the prepared THC tablets and comparing their release profiles using fit factors (f1 and f2). The results of the fit factor comparisons made between the dissolution profiles of THC tablets proved the discriminative ability of the medium. The validation of the developed dissolution method was performed by international guidelines and the method showed specificity, linearity, accuracy, and precision within the acceptable range. Conclusion: The proposed dissolution method was found to be adequate for the routine quality control analysis of THC, as there is no specified dissolution method for the drug in the pharmacopoeia. [ABSTRACT FROM AUTHOR]

Background: Activation of the intrarenal renin-angiotensin system (RAS) is implicated in the pathogenesis of kidney injury and hypertension. We aimed to investigate the protective effect of tetrahydrocurcumin (THU) on intrarenal RAS expression, kidney injury, and systolic blood pressure (SBP) in high-fat diet (HFD)-induced type 2 diabetic mice. Methods: Eight-week-old male mice were fed a regular diet (RD) or HFD for 12 weeks, and THU (50 or 100 mg/kg/day) was intragastrically administered with HFD. Physiological and metabolic changes were monitored and the expression of RAS components and markers of kidney injury were assessed. Results: HFD-fed mice exhibited hyperglycemia, insulin resistance, and dyslipidemia compared to those in the RD group (P<0.05). Kidney injury in these mice was indicated by an increase in the ratio of albumin to creatinine, glomerular hypertrophy, and the effacement of podocyte foot processes. Expression of intrarenal angiotensin-converting enzyme, angiotensin II type I receptor, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-4, and monocyte chemoattractant protein-1 was also markedly increased in HFD-fed mice. HFD-fed mice exhibited elevated SBP that was accompanied by an increase in the wall thickness and vascular cross-sectional area (P<0.05), 12 weeks post-HFD consumption. Treatment with THU (100 mg/kg/day) suppressed intrarenal RAS activation, improved insulin sensitivity, and reduced SBP, thus, attenuating kidney injury in these mice. Conclusion: THU alleviated kidney injury in mice with HFD-induced type 2 diabetes, possibly by blunting the activation of the intrarenal RAS/nicotinamide adenine dinucleotide phosphate oxidase IV (NOX4)/monocyte chemoattractant protein 1 (MCP-1) axis and by lowering the high SBP. [ABSTRACT FROM AUTHOR]

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.

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.

Analogs of curcumin and tetrahydrocurcumin are compounds that have been studied for a long time for their biological activities such as anticancer, antibacterial, antioxidant, antidiabetes and antiviral. This research is aimed to study the potency of curucmin and tetrahydrocurcumin analogs as antiviral agent against papain-like protease/deubiquitinase protein in Covid-19 drug virtually by using molecular docking of the analogs against 3E9S protein with PLANTS and MOE used as the docking programs. The results show that THHGV-6 is the most promising compound by using MOE method while THA-104 is the most potent one by using plants method. THA-102 is the most potent compound among all the tested ligands by using both MOE and PLANTS method. None of curcumin analogs show antiviral potency but many analogs of tetrahydrocurcumin show antiviral potency against 3E9S. This is in which may be developed further as antiSARS-Covid. [ABSTRACT FROM AUTHOR]

Hyperlipidemia is one of the major risk factors of cardiovascular complication in diabetes. A study was undertaken to evaluate the antihyperlipidemic activity of tetrahydrocurcumin (THC). Oral administration of THC (80mg/kg bodyweight) to streptozotocin-nicotinamide induced diabetic rats for 45 days, significantly reduced the elevated serum very low density lipoprotein (VLDL) and low density lipoprotein (LDL) - cholesterol levels and significantly increased the serum high-density lipoprotein (HDL)-cholesterol. THC showed a better effect when compared with curcumin. Results of the present study indicate that THC showed antihyperlipidemic effect in addition to its antidiabetic effect in type 2 diabetic rats. [ABSTRACT FROM AUTHOR]

Diabetes is a major health problem affecting major populations worldwide. It is characterized by absolute or relative deficiencies in insulin secretion and/or insulin action associated with chronic hyperglycemia and disturbances of carbohydrate, lipid and protein metabolism. As a consequence of the metabolic derangements in diabetes, various complications develop including both macro and micro-vascular dysfunctions. Pancreatic cell dysfunction and insulin resistance are the two hallmarks of type 2 diabetes mellitus. Treatment of diabetes without any side effects is still a challenge to the medical system. There is an increasing demand by patients to use the natural products with antidiabetic activity, because insulin and oral hypoglycemic drugs are having so many side effects. Streptozotocin (STZ)-nicotinamide type 2 model shares a number of features with human type 2 diabetes and is characterized by moderate stable hyperglycemia, glucose intolerance, altered but significant glucose-stimulated insulin secretion, in vivo and in vitro. Tetrahydrocurcumin (THC) is one of the major colorless metabolite of curcumin. THC has been reported to exhibit the same physiological and pharmacological properties of curcumin. Curcumin is rapidly metabolized during absorption from the intestine, yielding THC, which has shown the strongest antioxidant activity among all curcuminoids. THC one of the active metabolites in curcumin on blood glucose and plasma insulin in streptozotocin induced diabetic rats. Different doses of THC (20, 40 and 80 mg\kg body weight) were orally administered to diabetic rats for 45 days, after which activities 6-weeks treatment with various doses of THC and curcumin on glucose levels were assayed. [ABSTRACT FROM AUTHOR]

Curcumin, a secondary metabolite from the turmeric plant is one of the most promising natural products, which has been studied extensively for decades. It has demonstrated several pharmacological activities in vitro and in vivo. Various studies have indicated that the pharmacological activity of curcumin is contributed by its metabolites.The aim of this review is to present an overview of metabolic products of curcumin produced upon its reduction like di, tetra, hexa and octa-hydrocurcumin. In addition, this paper has systematically analyzed the current information regarding medicinal use of reduced metabolites of curcumin and identified the limitations which have hindered its widespread usage in the medical world. Several diverse therapeutic effects have shown to be exhibited by reduced metabolites of curcumin such as antioxidant, anti-cancerous, anti-inflammatory and immunoregulatory activities. The potential underlying molecular mechanisms of the biological activities of reduced metabolites of curcumin have also been highlighted, which may provide insight into the principle of effectiveness of curcumin.

Curcumin, a natural ingredient present in turmeric rhizome is known for its various therapeutic activities such as antioxidant, anti-inflammatory, anticancer, antidiabetic, NF-kB activation suppresser. The hydrogenated derivative of curcumin, i.e., tetrahydrocurcumin, is also found to reveal the same activities. Moreover, the pro-oxidant effect of curcumin is reported, whereas tetrahydrocurcumin does not show any pro-oxidant effects. This contrasting behaviour of the two is attributed to their structures, because conjugation is involved only in curcumin, not in the tetrahydrocurcumin. It can be evidently concluded that double bonds affect the keto-enol ratio of the molecules and are therefore responsible for the degradation of curcumin, whereas tetrahydrocurcumin remains stable. Nevertheless, these double bonds are liable to affect the kinetics of beneficial activities of curcumin and tetrahydrocurcumin. [ABSTRACT FROM AUTHOR]

Background: Tetrahydrocurcumin (THC) is the major active metabolite of curcumin, which is a dietary factor derived from Curcuma species. Our previous study demonstrated a significant beneficial effect of THC in mice with allergic asthma. Glucocorticosteroids (GCs) are commonly used drugs in asthma. Whether THC supplementation could promote the beneficial effects of GC therapy on asthma has not yet been reported. The current study aimed to investigate the combined efficacy of GC and THC treatment in a mouse model of allergic asthma. Methods: BALB/c mice were randomly divided into 5 groups: the control group, ovalbumin (OVA)-induced group, and OVA-induced mice treated with dietary THC only, intraperitoneal injection of dexamethasone (DEX) only, or THC combined with DEX. The nasal symptoms, histopathological alterations of lung tissues, lung cytokine production, and Th cell subsets were assessed. Results: THC or DEX had beneficial effects on nasal symptoms and pathological lung changes, and the therapeutic effects between THC and DEX treatment were comparable. Importantly, compared to the monotherapy groups (THC or DEX only), the combination of THC and DEX showed a significantly reduced nasal rubbing frequency, lower mucus hyperproduction, lower Th2 and Th17 cell numbers as well as lower related cytokine levels (IL-4, IL-5, and IL-17A). Conclusions: Supplementation with THC can enhance the therapeutic effects of DEX to alleviate airway symptoms, lung inflammation, and the Th2 response. Our findings suggest that dietary administration of THC could act as an add-on therapy for asthma treated with GCs. [ABSTRACT FROM AUTHOR]

High‐altitude cerebral oedema (HACE) is a potentially fatal manifestation of high‐altitude sickness and is caused partly by inflammation and the blood–brain barrier disruption. Tetrahydrocurcumin (THC) has been reported to exert effective antioxidative and anti‐inflammatory effects; This study sought to elucidate the underlying mechanism of THC in mitigating HACE using a mouse model. Our results revealed that prophylactic administration of THC (40 mg/kg) for 3 days significantly alleviated the increase in brain water content (BWC), interleukin‐1β (IL‐1β) and TNF‐α levels caused by acute hypobaric hypoxia (AHH). Additionally, superoxide dismutase (SOD) activity was increased by THC to enhance the ability to resist hypoxia. Histological and ultrastructural analysis of the cerebrum revealed that THC administration mitigated AHH‐induced pericellular oedema and reduced the perivascular space, resulting in the simultaneous remission of oedema and protection of mitochondria in the cerebrum. In vitro, astrocytes exposed to hypoxia (4% O2) for 24 hr exhibited and increase in IL‐1β expression followed by an increase in vascular endothelial growth factor (VEGF) levels. Furthermore, THC administration remarkably downregulated VEGF, matrix metallopeptidase‐9 (MMP‐9), and nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) expression, both in vivo and in vitro. Our data highlight the potential prophylactic activity of THC in HACE, it effectively mitigates AHH‐induced cerebral oedema and inflammation is associated with the inhibition of the NF‐κB/ VEGF/MMP‐9 pathways. [ABSTRACT FROM AUTHOR]

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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]

Abstract Tetrahydrocurcumin (THC) is a major metabolite of curcumin and plays an important role in curcumin-induced biological effects. THC is a promising preventive and chemotherapeutic agent for cancer. A series of new pyrazole derivatives of THC have been synthesized as potent anticancer agents. Direct condensation of THC with various substituted hydrazines leads to new pyrazole derivatives of THC (1–18). The prepared compounds have been evaluated via in vitro MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay for their cell proliferation-inhibitory activity against human lung adenocarcinoma (A549), human cervical carcinoma (HeLa) and human breast carcinoma (MCF-7) cells. Most derivatives show significantly higher anticancer activity against all three tested cancer cell lines than the parent compound THC. Several compounds (7, 8, 12, 13 and 15) display promising anticancer activity against MCF-7 cell line with IC50 values ranging from 5.8 to 9.3 µM. The most active compound (8) is substituted with 4-bromophenyl group at the pyrazole ring and inhibits the growth of all three tested cancer cell lines with an IC50 values of (8.0 µM, A549), (9.8 µM, HeLa) and (5.8 µM, MCF-7). The obtained compounds can be a good starting point for the development of new lead molecules in the fight against cancer. Graphical Abstract

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 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.

Tetrahydrocurcumin (THC) has been well known for its superior antioxidant properties. Therefore, it is speculated that it might be effective to relieve oxidative stress-induced diseases, such as skin hyperpigmentation. In this work, an in vitro B16F10 melanoma cell model was used to study the impact of THC on the melanogenic process under stressed conditions. It was demonstrated that THC could effectively inhibit the α-MSH (melanocyte-stimulating hormone) induced melanin production in B16F10 melanoma cells and the expressions of three key enzymes involved with the biosynthetic process of melanin, tyrosinase (TYR), tyrosinase-related protein 1 (TRP-1), and tyrosinase-related protein 2 (TRP-2), were all significantly reduced. In addition, an in vitro human keratinocyte cell model was used to investigate the potential protective role of THC on H2O2-induced cytotoxicity. It was found that THC could prevent H2O2-induced oxidative stress based on the results of both the cell viability study and the intracellular ROS (reactive oxygen species) study assessed by the flow cytometry. Last, THC was formulated into a lecithin based nanoemulsion, and an in vitro Franz diffusion cell study using Strat-M® membrane concluded that the nanoemulsion could significantly enhance the membrane permeation compared to the unformatted THC suspension. This research demonstrated the anti-melanogenic benefits of THC on the melanoma and keratinocyte cell models and the topical delivery efficacy could be significantly enhanced using a lecithin based nanoemulsion.

Cereals are subject to contamination by pathogenic fungi, which damage grains and threaten public health with their mycotoxins. Fusarium graminearum and its mycotoxins, trichothecenes B (TCTBs), are especially targeted in this study. Recently, the increased public and political awareness concerning environmental issues tends to limit the use of traditional fungicides against these pathogens in favor of eco-friendlier alternatives. This study focuses on the development of biofungicides based on the encapsulation of a curcumin derivative, tetrahydrocurcumin (THC), in polysaccharide matrices. Starch octenylsuccinate (OSA-starch) and chitosan have been chosen since they are generally recognized as safe. THC has been successfully trapped into particles obtained through a spray-drying or freeze-drying processes. The particles present different properties, as revealed by visual observations and scanning electron microscopy. They are also different in terms of the amount and the release of encapsulated THC. Although freeze-dried OSA-starch has better trapped THC, it seems less able to protect the phenolic compound than spray-dried particles. Chitosan particles, both spray-dried and lyophilized, have shown promising antifungal properties. The IC50 of THC-loaded spray-dried chitosan particles is as low as 0.6 ± 0.3 g/L. These particles have also significantly decreased the accumulation of TCTBs by 39%.

It has been reported that tetrahydrocurcumin has hypoglycemic, hypolipidemic, anti-metastasis, anticancer and anti-depressant pharmacological effects, and its antioxidative, hypoglycemic and hypolipidemic properties are better than those of curcumin. The present study assessed whether tetrahydrocurcumin exerts a neuroprotective effect against spinal cord injury (SCI) and investigated the underlying mechanisms. In a rat model of SCI, tetrahydrocurcumin enhanced the average Basso-Beattie-Bresnahan scores, inhibited water accumulation in the spinal cord and decreased inflammatory factors. Furthermore, oxidative stress and apoptosis (caspase-3 activity and B-cell lymphoma 2-associated X protein levels) were also suppressed in SCI rats treated with tetrahydrocurcumin. Tetrahydrocurcumin effectively decreased the gene expression of matrix metalloproteinase-3 and −13, as well as cyclooxygenase-2, promoted the phosphorylation of Akt and enhanced the protein expression of forkhead box (FOX)O4 in SCI rats. The present study delineates that tetrahydrocurcumin protects against SCI and inhibits the oxidative stress response by regulating the FOXO4 in SCI model rats. [ABSTRACT FROM AUTHOR]

Ocular drug delivery has been a well-known route for the drug administration for the treatment of ocular diseases. However, numerous anatomical and physiological barriers prevailing in the eye itself create considerable challenges for achieving the necessitated therapeutic efficacy along with ocular bioavailability. However, recent advances in nanoengineered strategies hold definite promises in terms of devising improved ophthalmic medicines for the effective drug delivery to target the sites with enhanced ocular bioavailability. Curcumin, a hydrophobic polyphenol yellow colored compound, and its metabolic reduced product, tetrahydrocurcumin (THC), have been known for their beneficial pharmacological functions, such as anti-inflammatory or anti-oxidant activities at various tissue sites. However, the low aqueous solubility of these compounds results in their poor bioavailability, thereby limiting their widespread application. Therefore, in the present study, we investigated the changes in drug solubility by forming inclusion complexes with different derivatives of hydroxypropyl (HP)-cyclodextrins (CD). To this end, the spray drying technique was used for nanoengineering curcumin or THC-loaded formulations to improve the stability of formulations during the storage. The formulations were characterized in terms of physicochemical properties and cellular permeability. The results demonstrated that the encapsulation of curcumin (or THC) into the HP-CDs significantly increased the drug solubility and enhanced the corneal and retinal epithelial permeability. Curcumin or THC complexes in HP-CDs with improved bioavailability also induced anti-oxidant activity (SOD1, CAT1, and HMOX1) in higher levels in the ocular epithelial cells and showed oxidative protection effects in rabbit cornea tissues that will boost up their application in ocular medicine. [ABSTRACT FROM AUTHOR]

Wound healing refers to the healing process of skin and other tissues appear to be broken or defective after one body suffers external force. Accelerating wound healing through the use of natural products isolated from plants and microbes is a hot research topic. Tetrahydrocurcumin is one of the major in vivo colorless hydrogenated metabolites of curcumin with superior wound healing and anti-inflammatory properties. The poor bioavailability of these curcuminoids limits their clinical applications. Preparation of curcuminoids-loaded nanoparticles is one appropriate method of addressing this issue. In this study, tetrahydrocurcumin nanoparticles were firstly used for wound healing. In vitro experiments revealed that tetrahydrocurcumin-loaded MPEG-PLA nanoparticles (THC-NPs) could stimulate the closure of defect by enhancing directional migration of human fibroblasts in tetrahydrocurcumin dose-dependent manner. In addition, we also evaluated the effect of sodium alginate/chitosan dressings featuring THC-NPs on wound healing. We found that the nanometer dressings (sodium alginate/chitosan dressings featuring THC-NPs) could accelerate wound healing by improving collagen deposition, increasing vascular density in a rat model of wound repair. These results demonstrated that THC-NPs could promote cutaneous healing by increasing the synthesis of collagen I and III, revascularization and improving the migration of fibroblasts. Thus, THC-NPs have the potential for enhancing wound healing progress. [ABSTRACT FROM AUTHOR]

Objective: Tetrahydrocurcumin (THC) has been used as a component of skin whitening cream. However, very little is known about the mechanisms for how THC regulates melanogenesis. The aim of the present study was to investigate mechanisms involved in the regulation of melanogenesis by THC using B16F10 murine melanoma cells. Methods: B16F10 cells were treated with various concentrations of THC (0–30 µg/mL) in the presence of 0.1 nM ±-melanocyte stimulating hormone (±-MSH). Total melanin content; intracellular tyrosinase activity; and levels of melanogenic proteins, i.e., microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein 1 (TYRP1), and signaling proteins, i.e, Akt, glycogen synthase kinase 3β (GSK3β), and β-catenin, were analyzed. Change in cell morphology was also observed. Results: THC-Treatment caused a significant and dose-dependent decrease in total melanin content compared to control cells treated with α-MSH alone. At the early stage of melanogenesis, when melanin secretion was minimal, THC-treatment caused decreases in the activity of tyrosinase and the levels of tyrosinase and MITF proteins. Conversely, at the late stage of melanogenesis, when melanin secretion was evidently exhibited in control cells, remarkable increases in the intracellular levels of tyrosinase and TYRP1, the melanosomal proteins, were observed in THC-treated cells. THC-treatment caused decreases in Akt and GSK3β phosphorylation and β-catenin content. A significant alteration of cell morphology, i.e. elongation and loss of dendritic structure, was also observed. Conclusion: The present study demonstrated that THC-treatment inhibited α-MSH-induced melanin synthesis in B16F10 cells by downregulating MITF and tyrosinase proteins and decreasing tyrosinase activity. In addition, THC inhibited secretion of melanosomes, which appears to be associated with cell morphology alteration accompanying a loss of dendritic structure. THC caused decreases in the phosphorylation of Akt and GSK3β and the content of β-catenin, suggesting involvement of GSK3β activation and subsequent attenuation of β-catenin signaling in the anti-melanogenic effects of THC. [ABSTRACT FROM AUTHOR]

• First UHPLC-MS/MS report to determine curcumin, tetrahydrocurcumin, quercetin, and paeoniflorin simultaneously. • The method was successfully applied to a pharmacokinetic study after oral co-administration of CUR, QR and PF to rats. • The UHPLC-MS/MS method was simple, rapid, sensitive and reliable. • The effect of QR and PF combination on the pharmacokinetics of CUR and THC was evaluated for the first time. • This study will provide a basic reference method for the analysis of the pharmacokinetic interaction of CUR, QR and PF. Curcumin (CUR) is a bioactive compound present in many composite prescriptions of traditional Chinese medicine together with quercetin (QR) and paeoniflorin (PF). Little is known about the influence of QR and PF on the absorption and metabolism of CUR when the three compounds are orally co-administered. In this study, a rapid, sensitive, and reliable ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the simultaneous determination of CUR, tetrahydrocurcumin (THC), QR, and PF in rat plasma by using tinidazole as the internal standard (IS). A liquid-liquid extraction method with ethyl acetate was used to pre-treat the plasma samples. Chromatographic separation was conducted on a C18 column with isocratic elution using acetonitrile and 0.1% formic acid water solution (80:20, v/v) as the mobile phase at the flow rate of 0.3 mL/min. A TSQ Quantum Access Max API mass spectrometer equipped with electrospray ionisation (ESI) source in selection reaction monitoring (SRM) mode was employed to determine transitions of m / z 369.0 → 176.9, 373.1 → 137.0, 303.0 → 228.9, 478.9 → 120.9, 248.1 → 121.0 for CUR, THC, QR, PF, and IS, respectively. The selectivity, precision, accuracy, extraction recovery, matrix effect, and stability of the method were validated. This developed and validated method was successfully applied in the pharmacokinetic study of CUR, THC, QR, and PF in rats. The effects of QR and PF on the pharmacokinetics of CUR and its metabolite, THC, were evaluated in the plasma of Sprague-Dawley rats that were orally co-administered CUR, QR, and PF. The results showed that the combined use of QR, PF, and CUR has a possible influence on the metabolism and excretion of CUR. Our work provides a fundamental method for the rapid simultaneous determination of CUR, THC, QR, and PF in rat plasma. Furthermore, this study will provide a basic method for the analysis of pharmacokinetic interaction of CUR, QR, and PF and offer a scientific basis for a possible combination therapy with the three compounds. [ABSTRACT FROM AUTHOR]

A vaginal microbicide is a front-line women-dependent approach and an alternative to a condom for prevention of unprotected sexual intercourse-associated HIV. The microbicide research is still in its infancy with several products in the clinical studies being reported to have good efficacy, safe, but with poor adherence. One such molecule reported with an excellent efficacy when tested preclinically is curcumin, a natural polyphenol derived from Curcuma longa. Despite its potential HIV-1 inhibitory activity, it has intense yellow color staining properties, which would result in poor consumer compliance and adherence for vaginal application. To address this issue, tetrahydrocurcumin (THC), a colorless derivative of curcumin, was subjected to in silico screening (molecular docking and dynamics simulation studies) using homology model of gp120-CD4 binding. It was found that THC exhibited equivalent gp120-CD4 binding inhibitory activity as compared with curcumin due to its stable hydrophobic interactions with residues Asp368 and Trp427 deeper in the Phe43 cavity of CD4 receptor. Hence, it can be effectively used as a potential microbicide candidate. THC, a BCS Class II molecule exhibits poor solubility, spreadability, and intracellular uptake when used in the conventional form. Thus, it was decided to develop a lipid-based nanomicrobicide gel for delivery of THC. The developed THC-loaded o/w microemulsion gel was characterized for physicochemical properties (globule size, drug content, drug release, and permeation) and further used for in vitro cell line studies (cell viability, cellular uptake, and anti-HIV activity). The developed formulation was found to be stable with coitus-independent release profile and exhibited a rapid time-independent intracellular uptake. In addition, it exhibited a fourfold increase in efficacy as compared with conventional THC. Thus, the novel THC-loaded o/w microemulsion gel exhibited the potential for prevention of HIV-1 infection associated with unprotected sexual intercourse. [ABSTRACT FROM AUTHOR]

Curcumin has chemopreventative properties against a variety of tumours, but has poor bioavailability. Here, two new bis‐cyclometallated iridium(III) complexes have been prepared, featuring the natural product curcumin (CUR) or its reduced form, tetrahydrocurcumin (THC), as bidentate, anionic O O‐binding ligands. The iridium THC complex is highly luminescent in deoxygenated solution and efficiently generates singlet oxygen under aerated conditions, whereas in the CUR analogue, other non‐radiative decay pathways are competitive. The complexes are rapidly taken up by a variety of human tumour cell lines from solutions of micromolar concentration. They show negligible cytotoxicity in the absence of irradiation. When briefly irradiated with visible light, Ir‐THC becomes highly phototoxic, inducing rapid apoptosis within 2 h. The results show the high potential of such complexes as sensitizers in photodynamic therapy (PDT). [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]

Most anticancer agents induce cancer cell death; however, multidrug-resistant cancers often lead to treatment failure. The effective use of curcumin as an anticancer agent has been demonstrated in clinical trials. Tetrahydrocurcumin, a major curcumin metabolite, exhibits pharmacological activities similar to those of curcumin. Curcumin induces cell death mainly through the apoptosis pathway, and tetrahydrocurcumin induces cell death mainly via an autophagy pathway in HL60 cells. Here, we investigated whether curcumin and tetrahydrocurcumin can induce apoptosis- and autophagy-mediated cell deaths in Ara-C-resistant cancer cells, respectively. The results demonstrated that curcumin and tetrahydrocurcumin induced cell death by apoptosis and autophagy, respectively, in Ara-C-resistant HL60 cells. Thus, curcumin and tetrahydrocurcumin have potential applications in the treatment of acute myeloid leukemia with Ara-C resistance. [ABSTRACT FROM AUTHOR]

Abstract Pelleted preparations were formulated from sacran (Sac), an anionic, sulfated, carboxyl-containing polysaccharide, which is extracted from the Japanese indigenous cyanobacterium Aphanothece sacrum , and surface-deacetylated chitin nanofibers (SDACNF). The use of this material as an extended-release excipient for tetrahydrocurcumin (THC), a model drug that is used to treat wounds via its radical scavenging ability was examined. The THC used in the study was complexed with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), which increases its water solubility. The radical scavenging activity of the THC/HP-β-CD complex (molar ratio of 1:1) was significantly higher than the values for SDACNF or Sac alone. The rate of release of THC from the Sac/SDACNF pellets containing the THC/HP-β-CD complex decreased with increasing Sac content in the pellet, suggesting that Sac/SDACNF (1:1) and Sac alone pellets function as extended-release excipients for THC. The findings reported here indicate that this can be attributed to the ability of the Sac component to retain fluids, thus extending the effects of the drug. In view of the above experimental outcomes, i.e. wound healing efficacy, fluid absorption, retention and the extended drug release of the system indicates that this preparation, in the appropriate ratios, has the potential for use as a controlled-release drug in wound healing. [ABSTRACT FROM AUTHOR]

Purpose: Investigation of the impact of co-medication on the plasma levels of curcumin and tetrahydrocurcumin (THC) in cancer patients and a comparison of the pharmacokinetics of curcumin and plasma levels of THC between cancer patients and healthy individuals following intravenous infusion of Lipocurc™ (liposomal curcumin).Methods: Correlation analysis was used to determine the impact of co-medication on infusion rate normalized plasma levels of curcumin and THC in cancer patients and to compare the plasma levels of curcumin and THC at different infusion rates between cancer patients and healthy individuals. In vitro hepatocyte and red blood cell distribution experiments were conducted with Lipocurc™ to support clinical findings. Plasma concentration time data were analyzed by the non-compartmental method to determine and compare the pharmacokinetic parameters of curcumin in cancer patients and healthy individuals.Results: Of 44 co-medications studied, three medications targeting the renin-angiotensin system, Lisinopril, Ramipril, and Valsartan elevated plasma levels of curcumin and THC in three cancer patients infused with Lipocurc™. Cell distribution experiments indicated that the disposition of curcumin in red blood cells may be a target for elevation of the plasma levels of curcumin. Plasma levels of curcumin in cancer patients increased to a greater extent with increased infusion rate compared to healthy individuals. Upon termination of infusion, the elimination phase for curcumin was shorter with a shorter terminal half-life and smaller volume of distribution for curcumin in cancer patients compared to healthy individuals.Conclusion: Either co-medications or health status, or both, can impact the pharmacokinetics of curcumin infusion (as Lipocurc™) in cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: Tetrahydrocurcumin (THC), a hydrophobic polyphenolic bioactive substance extracted from turmeric, has been established as a natural anticancer agent. Unfortunately, its sparing solubility (approximately 1.3%) in water and its reduced systemic bioavailability has limited its efficacy. This study explores the use of an organic-based drug delivery approach via encapsulation to circumvent the pitfalls of THC's poor solubility and potentially improve its chemotherapeutic properties. Methods: An inclusion complex of THC with β-cyclodextrin (β-CD) at a molar ratio of 2:1 was formed and characterized using UV-vis spectroscopy, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). The inclusion complex's solubility assessment and drug release study were evaluated and compared with pure THC. The anticancer effects of the inclusion complex on colorectal cancer cells (SW480 and HCT116 cells) were investigated by MTT assays, migration assays, Transwell invasion assays, Annexin-V/PI staining assays, and poly adenosine diphosphate-ribose polymerase (PARP) cleavage assays. Results: The inclusion complex displayed higher aqueous dispersion (65-fold) and its physiochemical characterization confirmed the successful formation of a β-CD inclusion complex encompassing a hydrophobic cavity. Through the presence of an inclusion complex, cell viability was potentially reduced with an SI value >10 while the apoptosis rate was increased (p < 0.05) in vitro. Additionally, the complexation further enhanced both anti-migration and anti-invasion capabilities in comparison to pure THC. Both formulations were consistent in terms of caspase 3 activation. Conclusion: These findings provide evidence of the potential use of this formulation in rendering THC and conceptually other hydrophobic agents with an improved chemotherapeutic efficacy against various malignancies. [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]

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]

Astrocytes and the activation of inflammatory factors are associated with depression. Tetrahydrocurcumin (THC), the principal metabolite of natural curcumin, is renowned for its anti-inflammatory properties. In this research, we explored the impact of THC on the expression of inflammatory factors, neurotrophins, and transforming growth factor β1 (TGF-β1) in the prefrontal cortex after chronic restraint stress (CRS) in mice and in lipopolysaccharide (LPS)-induced TNC1 astrocytes. Our findings indicated that THC mitigated the anxiety and depression-like behaviours observed in CRS mice. It also influenced the expression of TGF-β1, p-SMAD3/SMAD3, sirtuin 1 (SIRT1), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), inducible nitric oxide synthase (iNOS), and tumour necrosis factor α (TNF-α). Specifically, THC augmented the expressions of TGF-β1, p-SMAD3/SMAD3, SIRT1, BDNF, and GDNF, whilst diminishing the expressions of iNOS and TNF-α in LPS-induced astrocytes. However, when pre-treated with SB431542, a TGF-β1 receptor inhibitor, it nullified the aforementioned effects of THC on astrocytes. Our results propose that THC delivers its anti-depressive effects through the activation of TGF-β1, enhancement of p-SMAD3/SMAD3 and SIRT1 expression, upregulation of BDNF and GDNF, and downregulation of iNOS and TNF-α. This research furnishes new perspectives on the anti-inflammatory mechanism that underpins the antidepressant-like impact of THC. [ABSTRACT FROM AUTHOR]

Background: Tetrahydrocurcumin (THC), an active metabolite of curcumin, has been reported to have similar biological effects to curcumin, but the mechanism of the antitumor activity of THC is still unclear. Methods: The present study was to investigate the antitumor effects and mechanism of THC in human breast cancer MCF-7 cells using the methods of MTT assay, LDH assay, flow cytometry analysis, and western blot assay. Results: THC was found to have markedly cytotoxic effect and antiproliferative activity against MCF-7 cells in a dose-dependent manner with the IC50 for 24 h of 107.8 μM. Flow cytometry analysis revealed that THC mediated the cell-cycle arrest at G0/G1 phase, and 32.8% of MCF-7 cells entered the early phase of apoptosis at 100 μM for 24 h. THC also dose-dependently led to apoptosis in MCF-7 cells via the mitochondrial pathway, as evidenced by the activation of caspase-3 and caspase-9, the elevation of intracellular ROS, a decrease in Bcl-2 and PARP expression, and an increase in Bax expression. Meanwhile, cytochrome C was released to cytosol and the loss of mitochondria membrane potential (Δψm) was observed after THC treatment. Conclusion: THC is an excellent source of chemopreventive agents in the treatment of breast cancer and has excellent potential to be explored as antitumor precursor compound.

Curcumin, a bioactive from Curcuma longa, has been shown to possess anti-melanogenic activity previously; however, the effects of its hydrogenated metabolites (HMs)—Tetrahydrocurcumin (THC), Hexahydrocurcumin (HHC), and Octahydrocurcumin (OHC)—on melanogenesis have not been sufficiently explored. We have studied and compared three HMs (THC, HHC, and OHC) with the parent compound, curcumin (PC), on melanin synthesis in B16F10 mouse and MNT-1 human melanoma cells. Our results demonstrated that all the HMs were nontoxic over the concentration range 5–40 µM, while PC was nontoxic at 5 µM but induced toxicity at 20 and 40 µM in B16F10 cells. All three HMs enhanced melanin synthesis, while PC (5 µM) inhibited it. THC (40 µM) significantly stimulated melanin synthesis to a greater degree than HHC and OHC in both B16F10 and MNT-1 cells; the order of melanogenesis stimulation was THC = OHC > HHC in B16F10 mouse cells, while it was THC > HHC > OHC in MNT-1 cells. HMs stimulated melanogenesis by pathways not involving tyrosinase, as neither the intracellular tyrosinase activity nor the protein levels of tyrosinase were affected. In addition, mushroom tyrosinase activity, using L-Dihydroxyphenylalanine (L-DOPA) as the substrate, showed no direct effects of HMs. In summary, our results demonstrate that the HMs enhanced melanogenesis, which establishes that the hydrogenation of the heptadiene moiety of curcumin leads to a loss of its anti-melanogenic activity and instead results in the stimulation of melanogenesis. This stimulation is not further enhanced upon hydrogenation of the β-diketone, which was noted in MNT-1 cells, although the correlation to the number of keto groups differed in B16F10 cells where HHC was the weakest stimulator of melanogenesis. Collectively, THC with both keto groups intact is the best stimulator. Moreover, our results also validate that the electrophilicity of curcumin is necessary for its anti-melanogenic activity, as the non-electrophilic HMs did not inhibit melanogenesis. Furthermore, our results suggest that THC might hold promise as a stimulator of melanogenesis for treatment of hypopigmentation disorders and anti-graying therapies. Future studies to probe the molecular signaling mechanisms and test whether the pro-melanogenic activity of HMs is retained in primary human melanocytes are warranted.

In recent decades, cancer has been one of the leading causes of death worldwide. Despite advances in understanding the molecular basis of tumorigenesis, diagnosis, and clinical therapies, the discovery and development of effective drugs is an active and vital field in cancer research. Tetrahydrocurcumin is a major curcuminoid metabolite of curcumin, naturally occurring in turmeric. The interest in tetrahydrocurcumin research is increasing because it is superior to curcumin in its solubility in water, chemical stability, bioavailability, and anti-oxidative activity. Many in vitro and in vivo studies have revealed that tetrahydrocurcumin exerts anti-cancer effects through various mechanisms, including modulation of oxidative stress, xenobiotic detoxification, inflammation, proliferation, metastasis, programmed cell death, and immunity. Despite the pharmacological similarities between tetrahydrocurcumin and curcumin, the structure of tetrahydrocurcumin determines its distinct and specific molecular mechanism, thus making it a potential candidate for the prevention and treatment of cancers. However, the utility of tetrahydrocurcumin is yet to be evaluated as only limited pharmacokinetic and oral bioavailability studies have been performed. This review summarizes research on the anti-cancer properties of tetrahydrocurcumin and describes its mechanisms of action.

Curcumin exerts a wide range of beneficial physiological and pharmacological activities, including antioxidant, anti-amyloid, anti-inflammatory, anti-microbial, anti-neoplastic, immune-modulating, metabolism regulating, anti-depressant, neuroprotective and tissue protective effects. However, its poor solubility and poor absorption in the free form in the gastrointestinal tract and its rapid biotransformation to inactive metabolites greatly limit its utility as a health-promoting agent and dietary supplement. Recent advances in micro- and nano-formulations of curcumin with greatly enhanced absorption resulting in desirable blood levels of the active forms of curcumin now make it possible to address a wide range of potential applications, including pain management, and as tissue protective. Using these forms of highly bioavailable curcumin now enable a broad spectrum of appropriate studies to be conducted. This review discusses the formulations designed to enhance bioavailability, metabolism of curcumin, relationships between solubility and particle size relative to bioavailability, human pharmacokinetic studies involving formulated curcumin products, the widely used but inappropriate practice of hydrolyzing plasma samples for quantification of blood curcumin, current applications of curcumin and its metabolites and promising directions for health maintenance and applications.

Curcumin (CUR), a promising naturally occurring dietary compound, is commonly recognized as the potential anti-inflammatory agent. While the application of CUR was hampered by its low stability and poor systemic bioavailability, it has been suggested that the biological activities of CUR are intimately related to its metabolites. In the current investigation, we aimed to comparatively explore the anti-inflammatory effects of tetrahydrocurcumin (THC), octahydrocurcumin (OHC), and CUR, and to elucidate the underlying action mechanisms on experimental mice models of acute inflammation, i.e., xylene-induced ear edema, acetic acid-induced vascular permeability, and carrageenan-induced paw edema. The results showed that THC and OHC exerted significant and dose-dependent inhibitions on the formation of ear edema induced by xylene and paw edema provoked by carrageenan and inhibited the Evans blue dye leakage in peritoneal cavity elicited by acetic acid. Moreover, THC and OHC treatments were more effective than CUR in selectively inhibiting the expression of cyclooxygenase 2 (COX-2) and suppressing nuclear factor-κB (NF-κB) pathways via transforming growth factor β activated kinase-1 (TAK1) inactivation in the carrageenan-induced mouse paw edema model.

In recent years, numerous researchers have made local chemical modifications to the structure of curcumin while its basic structure remains unchanged, thus, producing curcumin derivatives. In this article, tetrahydrocurcumin was obtained by hydrogenation of curcumin, DFT calculation and characterization at the theoretical level of B3LYP/6 -311++G(d,p) were carried out. The observed IR and Raman spectra are in good agreement with the theoretical spectra. The FMO and ESP of tetrahydrocurcumin are predicted. The interaction in the system is shown graphically and analyzed by IGMH. Compared with curcumin, tetrahydrocurcumin lacks the unsaturated C = C bond, which makes it more stable and more bioavailable. Molecular docking with antioxidant targets elucidated the ligand-protein interaction and molecular dynamics simulation showed the antioxidant activity of tetrahydrocurcumin. The antioxidant activity of tetrahydrocurcumin was proved by DPPH• and •OH radical scavenging experiments. In essence, these derivatives exhibit enhanced physiological activity in certain aspects compared to the original curcumin. Moreover, the computational pharmacology techniques lay a theoretical groundwork for the development and modification of high-efficiency, low-toxicity drugs that interface with various targets of curcumin in the future.Communicated by Ramaswamy H. Sarma.

The plant-derived polyphenol curcumin alleviates the inflammatory and metabolic effects of obesity, in part, by reducing adipose tissue inflammation. We hypothesized that the benefits of curcumin supplementation on diet-induced obesity and systemic inflammation in mice occur through downregulation of white adipose tissue (WAT) inflammation. The hypothesis was tested in adipose tissue from high-fat diet-induced obese mice supplemented with or without curcumin and in 3T3-L1 adipocytes treated with or without curcumin. Male B6 mice were fed a high-fat diet (HFD, 45% kcal fat) with or without 0.4% ( w / w ) curcumin supplementation (HFC). Metabolic changes in these mice have been previously reported. Here, we determined the serum levels of the curcumin metabolites tetrahydrocurcumin (THC) and curcumin-O-glucuronide (COG) using mass spectrometry. Moreover, we determined interleukin 6 (IL-6) levels and proteomic changes in LPS-stimulated 3T3-L1 adipocytes treated with or without curcumin by using immunoassays and mass spectrometry, respectively, to gain further insight into any altered processes. We detected both curcumin metabolites, THC and COG, in serum samples from the curcumin-fed mice. Both curcumin and its metabolites reduced LPS-induced adipocyte IL-6 secretion and mRNA levels. Proteomic analyses indicated that curcumin upregulated EIF2 and mTOR signaling pathways. Overall, curcumin exerted anti-inflammatory effects in adipocytes, in part by reducing IL-6, and these effects may be linked to the upregulation of the mTOR signaling pathway, warranting additional mechanistic studies on the effects of curcumin and its metabolites on metabolic health.

Tetrahydrocurcumin (THC) is a metabolite of curcumin and a valuable lead structure in medicinal chemistry due to its curcumin‐induced biological effects and its derivatives can be promising antitumor agents. Thirteen Schiff base derivatives of THC (1‐13) were synthesized by direct condensation of THC with various primary amines in moderate to very good yield (45‐94%) and their structures confirmed by 1H NMR, 13C NMR, HR‐ESI‐MS and IR techniques. Furthermore, these compounds were screened for in vitro anticancer activity against three human cancer cell lines including human epithelial lung carcinoma (A549), human epithelial cervical cancer (HeLa) and human breast adenocarcinoma (MCF‐7). Most compounds exhibit moderate to good anticancer activity against all three tested cell lines and are significantly more active than THC. Compound 12 bears an N‐(4‐trifluromethyl)phenylethyl group and is the most active compound with IC50 values ranging from 4.8 to 12.7 μM. The results obtained herein are important for further structure modifications of THC and the exploitation of the therapeutic potential of THC derivatives as anticancer agents. A series of 13 Schiff bases were synthesized through structural modification on the tetrahydrocurcumin scaffold. The newly synthesized target compounds evaluated for their in vitro anticancer activity against human epithelial lung carcinoma (A549), human epithelial cervical cancer (HeLa) and human breast adenocarcinoma (MCF‐7). Selectivity towards human breast adenocarcinoma (MCF‐7) over other cancer cells was observed and the most active compound 12 exhibited higher potency against all three cancer cell lines. [ABSTRACT FROM AUTHOR]

Abstract Acetaminophen (APAP) overdose-induced hepatotoxicity is tightly associated with oxidative stress. Tetrahydrocurcumin (THC) and octahydrocurcumin (OHC), the primary and final hydrogenated metabolites of curcumin (CUR), possess stronger antioxidant activity in vitro. The present study was performed to investigate the potential and mechanism of OHC and THC against APAP-induced hepatotoxicity in parallel to CUR. Our results showed that OHC and THC dose-dependently enhanced liver function (ALT and AST levels) and alleviated histopathological deterioration. Besides, OHC and THC significantly restored the hepatic antioxidant status by miring level of MDA and ROS, and elevated levels of GSH, SOD, CAT and T-AOC. In addition, OHC and THC markedly suppressed the activity and expressions of CYP2E1, and bound to the active sites of CYP2E1. Moreover, OHC and THC activated the Keap1-Nrf2 pathway and enormously enhanced the translational activation of Nrf2-targeted gene (GCLC, GCLM, NQO1 and HO-1) against oxidative stress, via inhibiting the expression of Keap1 and blocking the interaction between Keap1 and Nrf2. Particularly, OHC and THC exerted superior hepato-protective and antioxidant activities to CUR. In conclusion, OHC and THC possess favorable hepato-protective effect through restoring antioxidant status, inhibiting CYP2E1 and activating Keap1-Nrf2 pathway, which might represent promising antioxidants for the treatment of APAP-induced hepatotoxicity. Graphical abstract Image 1 Highlights • OHC and THC effectively attenuated hepatotoxicity induced by APAP. • OHC and THC possessed superior hepato-protective effect to CUR. • OHC and THC suppressed the CYP2E1 activity and expression, and bound to CYP2E1. • OHC and THC activated the Keap1-Nrf2 pathway and induced the Nrf2-targeted genes. • OHC and THC blocked the interaction between Keap1 and Nrf2. [ABSTRACT FROM AUTHOR]

Summary: Background: 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. Objective: The current study sought to investigate the efficacy of dietary THC on allergic asthma compared to that of Cur in an animal model. Methods: 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. Results: 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). Conclusion and Clinical Relevance: 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. [ABSTRACT FROM AUTHOR]

Curcumin (CUR), a promising naturally occurring dietary compound, is commonly recognized as the potential anti-inflammatory agent. While the application of CUR was hampered by its low stability and poor systemic bioavailability, it has been suggested that the biological activities of CUR are intimately related to its metabolites. In the current investigation, we aimed to comparatively explore the anti-inflammatory effects of tetrahydrocurcumin (THC), octahydrocurcumin (OHC), and CUR, and to elucidate the underlying action mechanisms on experimental mice models of acute inflammation, i.e., xylene-induced ear edema, acetic acid-induced vascular permeability, and carrageenan-induced paw edema. The results showed that THC and OHC exerted significant and dose-dependent inhibitions on the formation of ear edema induced by xylene and paw edema provoked by carrageenan and inhibited the Evans blue dye leakage in peritoneal cavity elicited by acetic acid. Moreover, THC and OHC treatments were more effective than CUR in selectively inhibiting the expression of cyclooxygenase 2 (COX-2) and suppressing nuclear factor-κB (NF-κB) pathways via transforming growth factor β activated kinase-1 (TAK1) inactivation in the carrageenan-induced mouse paw edema model. [ABSTRACT FROM AUTHOR]

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 . [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 300-500 nm. 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 12 h with a final cumulative release of 94.24%. [ABSTRACT FROM AUTHOR]

SIRT1, an NAD+-dependent histone/protein deacetylase, has diverse physiological actions. Recent studies have demonstrated that SIRT1 is overexpressed in colorectal cancer, suggesting its oncogenic potential. However, the molecular mechanisms by which overexpressed SIRT1 induces the progression of colorectal cancer and its inhibition remain largely unknown. Curcumin (diferuloymethane), a major component of the spice turmeric derived from the plant Curcuma longa L., has been reported to exert chemopreventive and anti-carcinogenic effects on colon carcinogenesis. In the present study, we found that curcumin reduced the expression of SIRT1 protein without influencing its mRNA expression in human colon cancer cells, suggesting posttranslational regulation of SIRT1 by this phytochemical. Notably, ubiquitination and subsequent proteasomal degradation of SIRT1 were induced by curcumin treatment. Results of nano-LC-ESI-MS/MS revealed the direct binding of curcumin to cysteine 67 of SIRT1. In line with this result, the protein stability and clonogenicity of a mutant SIRT1 in which cysteine 67 was substituted by alanine were unaffected by curcumin. Taken together, these observations suggest that curcumin facilitates the proteasomal degradation of oncogenic SIRT1 through covalent modification of SIRT1 at the cysteine 67 residue. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]