Tetrahydrocurcumin ameliorates hepatic steatosis by restoring hepatocytes lipophagy through mTORC1-TFEB pathway in nonalcoholic steatohepatitis.

PURPOSE: To investigate the therapeutic effect and underlying mechanism of tetrahydrocurcumin (THC) on nonalcoholic steatohepatitis (NASH) induced by high-fat diet (HFD). METHODS: NASH rat model was established through long-term feeding HFD, and the steatosis cell model was stimulated via palmitate acid (PA). The therapeutic effect of THC was evaluated in terms of liver function, lipid metabolism, liver pathophysiology, inflammation and oxidative stress in vivo, and lipid accumulation in vitro. The alteration in lipophagy was identified by using western blot and immunofluorescence. mTORC1-TFEB signaling pathway was measured by qRT-PCR, western blot and protein-ligand docking. In addition, chloroquine and MHY1485 were further introduced to validate the effect of THC on lipophagy and mTORC1-TFEB signaling pathway, respectively. RESULTS: THC effectively improved hepatic steatosis, inflammation and oxidative stress in NASH rats, and reduced lipid accumulation in steatosis L02 cells and Hep G2 cells. THC promoted lipophagy with increasing LC3B-II as well as decreasing P62 expression via lysosomal biogenesis upregulation, which was greatly weakened after chloroquine intervention. mTORC1-TFEB is a critical pathway for regulating lysosome in autophagy, THC treatment induced TFEB nucleus translocation via inhibiting mTORC1 to upregulate lysosomal biogenesis. However, these effects were partly eliminated by mTORC1 activator MHY1485. CONCLUSION: THC restored lipophagy to reduce lipid accumulation by regulating mTORC1-TFEB pathway in NASH rats and steatosis hepatocytes. These findings suggested that THC represents a therapeutic candidate for NASH treatment.

Conformational alterations and functional changes of pepsin induced by a novel food supplement tetrahydrocurcumin: Multispectral techniques and computer simulations.

Tetrahydrocurcumin (THC), as a novel food supplement, has generated significant interests for its potential impact on health and nutrition. Pepsin serves as the primary enzyme involved in the digestive mechanism. This research investigated the conformational and functional alterations of pepsin induced by THC using multispectral techniques and computer simulations. The results showed that THC enters the cavity of pepsin, in which hydrophobic forces play a major role. The binding constant is 1.044 × 104 M-1 at 310 K. The upregulation or downregulation effect of THC on pepsin activity depends on its concentration. Molecular docking outcomes indicated that THC was encapsulated by various amino acids and established H-bonds with Tyr189 and Ser294, revealing that hydrogen bonds also contribute to maintaining the stability of THC-pepsin complex. In addition, the altered activity of pepsin may be related to the interaction between THC and the amino acids at the active site (Asp32) according to energy contribution results. 3D fluorescence spectroscopy, CD spectra and molecular dynamic simulations show that THC causes conformational changes in pepsin. The existence of THC makes pepsin structure to be less dense, leading to the decrease of energy traps. This suggests that pepsin becomes conformationally more suitable to bind to THC.

A Multifunctional Nanocomposite Hydrogel Delivery System Based on Dual-Loaded Liposomes for Scarless Wound Healing.

Increased inflammatory responses and oxidative stress at the wound site following skin trauma impair healing. Furthermore, skin scarring places fibroblasts under severe mechanical stress and aggravates pathological fibrosis. A novel liposomal composite hydrogel is engineered for wound microenvironment remodeling, incorporating dual-loaded liposomes into gelatin methacrylate to create a nanocomposite hydrogel. Notably, tetrahydrocurcumin (THC) and hepatocyte growth factor (HGF) are encapsulated in the hydrophobic and hydrophilic layers of liposomes, respectively. The composite hydrogel maintains porous nanoarchitecture, demonstrating sustainable THC and HGF release and enhanced mechanical properties and biocompatibility. This system effectively promotes cell proliferation and angiogenesis and attenuates apoptosis. It decreases the expression of the inflammatory factors by inhibiting the high-mobility group box /receptor for advanced glycation end product/NF-κB (HMGB1/RAGE/NF-κB)pathway and increases macrophage polarization from M1 to M2 in vitro, effectively controlling inflammatory responses. It exhibits remarkable antioxidant properties by scavenging excess reactive oxygen species and free radicals. Most importantly, it effectively prevents scar formation by restraining the transforming growth factor beta (TGF-ß)/Smads pathway that downregulates associated fibrotic factors. It demonstrates strong therapeutic effects against inflammation and fibrosis in a rat skin wound model with biosafety, advancing the development of innovative hydrogel-based therapeutic delivery strategies for clinical scarless wound therapy.

Synthesis, Anticancer Activity, and Molecular Docking of New 1,2,3-Triazole Linked Tetrahydrocurcumin Derivatives.

Cancer is one of the deadliest diseases to humanity. There is significant progress in treating this disease, but developing some drugs that can fight this disease remains a challenge in the field of medical research. Thirteen new 1,2,3-triazole linked tetrahydrocurcumin derivatives were synthesized by click reaction, including a 1,3-dipolar cycloaddition reaction of tetrahydrocurcumin baring mono-alkyne with azides in good yields, and their in vitro anticancer activity against four cancer cell lines, including human cervical carcinoma (HeLa), human lung adenocarcinoma (A549), human hepatoma carcinoma (HepG2), and human colon carcinoma (HCT-116) were investigated using MTT(3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetraz-olium bromide) assay. The newly synthesized compounds had their structures identified using NMR HRMS and IR techniques. Some of prepared compounds, including compounds 4g and 4k, showed potent cytotoxic activity against four cancer cell lines compared to the positive control of cisplatin and tetrahydrocurcumin. Compound 4g exhibited anticancer activity with a IC50 value of 1.09 ± 0.17 µM against human colon carcinoma HCT-116 and 45.16 ± 0.92 µM against A549 cell lines compared to the positive controls of tetrahydrocurcumin and cisplatin. Moreover, further biological examination in HCT-116 cells showed that compound 4g can arrest the cell cycle at the G1 phase. A docking study revealed that the potential mechanism by which 4g exerts its anti-colon cancer effect may be through inhabiting the binding of APC-Asef. Compound 4g can be used as a promising lead for further exploration of potential anticancer agents.

Tetrahydrocurcumin Attenuates Polymyxin B Sulfate-Induced HK-2 Cells Apoptosis by Inhibiting Endoplasmic Reticulum Stress-Mediated PERK/eIF2α/ATF4/CHOP Signaling Pathway Axis.

The clinical application of polymyxin B (PMB) is limited by its nephrotoxic effects, making the reduction of PMB-induced nephrotoxicity has become a pressing concern for clinicians. Tetrahydrocurcumin (THC), known for its beneficial characteristics in biological functions, presents an attractive option for intervention therapy to mitigate PMB-induced nephrotoxicity. However, the underlying mechanism of how THC mitigates PMB-induced nephrotoxicity is still poorly understood. Here, we first evaluated the potential of THC intervention therapy to mitigate PMB-induced nephrotoxicity in an in vitro model of PMB-induced cell injury. Moreover, we demonstrated that THC effectively protected HK-2 cells from PMB-induced apoptosis by using cell counting kit-8 and flow cytometry assay. THC could also suppress PMB-induced endoplasmic reticulum (ER) stress via PERK/eIF2α/ATF4/CHOP pathway. In addition, using PERK inhibitor GSK2606414 to inhibit ER stress also alleviated PMB-induced apoptosis. Taken together, these findings provide novel insights that THC possesses the ability to alleviate PMB-induced nephrotoxicity by inhibiting the ER stress-mediated PERK/eIF2α/ATF4/CHOP axis, which sheds light on the benefits of THC as an intervention strategy to reduce PMB-induced nephrotoxicity, thus providing a potential avenue for improved clinical outcomes in patients receiving PMB treatment.

Characterizations on a GRAS Electrospun Lipid-Polymer Composite Loaded with Tetrahydrocurcumin.

Electrospun/sprayed fiber films and nanoparticles were broadly studied as encapsulation techniques for bioactive compounds. Nevertheless, many of them involved using non-volatile toxic solvents or non-biodegradable polymers that were not suitable for oral consumption, thus rather limiting their application. In this research, a novel electrospun lipid-polymer composite (ELPC) was fabricated with whole generally recognized as safe (GRAS) materials including gelatin, medium chain triglyceride (MCT) and lecithin. A water-insoluble bioactive compound, tetrahydrocurcumin (TC), was encapsulated in the ELPC to enhance its delivery. Confocal laser scanning microscopy (CLSM) was utilized to examine the morphology of this ELPC and found that it was in a status between electrospun fibers and electrosprayed particles. It was able to form self-assembled emulsions (droplets visualized by CLSM) to deliver active compounds. In addition, this gelatin-based ELPC self-assembled emulsion was able to form a special emulsion gel. CLSM observation of this gel displayed that the lipophilic contents of the ELPC were encapsulated within the cluster of the hydrophilic gelatin gel network. The FTIR spectrum of the TC-loaded ELPC did not show the fingerprint pattern of crystalline TC, while it displayed the aliphatic hydrocarbon stretches from MCT and lecithin. The dissolution experiment demonstrated a relatively linear release profile of TC from the ELPC. The lipid digestion assay displayed a rapid digestion of triglycerides in the first 3-6 min, with a high extent of lipolysis. A Caco-2 intestinal monolayer transport study was performed. The ELPC delivered more TC in the upward direction than downwards. MTT study results did not report cytotoxicity for both pure TC and the ELPC-encapsulated TC under 15 µg/mL. Caco-2 cellular uptake was visualized by CLSM and semi-quantified to estimate the accumulation rate of TC in the cells over time.

Polymeric scaffold integrated with nanovesicle-entrapped curcuminoids for enhanced therapeutic efficacy.

Aim: Polymeric scaffolds were developed fortified with nanovesicle-encapsulated individual curcumin (CUR) and tetrahydrocurcumin (THC) for improved therapeutic efficacy due to their low stability and efficacy in native form. Method: Nanovesicle-encapsulated individual CUR and THC were fabricated using thin-film hydration techniques and characterized. Results & conclusion: CUR/THC in native and vesicle-encapsulated form demonstrated diminished LPS-instigate nitric oxide (NO) levels in macrophage cells in a concentration-dependent demeanor. However, vesicle-encapsulated CUR/THC inhibited NO production at lower concentrations, compared with the native CUR/THC form. Furthermore, the scaffold fortified with vesicle-encapsulated CUR/THC demonstrated improved physical properties with excellent antioxidant, biocompatibility, and human keratinocyte cell proliferation ability. The results recommended that nanovesicle-encapsulated THC can be retained as a potential substitute for CUR with improved therapeutic efficacy.

[Box: see text].

Tetrahydrocurcumin Protects Against GSK3ß/PTEN/PI3K/Akt-Mediated Neuroinflammatory Responses and Microglial Polarization Following Traumatic Brain Injury.

Tetrahydrocurcumin (THC) and microglial polarization play crucial roles in neuroprotection during traumatic brain injury (TBI). However, whether THC regulates microglial polarization in TBI is unknown. Thus, we intended to analyze the functions and mechanism of THC in nerve injury after TBI via the regulation of microglial polarization. A TBI rat model was established, and modified neurological function score (mNSS), brain water content, Nissl staining, and Fluoro-Jade B (FJB) staining were used to evaluate neurological function. The expression of the M1-linked markers CD16 and CD86, as well as the M2-associated markers CD206 and YM-1, was analyzed via qRT-PCR, western blotting, and immunofluorescence. The levels of inflammatory cytokines were assessed via ELISA. Primary microglia were isolated from the brain and treated with lipopolysaccharide (LPS) to induce injury. TUNEL staining was used to measure primary microglial apoptosis. The expression of GSK3ß, PTEN, and PI3K/Akt pathway proteins was detected via western blotting. TBI induced nerve injury, while THC improved neurological function recovery after TBI. Further analysis indicated that THC enhanced M2 microglial polarization and attenuated the inflammatory reaction mediated by microglia both in vitro and in vivo. Moreover, we found that THC promoted the M2 microglial phenotype through upregulating GSK3ß expression. Additionally, we proved that GSK3ß activated the PI3K/Akt pathway by phosphorylating PTEN. In conclusion, we demonstrated that THC protected against nerve injury after TBI via microglial polarization via the GSK3B/PTEN/PI3K/Akt signaling axis, suggesting the potential of THC for TBI treatment by promoting microglial M2 polarization.

Molecular docking, drug-likeness and DFT study of some modified tetrahydrocurcumins as potential anticancer agents.

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.

Tetrahydrocurcumin Derivatives Enhanced the Anti-Inflammatory Activity of Curcumin: Synthesis, Biological Evaluation, and Structure-Activity Relationship Analysis.

Tetrahydrocurcumin, the most abundant curcumin transformation product in biological systems, can potentially be a new alternative therapeutic agent with improved anti-inflammatory activity and higher bioavailability than curcumin. In this article, we describe the synthesis and evaluation of the anti-inflammatory activities of tetrahydrocurcumin derivatives. Eleven tetrahydrocurcumin derivatives were synthesized via Steglich esterification on both sides of the phenolic rings of tetrahydrocurcumin with the aim of improving the anti-inflammatory activity of this compound. We showed that tetrahydrocurcumin (2) inhibited TNF-α and IL-6 production but not PGE2 production. Three tetrahydrocurcumin derivatives inhibited TNF-α production, five inhibited IL-6 production, and three inhibited PGE2 production. The structure-activity relationship analysis suggested that two factors could contribute to the biological activities of these compounds: the presence or absence of planarity and their structural differences. Among the tetrahydrocurcumin derivatives, cyclic compound 13 was the most active in terms of TNF-α production, showing even better activity than tetrahydrocurcumin. Acyclic compound 11 was the most effective in terms of IL-6 production and retained the same effect as tetrahydrocurcumin. Moreover, acyclic compound 12 was the most active in terms of PGE2 production, displaying better inhibition than tetrahydrocurcumin. A 3D-QSAR analysis suggested that the anti-inflammatory activities of tetrahydrocurcumin derivatives could be increased by adding bulky groups at the ends of compounds 2, 11, and 12.

Non-therapeutic plasma levels in individuals utilizing curcumin supplements in daily life.

Introduction: The spice curcumin and its metabolites are widely used by cancer patients but have not shown proven health benefits in clinical studies, likely due to low plasma concentrations after oral intake. However, public interest in curcumin continues to grow, and companies claim enhanced absorption in their formulations. This study aims to determine if daily oral intake of curcumin leads to sufficient plasma concentrations for health effects. The study was registered in the Dutch Clinical Trial Register with ID NL5931. Methods: We used a validated HPLC-MS/MS method to measure curcumin and its metabolites in 47 individuals using their own curcumin formulations. Questionnaires assessed other supplement and medication use. Plasma samples were collected before and 1.5 h after intake, analyzing curcumin and metabolite levels with and without ß-glucuronidase pretreatment to measure conjugated and unconjugated forms. Results: Plasma concentrations of curcumin, demethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin, ranged between 1.0 and 18.6 ng/mL. Adding ß-glucuronidase resulted in an increase of unconjugated curcumin plasma levels to 25.4 ng/mL; however still significantly below (1000-fold) a plasma concentration that is expected to have a beneficial health effect. The use of adjuvants like piperine did not result in higher curcumin plasma concentrations. Discussion: Our study shows that using oral curcumin supplements still does not result in therapeutic plasma levels. Health care practitioners need to be critical toward the claimed beneficial systemic health effects of current curcumin supplement use by their patients. Clinical Trial Registration: https://onderzoekmetmensen.nl/en/trial/25480, NL5931.

Synthesis, spectroscopic analysis, DFT, docking, MD and antioxidant activity of tetrahydrocurcumin.

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 role and mechanism of TGF-ß1 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 ß1 (TGF-ß1) 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-ß1, 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-ß1, 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-ß1 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-ß1, 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.

Tetrahydrocurcumin ameliorates postinfarction cardiac dysfunction and remodeling by inhibiting oxidative stress and preserving mitochondrial function via SIRT3 signaling pathway.

BACKGROUND: 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. PURPOSE: The objective was the investigation of the pharmacological effects of THC and its associated mechanisms in the pathogenesis of HF after MI. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.

Statistical optimization of tetrahydrocurcumin loaded solid lipid nanoparticles using Box Behnken design in the management of streptozotocin-induced diabetes mellitus.

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

Curcumin Alleviates High-fat Diet-induced Nonalcoholic Steatohepatitis via Improving Hepatic Endothelial Function with Microbial Biotransformation in Rats.

Hepatic endothelial function is central to the development of nonalcoholic steatohepatitis (NASH). Curcumin (Cur) is reportedly hepatoprotective, however, it remains unknown whether Cur improves hepatic endothelial function in NASH. Additionally, the poor bioavailability of Cur renders it difficult to elucidate its hepatoprotective effect, hence, its biotransformation should be considered. Herein, we investigated the effects and mechanisms of Cur and its bioconversion on hepatic endothelial function against high-fat diet-induced NASH in rats. The results revealed that Cur improved hepatic lipid accumulation, inflammation, and endothelial dysfunction by inhibiting NF-κB and PI3K/Akt/HIF-1α pathways, however, these effects were weakened via antibiotic addition, which was closely related to reduced tetrahydrocurcumin (THC) produce in the liver and intestinal content. Moreover, THC exerted a better effect than Cur on restoring liver sinusoidal endothelial cells function to attenuate steatosis and injury in L02 cells. Thus, these findings indicate that the effect of Cur on NASH is closely related to hepatic endothelial function improvement with intestinal microbial biotransformation.

Augmentation of Docetaxel-Induced Cytotoxicity in Human PC-3 Androgen-Independent Prostate Cancer Cells by Combination With Four Natural Apoptosis-Inducing Anticancer Compounds.

Docetaxel (DTX) is the treatment of choice for metastatic castration-resistant prostate cancer. However, developing drug resistance is a significant challenge for achieving effective therapy. This study evaluated the anticancer and synergistic effects on DTX of four natural compounds (calebin A, 3'-hydroxypterostilbene, hispolon, and tetrahydrocurcumin) using PC-3 androgen-resistant human prostate cancer cells. We utilized the CellTiter-Glo® luminescent cell viability assay and human PC-3 androgen-independent prostate cancer cells to determine the antiproliferative effects of the four compounds alone and combined with DTX. Cytotoxicity to normal human prostate epithelial cells was tested in parallel using normal immortalized human prostate epithelial cells (RWPE-1). We used cell imaging and quantitative caspase-3 activity to determine whether these compounds induce apoptosis. We also measured the capacity of each drug to inhibit TNF-α-induced NF-kB using a colorimetric assay. Our results showed that all four natural compounds significantly augmented the toxicity of DTX to androgen-resistant PC-3 prostate cancer cells at IC50. Interestingly, when used alone, each of the four compounds had a higher cytotoxic activity to PC-3 than DTX. Mechanistically, these compounds induced apoptosis, which we confirmed by cell imaging and caspase-3 colorimetric assays. Further, when used either alone or combined with DTX, the four test compounds inhibited TNF-α-induced NF-kB production. More significantly, the cytotoxic effects on normal immortalized human prostate epithelial cells were minimal and non-significant, suggesting prostate cancer-specific effects. In conclusion, the combination of DTX with the four test compounds could effectively enhance the anti-prostate cancer activity of DTX. This combination has the added value of reducing the DTX effective concentration. We surmise that calebin A, 3'-hydroxypterostilbene, hispolon, and tetrahydrocurcumin were all excellent drug candidates that produced significant antiproliferative activity when used alone and synergistically enhanced the anticancer effect of DTX. Further in vivo studies using animal models of prostate cancer are needed to confirm our in vitro findings.

Tetrahydrocurcumin (THC) enhanced the clearance of Cryptococcus deneoformans during infection in vivo.

Cryptococcal species often cause lung infections and are the main cause of fungal meningitis. Claudin-4 appears to be a major structural component that maintains a tight alveolar barrier and prevents fluid and electrolyte leakage into the alveolar space. We aimed to determine whether S7-tetrahydrocurcumin (THC) could clearance of C. deneoformans and regulate claudin-4 expression during C. deneoformans infection. We investigated the effect of THC on C. deneoformans infection and its possible mechanism in vivo. Transmission electron microscopy was used to observe the ultrastructure of the lung tissue and the invasion of Cryptococcus. To clarify the effect of THC, we examined claudin-4, c-Jun, and Smad2 expression. We also measured claudin-4 expression in pulmonary specimens from clinical patients. THC reduced cryptococcal cell invasion in the lungs, improved alveolar exudation, and reduced inflammation. Pretreatment with THC suppressed c-Jun and Smad2 expression, resulting in significantly increased claudin-4 levels. In contrast, the expression of claudin-4 in clinical specimens from patients with cryptococcal infection was higher than that in normal specimens. THC enhanced the clearance of C. deneoformans during infection in vivo. We investigated the expression of claudin-4 and the possible mechanism of THC against C. deneoformans infection.

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 ß 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.