6-Shogaol improves sorafenib efficacy in colorectal cancer cells by modulating its cellular accumulation and metabolism.

Carcinoma of the colon and rectum, also known as colorectal cancer, ranks as the third most frequently diagnosed malignancy globally. Sorafenib exhibits broad-spectrum antitumor activity against Raf, VEGF, and PDGF pathways in hepatocellular, thyroid, and renal cancers, but faces resistance in colorectal malignancies. 6-Shogaol, a prominent natural compound found in Zingiberaceae, exhibits antioxidant, anti-inflammatory, anticancer, and antiemetic properties. We investigated the influence of 6-shogaol on sorafenib's cytotoxic profile against colorectal cancer cell lines (HT-29, HCT-116, CaCo-2, and LS174T) through its effects on cellular accumulation and metabolism. Cytotoxicity was assessed using the sulpharodamine B assay, caspase-3 and c-PARP cleavage, cell cycle distribution analysis, and P-gp efflux activity. 6-Shogoal showed considerable cytotoxicity with decreased IC50 in colorectal cancer cell lines. Combining sorafenib and 6-shogaol increased c-PARP and pro-caspase-3 concentrations in HCT-116 cells compared to sorafenib alone. In combination, pro-caspase-3 concentrations were decreased in CaCo-2 cells compared to alone. Sorafenib combinations with 6-shogaol showed a significant drop in cell cycle distribution from 16.96±1.10 % to 9.16±1.85 %, respectively. At 100 µM, sorafenib and 6-shogaol showed potent and significant activity with intra-cellular rhodamine concentration on P-gp efflux activity in CRC cell lines. In conclusion, 6-shogaol substantially improved the cytotoxic profile of sorafenib by affecting its cellular uptake and metabolism. Future research should focus on dosage optimization and formulation and evaluate the efficacy and safety of the combination in animal models with colorectal cancer.

[Screening and engineering of a protocatechuic acid decarboxylase for efficient biosynthesis of catechol].

Catechol (CA) is an important chemical and pharmaceutical intermediate with wide applications. At present, CA is produced by phenol hydroxylation with non-renewable petrochemical resources, which causes serious environmental pollution. Hence, the biosynthesis of CA attracts much attention recently. However, due to the low activities of protocatechuic acid (PCA) decarboxylases, the production efficiency of biosynthetic catechol is too low to meet the requirements of large-scale industrial production. To improve the yield of CA, we screened 21 PCA decarboxylases from different species. RbAroY originated from Rikenellaceae had the best catalytic performance. The whole-cell biocatalyst ER11 with RbAroY was able to produce CA at a titer of 13.54 g/L. Then, the online tool HotSpot Wizard was employed to measure the enzyme stability, which revealed 10 potential mutation sites causing significant decreases in Gibbs free energy. The whole-cell biocatalyst ERT01 with the mutated RbAroYG99A could produce CA at a titer of 15.16 g/L, which increased by 12% compared with that of the wild-type whole-cell biocatalyst. After optimization of the biocatalytic conditions, the whole-cell biocatalyst ERT01 was able to produce CA at a titer of 25.70 g/L with PCA as the substrate. Finally, with the fermentation broth of 3-dehydroshikimate as the substrate, the whole-cell biocatalyst DER03 expressing both 3-dehydroshikimate dehydratase and PCA decarboxylase realized the production CA at a titer of 29.55 g/L, which is currently the highest biosynthetic titer reported. This study provides a reference for the industrial production of CA by biosynthesis.

Laccase-mediated chemoselective C-4 arylation of 5-aminopyrazoles.

Chemoselective arylation of 5-aminopyrazoles was performed through oxidative formation of orthoquinones from catechols catalyzed by Myceliophthora thermophila laccase (Novozym 51003), and subsequently nucleophilic attack of 5-aminopyrazole to the catechol intermediates. The C-4 arylated products were obtained under extremely mild conditions without the need for amine protection or halogenation of the substrates. From this method, 10 derivatives with moderate to good efficiency (42-94%) were prepared.

Coagulopathy-independent injectable catechol-functionalized chitosan shape-memory material to treat non-compressible hemorrhage.

Uncontrolled non-compressible hemorrhage, which is often accompanied by coagulopathy, is a major cause of mortality following traumatic injuries in civilian and military populations. In this study, coagulopathy-independent injectable catechol-modified chitosan (CS-HCA) hemostatic materials featuring rapid shape recovery were fabricated by combining controlled sodium tripolyphosphate-crosslinking with hydrocaffeic acid (HCA) grafting. CS-HCA exhibited robust mechanical strength and rapid blood-triggered shape recovery. Furthermore, CS-HCA demonstrated superior blood-clotting ability, enhanced blood cell adhesion and activation, and greater protein adsorption than commercial hemostatic gauze and Celox. CS-HCA showed enhanced procoagulant and hemostatic capacities in a lethal liver-perforation wound model in rabbits, particularly in heparinized rabbits. CS-HCA is suitable for mass manufacturing and shows promise as a clinically translatable hemostat.

Sea urchin-like Ni3(HITP)2 as the substrate of molecular imprinted polymer: the voltammetric mechanism for sensitive detection of dopamine.

An electrochemical sensor composed of conductive metal-organic framework [Ni3(HITP)2] and molecular imprinted polymers (MIP) is fabricated to detect dopamine. Ni3(HITP)2 promotes electrons transfer due to the structure of in-plane charge delocalization and layered expansion conjugation. The combination of MIP with Ni3(HITP)2 improves the selectivity and conductivity, exhibiting a wide detection range (0.06 ~ 200 µM) and a low detection limit (0.109 µM). The kinetic mechanism on the electrode surface is an adsorption controlled process, with the equal number of electrons and protons participating in oxidation in the electrocatalytic process of catechol converting to o-quinone.

Innovation in prevention of poison oak contact dermatitis.

Poison oak-induced contact dermatitis poses a significant challenge due to its urushiol oil-induced allergic reactions. Conventional preventive measures like avoidance and post-exposure cleansing are often impractical, necessitating innovative strategies. This comprehensive review explores emerging technologies and formulations for preventing poison oak dermatitis. Literature search via PubMed and Covidence identified 13 relevant studies, with six discussing preventive measures. Barrier methods, including occlusive creams and protective clothing, showed promise in reducing dermatitis risk. Immunotherapy, although investigated, requires further development. Complete avoidance, while effective, is often impractical. The complexity of poison oak management underscores the need for ongoing research to develop more effective preventive measures. This review highlights the current landscape, identifies gaps in knowledge, and emphasizes the importance of continued research for improved prevention and management of poison oak-induced dermatitis.

6-gingerol effect on rat liver following exposure to gold nanoparticles: From histopathologic findings to inflammatory and oxidative stress biomarkers.

Gold nanoparticles (AuNPs) have unique features which could be beneficial to various aspects of clinics and industry. Long-term exposure to AuNPs damages the physiologic functions and tissue structure of organs. Gingerol has anti-inflammatory and antioxidant properties. This study explored the effect of 6-gingerol on alleviation of AuNPs exposure effects in rats' liver. Thirty-two male Wistar rats were randomly assigned to four groups of negative control (received no AuNPs or treatment), positive control (received AuNPs but not treatment), and two study arms (both received AuNPs and one group 50 and the other 100 mg/Kg body weight 6-gingerol). All injections were performed intraperitoneally. After 30 days, serum levels of ALP, AST, ALT were assessed through ELISA method by an autoanalyzer while GGT, SOD, GPx, CAT, IL-6, IL-1ß, TNF-α, CRP, 8-OHdG, MDA, and Bax/Bcl2 were measured using an ELISA reader. Paraffin-embedded tissue sections of the livers from all groups were also prepared and H&E staining was performed on them for investigation of tissue changes. Statistical analyses were performed using SPSS version 26 and p = 0.05 was considered as the level of significancy. AuNPs exposure significantly increased the levels of ALP, AST, ALT, GGT, CRP, IL-6, IL-1ß, TNF-α, Bax/Bcl2, 8-OHdG, MDA (p < 0.001) in positive control groups compared to negative controls, while treatment with 6-gingerol significantly decreased the mentioned enzyme levels (p < 0.001). The level of antioxidant enzymes of SOD, GPx, and CAT, on the other hand, was found to be highest and lowest in negative and positive controls, respectively (p < 0.001). Treatment with 6-gingerol significantly decreased the mentioned enzyme levels (p < 0.001). Histology results showed no signs of degeneration, necrosis, or immune cell infiltration in negative controls, while positive controls showed dilated central veins and hyperemia along with infiltration of mononuclear immune cells to the portal area, tissue degeneration, and necrosis. The study arms showed improved signs as they showed normal trabecular structures with no clear portal space. Treatment with 6-gingerol seems to significantly and efficiently reduce the hepatic side effects of AuNPs exposure in Wistar rats.

Simultaneous Electrochemical Detection of Catechol and Hydroquinone Based on a Carbon Nanotube Paste Electrode Modified with Electro-Reduced Graphene Oxide.

Effectively detecting catechol (CC) and hydroquinone (HQ) simultaneously is crucial for environmental protection and human health monitoring. In the study presented herein, a novel electrochemical sensor for the sensitive simultaneous detection of CC and HQ was constructed based on an electrochemically reduced graphene oxide (ERGO)-modified multi-walled carbon nanotube paste electrode (MWCNTPE). Scanning electron microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy and electrochemical techniques were utilized to characterize the sensing interface and investigate the sensing mechanism. Under the optimal detection conditions, the oxidation peak currents of CC and HQ show a good linear relationship with their concentrations in the range of 0.4-400 µM with a detection limit of 0.083 µM for CC and 0.028 µM for HQ (S/N = 3). Moreover, the sensor exhibits good performance and can be applied successfully in the simultaneous detection of CC and HQ in tap water samples and urine samples with satisfactory results, indicating its promising application prospects.

Bioinspired Self-Growing Layered Hydrogel Enabled by Catechol Chemistry-Mediated Interfacial Catalytic System.

Tissue-inspired layered structural hydrogel has attracted increasing attention in artificial muscle, wound healing, wearable electronics, and soft robots. Despite numerous efforts being devoted to developing various layered hydrogels, the rapid and efficient preparation of layered hydrogels remains challenging. Herein, inspired by the self-growth concept of living organisms, an interfacial catalytic self-growth strategy based on catechol chemistry-mediated self-catalytic system of preparing layered hydrogels is demonstrated. Typically, the tannic acid-metal ion (e.g., TA-Fe3+) complex embedded in the hydrogel substrate would catalytically trigger rapid solid-liquid interfacial polymerization to grow the hydrogel layer without bulk solution polymerization. The self-growth process can be finely controlled by changing the growth time, the molar ratio of Fe3+/TA, and so on. The strategy is applicable to prepare various layered hydrogels as well as complex layered hydrogel patterns, allowing the customization of the physicochemical properties of the hydrogel. In addition, the self-adhesive layered hydrogel was prepared and can be utilized as a wearable strain sensor to monitor physiological activities and human motions. The demonstrated interfacial catalytic self-growth strategy will provide a route to design and fabricate layered hydrogel materials.

3-methoxycatechol causes vasodilation likely via KV channels: ex vivo, in silico docking and in vivo study.

Substituted catechols include both natural and synthetic compounds found in the environment and foods. Some of them are flavonoid metabolites formed by the gut microbiota which are absorbed afterwards. Our previous findings showed that one of these metabolites, 4-methylcatechol, exerts potent vasorelaxant effects in rats. In the current study, we aimed at testing of its 22 structural congeners in order to find the most potent structure and to investigate the mechanism of action. 3-methoxycatechol (3-MOC), 4-ethylcatechol, 3,5-dichlorocatechol, 4-tert-butylcatechol, 4,5-dichlorocatechol, 3-fluorocatechol, 3-isopropylcatechol, 3-methylcatechol and the parent 4-methylcatechol exhibited high vasodilatory activities on isolated rat aortic rings with EC50s ranging from ∼10 to 24 µM. Some significant sex-differences were found. The most potent compound, 3-MOC, relaxed also resistant mesenteric artery but not porcine coronary artery, and decreased arterial blood pressure in both male and female spontaneously hypertensive rats in vivo without affecting heart rate. It potentiated the vasodilation mediated by cAMP and cGMP, but did not impact L-type Ca2+-channels. By using two inhibitors, activation of voltage-gated potassium channels (KV) was found to be involved in the mechanism of action. This was corroborated by docking analysis of 3-MOC with the KV7.4 channel. None of the most active catechols decreased the viability of the A-10 rat embryonic thoracic aorta smooth muscle cell line. Our findings showed that various catechols can relax vascular smooth muscles and hence could provide templates for developing new antihypertensive vasodilator agents without affecting coronary circulation.

Comprehensive investigation of niosomal red palm wax gel encapsulating ginger (Zingiber officinale Roscoe): Network pharmacology, molecular docking, In vitro studies and phase 1 clinical trials.

Ginger, a Zingeberaceae family member, is notable for its anti-inflammatory properties. This study explores the pharmaceutical mechanisms of ginger and red palm wax co-extract, developing novel niosomal formulations for enhanced transdermal delivery. Evaluations included physical characteristics, drug loading, in vitro release, network pharmacology, molecular docking, and biocompatibility. The niosomal ginger with red palm wax gel (NGPW) exhibited non-Newtonian fluid properties. The optimized niosome formulation (cholesterol: Tween80: Span60 = 12.5: 20: 5 w/w) showed a high yield (93.23 %), high encapsulation efficiency (54.71 %), and small size (264.33 ± 5.84 nm), prolonging in vitro anti-inflammatory activity. Human skin irritation and biocompatibility tests on 1 % NGPW showed favorable cytotoxicity and hemocompatibility results (ISO10993). Network pharmacology identified potential targets, while molecular docking highlighted high affinities between gingerol and red palm wax compounds with TRPM8 and TRPV1 proteins, suggesting pain inhibition via serotonergic synapse pathways. NGPW presents a promising transdermal pain inhibitory drug delivery strategy.

A comparative study on surface-engineered nanoceria using a catechol copolymer design: colloidal stability vs. antioxidant activity.

Nanoceria (NC) are widely studied as potent nanozyme antioxidants, featuring unique multifunctional, self-regenerative, and high-throughput enzymatic functions. However, bare NC are reported to show poor colloidal stability in biological media. Despite this, the nexus between colloidal stability and antioxidant activity has rarely been assessed. Here, a library of three copolymeric stabilising agents was synthesised, each consisting of hydrophilic poly(oligo(ethylene glycol) methyl ether methacrylate) brushes (P(OEGMA)) and a novel catechol anchoring block, and used for surface engineering of NC. The colloidal stability of the surface-engineered NC was assessed in phosphate buffered saline (PBS) by monitoring their precipitation via UV-Vis spectrophotometry, and their catalase (CAT)- and superoxide dismutase (SOD)-like activities were analysed using fluorospectrophotometry. The obtained results indicate that P(OEGMA) coating improves colloidal stability of NC over 48 h, highlighting the stable attachment of catechol functionalities to the surface of NC. In addition, X-ray photoelectron spectroscopy (XPS) indicates that the catechol functionalities lead to an increase in Ce3+/Ce4+ ratio and the concentration of oxygen vacancies, depending on the number of catechol units. Altogether, surface engineering of NC optimally results in an increase in CAT- and SOD-like activities by, respectively, 41% (=57.7% H2O2 elimination) and 78% (=78.0% O2˙- elimination) relative to bare NC, signifying a positive correlation between colloidal stability and antioxidant activity of the NC nanozymes.

6-Gingerol modulates miRNAs and PODXL gene expression via methyltransferase enzymes in NB4 cells: an in silico and in vitro study.

This investigation delves into the influence of predicted microRNAs on DNA methyltransferases (DNMTs) and the PODXL gene within the NB4 cell line, aiming to elucidate their roles in the pathogenesis of acute myeloid leukemia (AML). A comprehensive methodological framework was adopted to explore the therapeutic implications of 6-gingerol on DNMTs. This encompassed a suite of bioinformatics tools for protein structure prediction, docking, molecular dynamics, and ADMET profiling, alongside empirical assessments of miRNA and PODXL expression levels. Such a multifaceted strategy facilitated an in-depth understanding of 6-gingerol's potential efficacy in DNMT modulation. The findings indicate a nuanced interplay where 6-gingerol administration modulated miRNA expression levels, decreasing in DNMT1 and DNMT3A expression in NB4 cells. This alteration indirectly influenced PODXL expression, contributing to the manifestation of oncogenic phenotypes. The overexpression of DNMT1 and DNMT3A in NB4 cells may contribute to AML, which appears modulable via microRNAs such as miR-193a and miR-200c. Post-treatment with 6-gingerol, DNMT1 and DNMT3A expression alterations were observed, culminating in the upregulation of miR-193a and miR-200c. This cascade effect led to the dysregulation of tumor suppressor genes in cancer cells, including downregulation of PODXL, and the emergence of cancerous traits. These insights underscore the therapeutic promise of 6-gingerol in targeting DNMTs and microRNAs within the AML context.

Gingerol nanoparticles attenuate complete Freund adjuvant-induced arthritis in rats via targeting the RANKL/OPG signaling pathway.

Rheumatoid arthritis (RA) is characterized by inflammatory joint pathology leading to the degradation of articular bone and cartilage, primarily triggered by synovial inflammation, resulting in joint discomfort. The metacarpophalangeal and proximal interphalangeal joints are predominantly affected. Treatment typically involves a combination of biological and synthetic disease-modifying antirheumatic drugs (DAMARDs) alongside steroid therapy. The application of nanomedicine has been instrumental in enhancing treatment efficacy by facilitating controlled release of pharmacologically active compounds, thus augmenting bioavailability and enabling targeted drug delivery. Gingerol, a constituent of ginger, possesses multifaceted properties. including anti-inflammatory, anti-oxidant, antidiabetic, and antipyretic effects. In this study, gingerol-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), coated with chitosan, were administered orally to rats over a period of 21 days to address RA induced by complete Freund adjuvant (CFA). The rats were segregated into four experimental groups. Upon completion of the treatment regimen, blood samples were collected for the assessment of cyclooxygenase-2 (COX-2), RA factor, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Subsequent gene expression analysis was conducted to evaluate the levels of interleukin-4 (IL-4), interleukin-17a (IL-17a), IL-6, interferon-gamma (INF-γ), TNF-α, interleukin-1 beta (IL-1ß), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL). Statistical analyses utilizing one-way ANOVA followed by Tukey tests were applied to the data. The gene expression profiling revealed significant disparities in mRNA levels of IL-1ß, IL-6, IL-4, IL-17a, RANKL, INF-γ, and TNF-α between the CFA-induced arthritis group and the control group. Consequently, it was inferred that gingerol-loaded PLGA NPs coated with chitosan exhibited heightened therapeutic efficacy in addressing CFA-induced arthritis in rats.

Catechol-Fe(III) complexes modified PVDF membrane for hazardous pollutants separation and antifouling properties.

Organic pollutants, such as toluene and xylene, in industrial wastewater negatively impact the environment. Membrane treatment is one of the best methods to reduce impurities in wastewater. Existing membranes that coat the water surface with hydrophilic material only effectively resist the initial fouling, resulting in poor oil and water selectivity. Here we report a simple and efficient method to enhance the water flux and antifouling properties of polyvinylidene fluoride (PVDF) membranes. This method involves developing and applying Catechol-Fe(III) complexes with a rough surface to the PVDF surface. Forming Catechol-Fe(III) complexes on the surface better anchors them to the membrane than the dip-coating method. The PVDF membranes with rough Catechol-Fe(III) complexes are superoleophobic, with an oil contact angle of 152 ° and high permeability, with pure water flux of 10487 Lm-2h-1bar-1 and 1 wt% toluene in water emulsion flux of 4697 Lm-2h-1bar-1. Overall, the straightforward manufacturing process, increased permeability, and outstanding antifouling capabilities of the PVDF membrane incorporating rough nanoparticles offer promising prospects for designing and implementing suitable membranes for oil in water emulsion separation applications.

Regulation of Neuropeptide Y Receptor Gene Expression and Hormone Level in Obese Male Rats Receiving 6-Gingerol and L-Arginine Supplementation.

Obesity and its associated disorders, such as hyperlipidemia, have become a global issue following the consumption of unhealthy, high-fat, and high- carbohydrate foods, which burdens the economies and the health systems of human societies worldwide. This study aimed to evaluate the effect of oral consumption of 6-gingerol and L-arginine supplements on obesity factors. Thirty rats in five groups were fed a diet specific to each group for 12 weeks and then treated with the oral administration of L-arginine (200 mg/day) and 6-gingerol (100 mg/day) for 12 weeks. The food and water intake and weight change, were then measured. In addition, plasma glucose, triglyceride, cholesterol, high-density lipoprotein (HDL), very-low-density lipoprotein (VLDL) , low-density lipoprotein (LDL), and serum hormone levels, including corticosterone, testosterone, and insulin, were measured, and NPY, Y1, and Y5 receptor gene expression were recorded using real-time PCR. Administration of 6-gingerol and L-arginine decreased food intake, weight gain, glucose levels, insulin levels, and homeostasis model assessment-insulin resistance (HOMA-IR) index compared to the HCD control group. In addition, corticosterone and testosterone levels in the study groups showed a significant decrease (P<0.05) and increase (P<0.01) compared to the control groups, respectively. Triglyceride, total cholesterol, HDL, and VLDL levels in the groups treated with L-arginine and gingerol alone or combined significantly decreased compared to the control group (P<0.01). This study confirms that 6-gingerol and L-arginine supplements prevent HCD-induced hyperlipidemia by controlling hormones and neurotransmitters involved in the general metabolism. .

Mussel Foot Protein-Inspired Adhesive Tapes with Tunable Underwater Adhesion.

Instant and strong adhesion to underwater adherends is a big challenge due to the continuous interference of water. Mussel foot protein-bioinspired catechol-based adhesives have garnered great interest in addressing this issue. Herein, a novel self-made catecholic compound with a long aliphatic chain was utilized to prepare thin (∼0.07 mm) and optically transparent (>80%) wet/underwater adhesive tapes by UV-initiated polymerization. Its adhesion activity was water-triggered, fast (<1 min), and strong (adhesion strength to porcine skin: ∼1.99 MPa; interfacial toughness: ∼610 J/m2, burst pressure: ∼1950 mmHg). The effect of the catechol/phenol group and positively charged moiety on the wet/underwater adhesion to abiotic/biotic substrates was investigated. On the wet/underwater adherends, the tape with catechol groups presented much higher interfacial toughness, adhesion strength, and burst pressure than the analogous tape with phenol groups. The tape with both the catechol group and cationic polyelectrolyte chitosan had a more impressive improvement in its adhesion to wet/underwater biological tissues than to abiotic substrates. Therefore, catechol and a positive moiety in the tape would synergistically enhance its wet/underwater adhesion to various substrates, especially to biological tissues. The instant, strong, and noncytotoxic tape may provide applications in underwater adhesion for sealing and wound closure.

Gingerol containing polymeric nanofibers: a healing touch for accelerated wound recovery.

OBJECTIVE: In the current research, 6-gingerol (GA)-loaded nanofiber drug delivery system were developed, and their potential usage in wound healing was evaluated. SIGNIFICANCE: This study investigates the effectiveness of nanofibrous membranes composed of sodium alginate (SA), poly(vinyl alcohol) (PVA), and 6-gingerol (GA) as delivery systems for anti-inflammatory agents in the context of wound dressings. METHODS: GA-loaded SA/PVA nanofiber was prepared using electrospinning. In vitro characterization of this nanofiber included the examination of comprehensive in vitro characterization, anti-inflammatory and antioxidant activities, cytotoxicity, a scratch tes and in vivo skin test. RESULTS: GA was extracted from Zingiber officinale, and its successful isolation was confirmed through analyses such as H-NMR, C-NMR. Then GA was electrospuned into the SA/PVA nanofibers, and scanning electron microscopy (SEM) imaging revealed that the fiber diameters of the formulations ranged between 148 nm and 176 nm. Anti-inflammatory and antioxidant studies demonstrated that the effectiveness of GA increased with higher doses; however, this increase was accompanied by decreased cell viability. In vitro release studies revealed that GA exhibited a burst release within the first 8 h, followed by a controlled release, reaching completion within 24 h. Within the scope of in vitro release kinetics, release data are mathematically compatible with the Weibull model with high correlation. The scratch test results indicated that TB2 (%1 GA) promoted epithelialization. Furthermore, it was determined that TB2 (%1 GA) did not cause any irritation. CONCLUSIONS: As a result, TB2 shows promise as a formulation for wound dressings, offering potential benefits in the field of wound care.

Synthesis, Structure, Electrochemical Properties, and Antioxidant Activity of Organogermanium(IV) Catecholate Complexes.

A series of novel organogermanium(IV) catecholates 1-9 of the general formula R'2Ge(Cat), where R' = Ph, Et, have been synthesized. Compounds were characterized by 1H, 13C NMR, IR spectroscopy, and elemental analysis. The molecular structures of 1-3, 6, and 8 in crystal state were established using single-crystal X-ray analysis. The complexes are tetracoordinate germanium(IV) compounds containing a dioxolene ligand in a dianion (catecholato) form. Electrochemical transformations of target germanium(IV) complexes have been studied by cyclic voltammetry. The electro-oxidation mechanism of complexes 1-5, 7, and 10 (the related complex Ph2Ge(3,5-Cat) where 3,5-Cat is 3,5-di-tert-butylcatecholate) involves the consecutive formation of mono- and dicationic derivatives containing the oxidized forms of redox-active ligands. The stability of the generated monocations depends both on the hydrocarbon groups at the germanium atom and on the substituents in the catecholate ring. Compounds 6, 8, and 9 are oxidized irreversibly under the electrochemical conditions with the formation of unstable complexes. The radical scavenging activity and antioxidant properties of new complexes were estimated in the reaction with DPPH radical, ABTS radical cation, and CUPRACTEAC assay. It has been found that compounds 8 and 9 with benzothiazole or phenol fragments are more active in DPPH test. The presence of electron-rich moieties in the catecholate ligand makes complexes 5 and 7-9 more reactive to ABTS radical cation. The value of CUPRACTEAC for organogermanium(IV) catecholates varies from 0.23 to 1.45. The effect of compounds 1-9 in the process of lipid peroxidation of rat liver (Wistar) homogenate was determined in vitro. It was found that most compounds are characterized by pronounced antioxidant activity. A feature of complexes 1, 3, and 5-9 is the intensification of the antioxidant action with the incubation time. In the presence of additives of complexes 3, 5, 6, and 8, an induction period was observed during the process of lipid peroxidation.

Cost-effectiveness Analysis of COMT-inhibitors as Adjuvant Treatments to Levodopa in Patients with Advanced Parkinson's Disease.

PURPOSE: We aimed to elicit scientific evidence on the cost-effectiveness of two catechol-O-methyltransferase inhibitors (COMT-i) versus no COMT-i in patients with advanced Parkinson's disease. METHODS: A mixed model of the decision tree and a Markov model with three health states by OFF-time level (<25%, ≥25%, and death) was constructed to compare opicapone (OPC), entacapone (ENT), and no COMT-i over a lifetime. A hypothetical cohort of 10,000 patients was created and simulated based on the characteristics of the BIPARK trial subjects. FINDINGS: Two COMT-i (OPC and ENT) were identified as a cost-effective option compared to no COMT-i. Probabilistic sensitivity analysis showed that over 90% of the simulations proved the robust cost-effectiveness of COMT-i. When the time horizon as the most influential factor decreases to a 5- and 10-year period, COMT-i can be a cost-saving option. Although ENT may be the preferred option over OPC economically because of its lower price, OPC can be acceptable if the drug price is reduced by 17%. IMPLICATIONS: Add-on treatment with COMT-i in patients with PD receiving levodopa/carbidopa appears to be cost-saving compared with not using COMT-i. In the future, it is necessary to evaluate the economic evaluation of COMT-i based on long-term real-world evidence.