Metabolite Of Curcumin Research Articles

Natural Products as Modulators of Aryl Hydrocarbon Receptor Signaling in Atopic Dermatitis Management

Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by immune dysregulation, skin barrier dysfunction, and a significant patient burden. Recent studies have highlighted the aryl hydrocarbon receptor (AhR) as a promising therapeutic target for AD management because of its pivotal role in modulating immune responses and maintaining skin barrier integrity. The dysfunction of the AhR pathway has been linked to AD pathogenesis, emphasizing the need for therapies that can restore its regulatory functions. Natural products have emerged as potential modulators of the AhR and are effective and safe alternatives to conventional treatments. Compounds such as curcumin, resveratrol, quercetin, and microbial metabolites have demonstrated the ability to activate AhR, reduce inflammation, and promote skin barrier function. These natural agents have fewer side effects and enhance patient compliance compared with conventional therapies, making them attractive candidates for long-term AD management. The integration of natural products targeting the AhR pathway provides a multifaceted approach that alleviates symptoms, addresses underlying disease mechanisms, and promotes sustainable improvements in skin health. This review highlights the therapeutic potential of natural AhR modulators and their potential roles in enhancing patient outcomes through novel integrative treatment strategies.

Curcumin and Curcumin Derivatives for Therapeutic Applications: In vitro and In vivo Studies

: Curcumin is a naturally derived phytochemical compound obtained from the turmeric plant Curcuma longaL. (Zingiberaceae family), which is a popular spice and food color and has been actively researched for decades. It has been shown to have a variety of pharmacological properties both in vitro and in vivo. Several investigations have shown that curcumin's metabolites contribute to its pharmacological effectiveness. Curcumin has potent anti-inflammatory and anti-tumor activity when used alone or in conjunction with conventional treatments. There are various unique and diverse pharmacological effects of curcumin against various disease conditions like diabetes, inflammation, cancer, malaria, and Alzheimer's. The in vitro and in vivo mechanisms by which curcumin exerts its pharmacological effects are reviewed. Based on data from the clinical and experimental evaluation of curcumin in animal models and human subjects, the review summarizes the pharmacological effect of curcumin and its derivatives concerning anti-tumor property, their mechanism of action, and their cellular target. The current research focuses on identifying curcumin's function in the immune system's cascade and determining the ideal effective dose (ED50). Through in-vitro and in-vivo experiments, the current study aims to comprehend and establish the role of curcumin in the healing of disease conditions.

Phthalate exposure and reproductive effects in rodents: a model for approaches on the protective role of natural products.

This review article summarizes the experimental findings in rodents published between 2014 and 2024 concerning phthalates exposure and reproductive outcomes. Rodents were chosen for this review since most studies that have developmental aspects in different phases of exposure and that address more in-depth reproductive mechanisms have been carried out in mice and rats. The evidence of adverse effects of phthalates on fetal development and human and animal reproduction is extensive, with impacts ranging from gene expression to physiological alterations. Despite the large volume of scientific papers pointing out the harmful effects of exposure to phthalates, isolated or in mixtures, at different developmental periods, most of them are associated with the maternal exposure and long-term effects in the offspring. Regular vegetables, fruits, fish, dairy products, and whole grains intake rich in bioactive compounds can mitigate the adverse effects of EDCs in humans and animals at different developmental periods. Various food bioactive compounds (FBCs) such as genistein, resveratrol, lycopene, vitamin E, curcumin, selenium, and plant secondary metabolites (PSMs) present antioxidant, anti-inflammatory, anti-tumor, and other biological properties with the potential to reduce of deleterious effects of phthalates on the reproductive tract. In this review, we aimed to summarize the main studies produced in the last decade about phthalate exposure and reproductive disorders in males and females (at different developmental critical windows). Additionally, we proposed some FBCs and PSMs that could attenuate the main adverse effects caused by phthalate exposure on male reproduction since there is a lack of studies with females.

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

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

Unveiling the role of gut microbiota in curcumin metabolism using antibiotic-treated mice

Curcumin might exert its therapeutic effects by interacting with gut microbiota. However, the role of gut microbiota in curcumin metabolism in vivo remains poorly understood. To address this, we used antibiotics to deplete gut microbiota and compared curcumin metabolism in control and antibiotic-treated mice. Using Q-TOF and triple quadrupole mass spectrometry, we identified and quantified curcumin metabolites, revealing distinct metabolic pathways in these two mice groups. The novel metabolites, hexahydro-dimethyl-curcumin and hexahydro-didemethyl-curcumin were exclusively derived from gut microbiota. Additionally, gut bacteria deconjugated curcumin metabolites back into their bioactive forms. Moreover, control mice exhibited significantly lower curcumin degradation, suggesting a protective role of gut microbiota against degradation. In conclusion, our results indicated that gut microbiota might enhance the effectiveness of curcumin by deconjugation, production of active metabolites, and protection against degradation in the large intestine. This study enhances our understanding of the interactions between curcumin and gut microbiota.

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

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

Oil-Based Curcuminoid Phospholipid Formulation Mimicking Natural Digestion Enhances Oral Bioavailability of Curcuminoids in Healthy Subjects.

Curcumin, the fat-soluble active ingredient and major compound of curcuminoids contained in the curcuma root, is known for its physiological low absorption and bioavailability. Various formulations and galenic technologies are currently available on the market. In this study, the product tested was provided as a soft gelatin capsule containing curcuminoids in an oily matrix mixed with phospholipids (oil/phospholipids [PL]-based, no new technologies applied or artificial excipients added). This was intended to improve bioavailability of curcuminoids as well as to mimic the natural digestion process of fat-soluble substances. In particular, the oral bioavailability of curcuminoids in the oil/PL-based formulation was compared with the pure curcuminoids extract alone (reference product), in a randomized, cross-over, single oral dose study design. Twelve healthy subjects were administered 200 mg curcuminoids under fasting conditions. Pharmacokinetic parameters were analyzed from individual concentration-time curves of total curcuminoids, as well as the curcumin metabolite tetrahydrocurcumin (THC). Results showed significantly higher AUC0-8h levels after the intake of the oil/PL-based formulation for total curcuminoids (205.60 vs. 112.50 ng/mL*h, P = .0001) as well as for THC (347.30 vs. 118.90 ng/mL*h, P < .0001) in comparison to the pure curcuminoids extract. Cmax was also significantly higher for both parameters analyzed (total curcuminoids: 47.54 vs. 21.16 ng/mL, P = .0001; THC: 96.69 vs. 29.83 ng/mL, P < .0001). In addition, the uptake kinetic of total curcuminoids was significantly fastened with the oil/PL-based curcuminoids formulation compared with the pure curcuminoids extract (P = .0446). These data suggest an improved impact on curcuminoids uptake of the oil/PL-based formulation and confirms its good tolerability.

Glucuronidation dynamics of curcumin and tetrahydrocurcumin for differential structures and chemical reactivities in human liver microsome and uridine diphosphate glucuronosyltransferase 2B7

THC is the main metabolite of curcumin with better bioactivity. This study aimed to explore the factors that cause differences in the bioactivity of curcumin and THC. We analyzed the metabolic activities of curcumin and THC and the factors responsible for the differences in their activities by glucuronidation activity assay, LC-MS, HPLC, homologous sequence comparisons, and molecular docking. Curcumin has higher metabolic activity than THC in HLM and UGT2B7, while the keto-enol isomers of curcumin and THC were distinctly different under different pH, and their structural transformations were hypothesized. Furthermore, UGT1A and UGT2B are differential sequences of curcumin and THC in UGTs. The binding sites and patterns of curcumin and THC in UGT2B7 are markedly different. In summary, the difference in keto-enolic interconversion isomerism between curcumin and THC is the main factor causing the difference in their activities, which provides a scientific basis for the development of curcumin.

New solid forms of tetrahydrocurcumin with improved solubility

Tetrahydrocurcumin (THC), one of the active metabolites of curcumin, possesses pharmacological activities similar to those of curcumin, such as hypoglycemic, hypolipidemic and antioxidant effects.

The role of tetrahydrocurcumin in disease prevention and treatment.

In recent decades, natural compounds derived from herbal medicine or dietary sources have played important roles in prevention and treatment of various diseases and have attracted more and more attention. Curcumin, extracted from the Curcumae Longae Rhizoma and widely used as food spice and coloring agent, has been proven to possess high pharmacological value. However, the pharmacological application of curcumin is limited due to its poor systemic bioavailability. As a major active metabolite of curcumin, tetrahydrocurcumin (THC) has higher bioavailability and stability than curcumin. Increasing evidence confirmed that THC had a wide range of biological activities and significant treatment effects on diseases. In this paper, we reviewed the research progress on the biological activities and therapeutic potential of THC on different diseases such as neurological disorders, metabolic syndromes, cancers, and inflammatory diseases. The extensive pharmacological effects of THC involve the modulation of various signaling transduction pathways including MAPK, JAK/STAT, NF-κB, Nrf2, PI3K/Akt/mTOR, AMPK, Wnt/β-catenin. In addition, the pharmacokinetics, drug combination and toxicology of THC were discussed, thus providing scientific basis for the safe application of THC and the development of its dietary supplements and drugs.

Anti-Inflammatory Mechanisms of Curcumin and Its Metabolites in White Adipose Tissue and Cultured Adipocytes.

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.

A Review on Antidiabetic Effect of Tetrahydrocurcumin in Type 2 Diabetes

Diabetes mellitus is possibly the world’s largest growing metabolic disease and as the knowledge on the heterogeneity of this disorder is advanced, the need for more appropriate therapy increases. Currently available drug regimes for management of diabetes mellitus have certain drawbacks and, therefore, there is a need for safer and more effective antidiabetic drugs. Natural products from medicinal plants continue to form a common platform for the discovery of new chemical entities in the modern drug discovery programmes. The belief that natural medicines are much safer than synthetic drugs has gained popularity in recent years and lead to tremendous growth of phytopharmaceutical usage. A wide array of plant derived active principles (phytochemicals) for possible use in the treatment of type 2 diabetes mellitus has been reported. Curcuma longa is commonly used in the treatment of diabetes by ayurvedic physicians. Curcumin is a biologically active component isolated from the rhizome of Curcuma longa that possess antihyperglycemic activity, hypolipidemic action and anti - renal lesion effect. The use of curcumin is recommended for prevention of advanced glycated end products (AGE) accumulation and the associated complications of diabetes. Tetrahydrocurcumin (THC), one of the active metabolites of curcumin on antioxidants status in streptozotocin (STZ) - nicotinamide induced diabetic rats. THC is used in the treatment of several diseases such as prevents cancer, protects against inflammation, atherosclerotic lesions, hepatotoxicity and nephrotoxicity and diabetes. 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. Curcuma longa has been used medically for many years to treat chronic disorders. The whole plants are used for treating diabetes. Curcumin has been reported to produce significant atihyperglycemic effect. Administration of THC has significant antidiabetic effect in STZ - nicotinamide induced diabetes. The THC exhibited its antidiabetic effect by influencing the carbohydrate metabolism, lipid metabolism, oxidative stress induced lipid peroxidation, membrane bound enzymes, insulin binding to erythrocyte receptor and collagen content and its characteristics. The antidiabetic effect of THC provides sufficient documentation to define its role and action for its potential and promising use in treating diabetes.

Effect of Tetrahydrocurcumin Compared to Curcumin in Carbohydrate Metabolism and Glycoprotein Components in Type 2 Diabetes - Systematic Review

Pancreatic β-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. Curcumin is a biologically active component isolated from the rhizome of Curcuma longa that possess antidiabetic and has been proven scientifically to possess high antioxidant activity and anticancer properties. Tetrahydrocurcumin (THC) is a major curcuminoid metabolite of curcumin, naturally occurring in turmeric. The interest in THC 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 THC exerts antidiabetic effects through various mechanisms, including modulation of oxidative stress, xenobiotic detoxification, inflammation, proliferation, metastasis, programmed cell death, and immunity. The activities of glycolytic enzymes such as hexokinase and glucose-6-phosphate dehydrogenase were found to be decreased whereas the activities of gluconeogenic enzymes (glucose-6-phosphatase and fructose-1,6-bisphosphatase) and polyol pathway enzyme-sorbitol dehydrogenase were significantly increased in diabetic control rats. In addition, the oligosaccharide moieties of glycoproteins (hexose, hexosamine, fucose and sialic acid) were also significantly increased in plasma and tissues of diabetic control rats. THC and curcumin administration to diabetic rats significantly reversed the above changes when compared to diabetic control rats. In diabetic controls, hepatic and skeletal muscle glycogen content was decreased significantly as compared to non-diabetic controls. Treatment with THC and curcumin increased the hepatic and skeletal muscle glycogen significantly. The antidiabetic and antioxidant effects of THC are more potent than those of curcumin at the same dose. The antihyperglycemic action of THC might be mediated via an enhancement of insulin action, as it is evidenced by the increased levels of insulin in diabetic rats treated with THC, which may be responsible for the reversal of changes in carbohydrate enzymes and glycoprotein components. The THC administration showed more effective than curcumin.

The role and mechanism of TGF-β1 in the antidepressant-like effects of tetrahydrocurcumin

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.

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

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

Positive Tetrahydrocurcumin-Associated Brain-Related Metabolomic Implications.

Tetrahydrocurcumin (THC) is a metabolite of curcumin (CUR). It shares many of CUR's beneficial biological activities in addition to being more water-soluble, chemically stable, and bioavailable compared to CUR. However, its mechanisms of action have not been fully elucidated. This paper addresses the preventive role of THC on various brain dysfunctions as well as its effects on brain redox processes, traumatic brain injury, ischemia-reperfusion injury, Alzheimer's disease, and Parkinson's disease in various animal or cell culture models. In addition to its strong antioxidant properties, the effects of THC on the reduction of amyloid β aggregates are also well documented. The therapeutic potential of THC to treat patterns of mitochondrial brain dysmorphic dysfunction is also addressed and thoroughly reviewed, as is evidence from experimental studies about the mechanism of mitochondrial failure during cerebral ischemia/reperfusion injury. THC treatment also results in a dose-dependent decrease in ERK-mediated phosphorylation of GRASP65, which prevents further compartmentalization of the Golgi apparatus. The PI3K/AKT signaling pathway is possibly the most involved mechanism in the anti-apoptotic effect of THC. Overall, studies in various animal models of different brain disorders suggest that THC can be used as a dietary supplement to protect against traumatic brain injury and even improve brain function in Alzheimer's and Parkinson's diseases. We suggest further preclinical studies be conducted to demonstrate the brain-protective, anti-amyloid, and anti-Parkinson effects of THC. Application of the methods used in the currently reviewed studies would be useful and should help define doses and methods of THC administration in different disease conditions.

Efficacy of TurmiZn, a Metallic Complex of Curcuminoids-Tetrahydrocurcumin and Zinc on Bioavailability, Antioxidant, and Cytokine Modulation Capability

Complexes of curcumin with metals have shown much-improved stability, solubility, antioxidant capability, and efficacy when compared to curcumin. The present research investigates the relative bioavailability, antioxidant, and ability to inhibit inflammatory cytokine production of a curcuminoid metal chelation complex of tetrahydrocurcumin-zinc-curcuminoid termed TurmiZn. In vitro uptake assay using pig intestinal epithelial cells showed that TurmiZn has an ~3-fold increase (p ≤ 0.01) in uptake compared to curcumin and a ~2-fold increase (p ≤ 0.01) over tetrahydrocurcumin (THC). In a chicken model, an oral 1-g dose of TurmiZn showed a ~2.5-fold increase of a specific metabolite peak compared to curcumin (p = 0.004) and a ~3-fold increase compared to THC (p = 0.001). Oral doses (5 g/Kg) of TurmiZn in rats also showed the presence of curcumin and THC metabolites in plasma, indicating bioavailability across cell membranes in animals. Determination of the antioxidant activity by a 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical scavenging assay indicated that TurmiZn was about 13x better (p ≤ 0.0001) than curcumin and about 4X better (p ≤ 0.0001) than THC, in reducing free radicals. In vitro experiments further showed significant (p ≤ 0.01) reductions of lipopolysaccharide (LPS)-induced proinflammatory cytokines such as interleukin (IL) IL-6, IL-8, IL-15, IL-18, and tumor necrosis factor (TNF)-alpha, while showing a significant (p ≤ 0.01) increase of granulocyte-macrophage colony-stimulating factor (GM-CSF) in dog kidney cells. In vivo cytokine modulations were also observed when TurmiZn was fed for 6 weeks to newborn chickens. TurmiZn reduced IL-1 and IL-6, but significantly reduced (p ≤ 0.01) IL-10 levels while there was a concurrent significant (p = 0.02) increase in interferon gamma compared to controls. Overall, these results indicate that TurmiZn has better bioavailability and antioxidant capability than curcumin or THC and has the ability to significantly modulate cytokine levels. Thus, TurmiZn could be an excellent candidate for a novel ingredient that can be incorporated into food and supplements to help overall health during the aging process.

Regional distributions of curcumin and tetrahydrocurcumin in the liver and small intestine of rats when orally co-administered with quercetin and paeoniflorin.

Curcumin (CUR), derived from the dietary spice turmeric, is a polyphenolic compound with various biological and pharmacological activities. Tetrahydrocurcumin (THC) is one of the major reductive metabolites of curcumin. A pharmacokinetic study using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) for the simultaneous determination of curcumin, THC, quercetin (QR), and paeoniflorin (PF) in rat plasma had been performed. In this study, the regional distributions of curcumin and tetrahydrocurcumin in the liver and the three segments of small intestine (duodenum, jejunum, and ileum) of rats when orally co-administered with quercetin and paeoniflorin were carried out. Drug concentrations were determined using UHPLC-MS/MS. The results showed that curcumin was well distributed in the small intestine, while the distributions of tetrahydrocurcumin in the liver, duodenum, jejunum were similar, but much more abundant in the ileum. When orally co-administered with quercetin and paeoniflorin, the tissue to plasma concentration ratios (Kp values) of curcumin in the three segments of the small intestine were increased, indicating that the presence of quercetin and paeoniflorin increases the distribution of curcumin in these regions. Moreover, the half-life (t1/2 ) of THC in the liver was significantly prolonged, and the Kp value of THC in the liver was increased and the Kp values in the small intestine were decreased, suggesting that the combination of quercetin and paeoniflorin might suppress the metabolism of curcumin in the small intestine. In brief, the combination had an effect on the distributions of curcumin and tetrahydrocurcumin in the liver and small intestine of rats.

Tetrahydrocurcumin regulates the tumor immune microenvironment to inhibit breast cancer proliferation and metastasis via the CYP1A1/NF-κB signaling pathway

The NF-κB signaling pathway is overactivated in tumor cells, and the activation of the NF-κB signaling pathway releases a large number of inflammatory factors, which enhance tumor immunosuppression and promote tumor metastasis. The cytochrome P450 (CYP450) system consists of important metabolic enzymes present in different tissues and progressive tumors, which may lead to changes in the pharmacological action of drugs in inflammatory diseases such as tumors. In this study, the anticancer effect of tetrahydrocurcumin (THC), an active metabolite of curcumin, on breast cancer cells and the underlying mechanism were investigated. Result showed that THC selectively inhibited proliferation and triggered apoptosis in breast cancer cells in a concentration- and time-dependent manner. Moreover, THC-induced cell apoptosis via a mitochondria-mediated pathway, as indicated by the upregulated ratio of Bax/Bcl-2 and reactive oxygen species (ROS) induction. In addition, THC could affect the CYP450 enzyme metabolic pathway and inhibit the expression of CYP1A1 and activation of the NF-κB pathway, thereby inhibiting the migration and invasion of breast cancer cells. Furthermore, after overexpression of CYP1A1, the inhibitory effects of THC on the proliferation, metastasis, and induction of apoptosis in breast cancer cells were weakened. The knockdown of CYP1A1 significantly enhanced the inhibitory effect of THC on the proliferation, metastasis, and apoptosis induction of breast cancer cells. Notably, THC exhibited a significant tumor growth inhibition and anti-pulmonary metastasis effect in a tumor mouse model of MCF-7 and 4T1 cells by regulating the tumor immunosuppressive microenvironment. Collectively, these results showed that TH could effectively trigger apoptosis and inhibit the migration of breast cancer cells via the CYP1A1/NF-κB signaling pathway, indicating that THC serves as a potential candidate drug for the treatment of breast cancer.

INVESTIGATION OF ANTI-SARS COV-2 ACTIVITY OF SOME TETRAHYDRO CURCUMIN DERIVATIVES: AN IN SILICO STUDY

Objective: In the current study, an in silico approach has been utilized to investigate the anti-SARS CoV 2 activity of some derivatives of Tetrahydro curcumin (THC), a curcumin metabolite. Methods: BioVia Draw 2017 was used to design 168 THC derivatives. All of the derivatives were docked using Maestro Schrodinger programme. Depending on the docking score, the ADME, drug-likeness, and toxicity prediction of a few THC derivatives were conducted. Results: 168 THC derivatives were designed. 14 derivatives exhibited a better binding score than Remdesivir. All 14 derivatives' pharmacokinetic characteristics were discovered to be within the acceptable range. Lipinski's rule of five was violated by all derivatives, including the reference drug, yet they all stayed within the recommended range. The greatest docking score among the 14 derivatives was displayed by Structure 21. A study on molecular dynamic (MD) stimulation showed that the protein-ligand complex was relatively stable. Toxicity prediction showed that 14 derivatives were non-hepatotoxic, non-cytotoxic, immunotoxic (except S21), non-mutagenic (except S31) and half of the developed structures were carcinogenic, while the other half, including the standard drug, was non-carcinogenic. Conclusion: Among 168 THC derivatives, 14 derivatives exhibited better binding score than the reference drug. For all 14 derivatives, pharmacokinetic, drug-likeness, and toxicity prediction were found to be satisfactory. It was discovered that the protein-ligand complex was thermodynamically stable. All 14 compounds present exciting prospects for further in vitro and in vivo investigation.