Anti-Allergic Effect of 3,4-Dihydroxybenzaldehyde Isolated from Polysiphonia morrowii in IgE/BSA-Stimulated Mast Cells and a Passive Cutaneous Anaphylaxis Mouse Model.

In this study, we investigated the anti-allergic effects of 3,4-dihydroxybenzaldehyde (DHB) isolated from the marine red alga, Polysiphonia morrowii, in mouse bone-marrow-derived cultured mast cells (BMCMCs) and passive cutaneous anaphylaxis (PCA) in anti-dinitrophenyl (DNP) immunoglobulin E (IgE)-sensitized mice. DHB inhibited IgE/bovine serum albumin (BSA)-induced BMCMCs degranulation by reducing the release of ß-hexosaminidase without inducing cytotoxicity. Further, DHB dose-dependently decreased the IgE binding and high-affinity IgE receptor (FcεRI) expression and FcεRI-IgE binding on the surface of BMCMCs. Moreover, DHB suppressed the secretion and/or the expression of the allergic cytokines, interleukin (IL)-4, IL-5, IL-6, IL-13, and tumor necrosis factor (TNF)-α, and the chemokine, thymus activation-regulated chemokine (TARC), by regulating the phosphorylation of IκBα and the translocation of cytoplasmic NF-κB into the nucleus. Furthermore, DHB attenuated the passive cutaneous anaphylactic (PCA) reaction reducing the exuded Evans blue amount in the mouse ear stimulated by IgE/BSA. These results suggest that DHB is a potential therapeutic candidate for the prevention and treatment of type I allergic disorders.

Preparation of External Stimulus-Free Gelatin-Catechol Hydrogels with Injectability and Tunable Temperature Responsiveness.

Gelatin is one of the most versatile biopolymers in various biomedical applications. A gelatin derivative gelatin-catechol (Gel-C) was developed in this study to further optimize its chemical and physical properties such as thermal reversibility and injectability. We found that Gel-C remains in a solution state at room temperature, and the temperature-dependent gelation capability of gelatin is well preserved in Gel-C. Its gel-forming temperature decreased to about 10 °C (about 30 °C for gelatin), and a series of gelatin derivatives with different gel-forming temperatures (10-30 °C) were formed by mixing gelatin and Gel-C in different ratios. Additionally, irreversible Gel-C hydrogels could be made without the addition of external stimuli by combining the physical cross-linking of gelatin and the chemical cross-linking of catechol. At the same time, properties of Gel-C hydrogels such as thermal reversibility and injectability could be manipulated by controlling the temperature and pH of the precursor solution. By simulating the formation of an irreversible Gel-C hydrogel in vivo, an in situ gelling system was fabricated by lowering the local temperature of the hydrogel with cold shock, thus realizing targeted and localized molecular delivery with prolonged retention time. This simple system integrated with the temperature responsiveness of gelatin and chemical cross-linking of catechol groups thus provides a promising platform to fabricate an in situ gelling system for drug delivery.

Dietary supplementation of gingerols- and shogaols-enriched ginger root extract attenuate pain-associated behaviors while modulating gut microbiota and metabolites in rats with spinal nerve ligation.

Neuroinflammation is a central factor in neuropathic pain (NP). Ginger is a promising bioactive compound in NP management due to its anti-inflammatory property. Emerging evidence suggests that gut microbiome and gut-derived metabolites play a key role in NP. We evaluated the effects of two ginger root extracts rich in gingerols (GEG) and shogaols (SEG) on pain sensitivity, anxiety-like behaviors, circulating cell-free mitochondrial DNA (ccf-mtDNA), gut microbiome composition, and fecal metabolites in rats with NP. Sixteen male rats were divided into four groups: sham, spinal nerve ligation (SNL), SNL+0.75%GEG in diet, and SNL+0.75%SEG in diet groups for 30 days. Compared to SNL group, both SNL+GEG and SNL+SEG groups showed a significant reduction in pain- and anxiety-like behaviors, and ccf-mtDNA level. Relative to the SNL group, both SNL+GEG and SNL+SEG groups increased the relative abundance of Lactococcus, Sellimonas, Blautia, Erysipelatoclostridiaceae, and Anaerovoracaceae, but decreased that of Prevotellaceae UCG-001, Rikenellaceae RC9 gut group, Mucispirillum and Desulfovibrio, Desulfovibrio, Anaerofilum, Eubacterium siraeum group, RF39, UCG-005, Lachnospiraceae NK4A136 group, Acetatifactor, Eubacterium ruminantium group, Clostridia UCG-014, and an uncultured Anaerovoracaceae. GEG and SEG had differential effects on gut-derived metabolites. Compared to SNL group, SNL+GEG group had higher level of 1'-acetoxychavicol acetate, (4E)-1,7-Bis(4-hydroxyphenyl)-4-hepten-3-one, NP-000629, 7,8-Dimethoxy-3-(2-methyl-3-buten-2-yl)-2H-chromen-2-one, 3-{[4-(2-Pyrimidinyl)piperazino]carbonyl}-2-pyrazinecarboxylic acid, 920863, and (1R,3R,7R,13S)-13-Methyl-6-methylene-4,14,16-trioxatetracyclo[11.2.1.0∼1,10∼.0∼3,7∼]hexadec-9-en-5-one, while SNL+SEG group had higher level for (±)-5-[(tert-Butylamino)-2'-hydroxypropoxy]-1_2_3_4-tetrahydro-1-naphthol and dehydroepiandrosteronesulfate. In conclusion, ginger is a promising functional food in the management of NP, and further investigations are necessary to assess the role of ginger on gut-brain axis in pain management.

Ginger and 6-gingerol prevent lipopolysaccharide-induced intestinal barrier damage and liver injury in mice.

BACKGROUND: Inflammation-related diseases present a significant public health problem. Ginger is a flavoring spice and medicinal herb with anti-inflammatory activity. This study investigated the preventive effects of ginger extract (GE) and its main bioactive component, 6-gingerol (6G), on lipopolysaccharide (LPS)-induced intestinal barrier dysfunction and liver injury in mice. RESULTS: GE and 6G were orally administered to mice for seven consecutive days before LPS administration. After 24 h, the mice were sacrificed. GE and 6G were found to significantly reverse LPS-induced inflammation in the mouse ileum by modifying the NF-κB pathway. They also alleviated apoptosis in the ileum by downregulating Bax and cytochrome c gene expression and by inhibiting the caspase-3 pathway. Through the aforementioned mechanisms, GE and 6G restored the intestinal barrier by increasing ZO-1 and claudin-1 protein expressions. Gut-derived LPS induced inflammation and apoptosis in the liver; these effects were markedly reversed through GE and 6G treatment. 6G was the most abundant component in GE, as evidenced through liquid chromatography-mass spectrometry, and accounted for >50% of total gingerols and shogaols in GE. CONCLUSION: The current results support the use of GE and 6G as dietary supplements to protect against gut-derived endotoxemia-associated inflammatory response and disorders. © 2021 Society of Chemical Industry.

ND0612 (levodopa/carbidopa for subcutaneous infusion) in patients with Parkinson's disease and motor response fluctuations: A randomized, placebo-controlled phase 2 study.

INTRODUCTION: ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations. METHODS: This was a randomized, placebo-controlled, double-blind, 2-period study evaluating the safety and pharmacokinetics of ND0612 in PD patients on an optimized oral levodopa regimen and experiencing ≥2 h/day of OFF time. During Period-1, patients received their current standard of care (SoC) levodopa/carbidopa and were randomized (2:1) to 14 days treatment with adjunct ND0612 (daily levodopa/carbidopa dose of 270/63 mg) or placebo infusion +SoC. During Period-2, 16 patients were randomized to receive 7 days treatment with ND0612 or ND0612 plus oral entacapone. Reduction in OFF time was analyzed as an exploratory measure using a futility design with a predefined margin of 1.6 h. RESULTS: ND0612 was well-tolerated; most patients experienced infusion site nodules (95% vs. 56% with placebo), which all resolved without sequelae. Patients treated with adjunct ND0612 during Period-1 avoided deep troughs in levodopa plasma levels and had a decreased fluctuation index versus placebo (1.6 ± 0.5 vs 3.1 ± 1.6 at end of Period-1, respectively). In Period-2, the coadministration of entacapone with continuous ND0612 SC infusion translated to an increase in mean levodopa AUC0-10h compared to baseline. Exploratory efficacy analysis of Period 1 showed mean ± SD OFF time reductions of -2.13 ± 2.24 [90%CI: -2.8, ∞] hours (p = 0.84 using H0 of µ0 ≤-1.6). CONCLUSION: Levodopa/carbidopa infusion with ND0612 was generally well-tolerated and resulted in reduced fluctuations in plasma levodopa concentrations when given with SoC oral levodopa. ND0612 met the efficacy endpoint for the futility design.

Characterization and in vivo evaluation of nanoformulations in FCA induced rheumatoid arthritis in rats.

Rheumatoid arthritis is an inflammatory arthropathy, autoimmune in nature, leading to disability of joints involving structural destruction of articular bone and cartilage due to inflammation in synovium resulting in joint stiffness, swelling and pain. Nanomedicine has played a crucial role in improving the efficacy of treatment by controlling the release of pharmacologically active ingredients to increase bioavailability and achieve uniform and targeted delivery of drug. In this study, we prepared celecoxib, gingerol and oleanic acid loaded PLGA nanoparticles by solvent evaporation method and nanoparticles were characterized by particle size, zeta potential, polydispersity index, entrapement efficiency and FTIR. FCA is induced in right hand paw of rats for induction of arthritis. Celecoxib, gingerol and oleanic acid loaded PLGA nanoparticles coated with chitosan were given orally to rats for the evaluation of anti-arthritic effect of this nanoformulation in rats. Animals were divided into six groups for 21 days trial. On 21st day blood samples were collected for evaluation of hematological and lipid profile parameters. The data was subjected to statistical analysis by applying one way ANOVA and tukey test. At the end of study it was concluded that PLGA loaded celecoxib, gingerol and oleanic acid coated with chitosan have excellent effects in minimizing the side effects and increasing the therapeutic efficacy of drugs.

ß-Cyclodextrin Inclusion Complexes with Catechol-Containing Antioxidants Protocatechuic Aldehyde and Protocatechuic Acid-An Atomistic Perspective on Structural and Thermodynamic Stabilities.

Protocatechuic aldehyde (PCAL) and protocatechuic acid (PCAC) are catechol derivatives and have broad therapeutic effects associated with their antiradical activity. Their pharmacological and physicochemical properties have been improved via the cyclodextrin (CD) encapsulation. Because the characteristics of ß-CD inclusion complexes with PCAL (1) and PCAC (2) are still equivocal, we get to the bottom of the inclusion complexation by an integrated study of single-crystal X-ray diffraction and DFT full-geometry optimization. X-ray analysis unveiled that PCAL and PCAC are nearly totally shielded in the ß-CD wall. Their aromatic rings are vertically aligned in the ß-CD cavity such that the functional groups on the opposite side of the ring (3,4-di(OH) and 1-CHO/1-COOH groups) are placed nearby the O6-H and O2-H/O3-H rims, respectively. The preferred inclusion modes in 1 and 2 help to establish crystal contacts of OH⋅⋅⋅O H-bonds with the adjacent ß-CD OH groups and water molecules. By contrast, the DFT-optimized structures of both complexes in the gas phase are thermodynamically stable via the four newly formed host-guest OH⋯O H-bonds. The intermolecular OH⋅⋅⋅O H-bonds between PCAL/PCAC 3,4-di(OH) and ß-CD O6-H groups, and the shielding of OH groups in the ß-CD wall help to stabilize these antioxidants in the ß-CD cavity, as observed in our earlier studies. Moreover, PCAL and PCAC in distinct lattice environments are compared for insights into their structural flexibility.

Antioxidant Effect of Hydroxytyrosol, Hydroxytyrosol Acetate and Nitrohydroxytyrosol in a Rat MPP+ Model of Parkinson's Disease.

3,4-Dihydroxyphenyl ethanol, known as hydroxytyrosol (HTy), is a phenylpropanoid found in diverse vegetable species. Several studies have demonstrated that HTy is a potent antioxidant. Thus, our study is aimed to evaluate the antioxidant effect of HTy and its derivatives, hydroxytyrosol acetate (HTyA) and nitrohydroxytyrosol (HTyN), in a model of oxidative stress induced by 1-methyl-4-phenylpyridinium (MPP+) in rats. Rats were administered intravenously (i.v.) in the tail with 1 mL saline solution or polyphenol compound (1.5 mg/kg) 5 min before intrastriatal infusion of 10 µg MPP+/8 µL. We found that rats injured with MPP+, pretreatment with HTy, HTyA or HTyN significantly decreased ipsilateral turns. This result was consistent with a significant preservation of striatal dopamine levels and decreased lipid fluorescence products (LFP), a marker of oxidative stress. Brain GSH/GSSG ratio, from rats pretreated with HTy or HTyN showed a significant preservation of that marker, decreased as a consequence of MPP+-induced oxidative damage. These results show an antioxidant effect of HTy, HTyA and HTyN in the MPP+ model of Parkinson's disease in the rat.

Protocatechudehyde improves mitochondrial energy metabolism through the HIF1α/PDK1 signaling pathway to mitigate ischemic stroke-elicited internal capsule injury.

ETHNOPHARMACOLOGICAL RELEVANCE: The internal capsule is vulnerable to ischemia, and mild ischemic stroke often results in lesion of the internal capsule, manifested as contralateral hemiplegia. Protocatechudehyde (PCA), a potential neuroprotective agent, has shown therapeutic effects in the study of a variety of nervous system diseases, including ischemic stroke. AIM OF THE STUDY: The aim of this study was to evaluate the effects of PCA on cerebral ischemia reperfusion (CI/R)-elicited internal capsule injury and to elucidate the role of mitochondrial energy metabolism in the underlying mechanism of neuroprotective effects on ischemic stroke. MATERIALS AND METHODS: A rat tMCAO model was established to investigate the therapeutic effects of intravenous PCA (20, 40, and 80 mg/kg, once per day, continued for 7 days) on CI/R-induced internal capsule injury and the regulation of PCA on molecules related to mitochondrial energy metabolism. In vitro, an OGD/R model of PC12 cells was established to further verify the therapeutic mechanism of PCA. RESULTS: Results showed that PCA dose-dependently attenuated neurological deficit, reduced cerebral infarction, alleviated histopathological damage, and improved mitochondrial ultrastructure of the internal capsule after CI/R. Moreover, PCA reversed the upregulation of HIF1α, PDK1 and pPDHA1 expression induced by CI/R and significantly increased the content of acetyl-CoA, ATP, and the activity of ATP synthase. In vitro, PCA treatment promoted cell survival, inhibited apoptosis, attenuated the dissipation of mitochondrial membrane potential in OGD/R-treated PC12 cells, and these therapeutic effects were reversed by the combination of cobalt chloride (CoCl2), a specific pharmacological inducer of HIF1a expression. CONCLUSIONS: These results indicate that PCA exerts a protective effect against CI/R-induced internal capsule injury and improves mitochondrial energy metabolism in the internal capsule, and the mechanism is associated with the inhibition of HIF1α/PDK1 signaling pathway.

[10]-Gingerol-Loaded Nanoemulsion and its Biological Effects on Triple-Negative Breast Cancer Cells.

The apoptotic, cytotoxic, and cytostatic activities for [10]-gingerol in triple-negative breast cancer cells (TNBCs) were already reported. However, despite these important antitumor activities, the compound has the disadvantage to have a hydrophobic characteristic, hindering in vivo administration. To surpass this issue, in this study we have created a [10]-gingerol-loaded nanoemulsion (10GNE) in order to increase the stability and solubility of the compound. The nanoemulsion was characterized and tested for its cytotoxic, cytostatic, and apoptotic effects on a panel of murine and human TNBC cell lines, as well as non-tumor cells, and compared with a [10]-gingerol-free nanoemulsion (NE) and with [10]-gingerol itself. Except for the murine 4T1.13 cell line, the IC50 of the free 10G molecule, after 72 h of incubation, was higher in all cell lines tested, both murine and human, demonstrating therefore the efficacy of the 10GNE regarding cytotoxicity. In murine tumor cells, 60 µM 10GNE was able to arrest cell cycle at sub-G0 phase and induce apoptosis, leading to 48% and 78% of total cell death in 4T1.13 and 4T1Br4 murine tumor cells, respectively. This represents an improvement compared to 10G-free molecule that only induced 74% of total apoptosis at 100 µM in 4T1Br4 cells. Taken together, our results show that nanoformulation preserved the [10]-gingerol cytotoxic and cytostatic properties and improved its apoptotic function on murine TNBC cell lines. These data open new perspectives to a more suitable drug-delivery approach for [10]-gingerol for TNBC treatment that should be further demonstrated using in vivo assays.

Nutraceutical Screening in a Zebrafish Model of Muscular Dystrophy: Gingerol as a Possible Food Aid.

Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is an inherited neuromuscular disorder that causes loss of muscle mass and motor skills. In the era of genomic medicine, there is still no known cure for DMD. In clinical practice, there is a growing awareness of the possible importance of nutrition in neuromuscular diseases. This is mostly the result of patients' or caregivers' empirical reports of how active substances derived from food have led to improved muscle strength and, thus, better quality of life. In this report, we investigate several nutraceutical principles in the sapje strain of zebrafish, a validated model of DMD, in order to identify possible natural products that, if supplemented in the diet, might improve the quality of life of DMD patients. Gingerol, a constituent of fresh ginger, statistically increased the locomotion of mutant larvae and upregulated the expression of heme oxygenase 1, a target gene for therapy aimed at improving dystrophic symptoms. Although three other compounds showed a partial positive effect on locomotor and muscle structure phenotypes, our nutraceutical screening study lent preliminary support to the efficacy and safety only of gingerol. Gingerol could easily be proposed as a dietary supplement in DMD.

Catechol functionalized chitosan/active peptide microsphere hydrogel for skin wound healing.

Chitosan-based thermosensitive hydrogels have been widely used in drug delivery and tissue engineering, but their poor bioactivity has limited their further applications. Integral active oyster peptide microspheres (OPM) with an average particle diameter of 3.9 µm were prepared with high encapsulation efficiency (72.8%) and loading capacity (11.9%), exhibiting desirable sustained release effects. Using catechol functionalized chitosan (CS-C) as the polymeric matrix, OPM as the filler, and ß-sodium glycerophosphate (ß-GP) as a thermal sensitizer, the thermosensitive hydrogel CS-C/OPM/ß-GP was prepared. Besides, the application of the hydrogel on wound healing was studied, and its biosafety was evaluated. The results of cell migration in vitro showed that the cell migration rate of CS-C/OPM/ß-GP reached 97.47 ± 5.41% within 48 h, indicating that the hydrogel accelerated the migration of L929 cells. As demonstrated in the mouse skin wound experiment, CS-C/OPM/ß-GP hydrogel not only inhibited the aggregation of diversified inflammatory cells and accelerated the generation of collagen fibers and new blood vessels of the wound, but also enhanced the synthesis of total protein (TP) in granulation tissue, and up-regulated the expression of Ki-67 and VEGF in the injury, thereby achieving fast wound healing. Safety evaluation results showed that CS-C/OPM/ß-GP hydrogel was not cytotoxic to L929 cells, and the hemolysis ratio was less than 5% within 1 mg/mL. In conclusion, CS-C/OPM/ß-GP hydrogel is expected as a promising medical dressing for wound healing.

Opicapone: A Review in Parkinson's Disease.

Oral opicapone (Ongentys®), a potent third-generation, peripheral catechol-O-methyltransferase (COMT) inhibitor, is approved as adjunctive therapy to preparations of levodopa/dopa-decarboxylase inhibitor (L-dopa/DDCI) in adults with Parkinson's disease (PD) and end-of dose (EoD) motor fluctuations. In pivotal global trials (BIPARK 1 and BIPARK 2; 14-15 weeks' duration), open-label extensions (OLEs) of BIPARK, and in the real-world setting (OPTIPARK; 3-6 months), opicapone 50 mg once daily was an effective and generally well tolerated adjunctive therapy to L-dopa/DDCI plus other PD therapy in adults with PD and EoD motor fluctuations. Adjunctive opicapone provided better efficacy than placebo for improvements in ON- and OFF-state time and fulfilled noninferiority to adjunctive entacapone for improvements in OFF time in BIPARK 1. These beneficial effects of adjunctive opicapone on motor fluctuations were maintained during 1 year of treatment in OLE studies. Given its efficacy and safety profile, adjunctive opicapone remains an important option in the management of adults with PD and EoD motor fluctuations who cannot be stabilized on preparations of L-dopa/DDCI.

Co-Delivery of Hispolon and Doxorubicin Liposomes Improves Efficacy Against Melanoma Cells.

Hispolon is a small molecular weight polyphenol that has antioxidant, anti-inflammatory, and anti-proliferative activities. Our recent study has demonstrated hispolon as a potent apoptosis inducer in melanoma cell lines. Doxorubicin is a broad spectrum first-line treatment for various kinds of cancers. In this study, co-delivery of doxorubicin and hispolon using a liposomal system in B16BL6 melanoma cell lines for synergistic cytotoxic effects was investigated. Liposomes were prepared using a lipid film hydration method and loaded with doxorubicin or hispolon. The formulations were characterized for particle size distribution, release profile, and encapsulation efficiency (EE). In addition, in vitro cytotoxicity, in vitro cell apoptosis, and cellular uptake were evaluated. Liposomes exhibited small particle size (mean diameter ~ 100 nm) and narrow size distribution (polydispersity index (< 0.2) and high drug EE% (> 90%). The release from liposomes showed slower release compared to free drug solution as an additional time required for the release of drug from the liposome lipid bilayer. Liposome loaded with doxorubicin or hispolon exhibited significantly higher cytotoxicity against B16BL6 melanoma cells as compared to doxorubicin solution or hispolon solution. Likewise, co-delivery of hispolon and doxorubicin liposomes showed two-fold and three-fold higher cytotoxicity, as compared to hispolon liposomes or doxorubicin liposomes, respectively. In addition, co-delivery of doxorubicin and hispolon in liposomes enhanced apoptosis more than the individual drugs in the liposome formulation. In conclusion, the co-delivery of hispolon and doxorubicin could be a promising therapeutic approach to improve clinical outcomes against melanoma.

Protocatechuic aldehyde from Salvia miltiorrhiza exhibits an anti-inflammatory effect through inhibiting MAPK signalling pathway.

BACKGROUND: The aerial parts of Salvia miltiorrhiza, which was considered to be the waste part and discarded during the root harvest, is rich in protocatechuic aldehyde (PAI). This study investigated the health-promoting effects of extracts and PAI from the aerial parts of Salvia miltiorrhiza, including its anti-inflammatory effects and the underlying mechanisms of action in vitro and in vivo. METHOD: Purification of the sample paste of Salvia miltiorrhiza was accomplished using HPLC analysis. TheMTT (Methylthiazolyldiphenyl-tetrazolium bromide) assay was employed to determine the cell viability. The production of inflammatory factors was detected by ELISA assays. The histopathological analysis was used to analyse the lungs and livers of mice treated with PAI. Western blot was performed to reveal the mechanism of PAI in anti-inflammatory. RESULTS: The extracts and PAI from the aerial parts of Salvia miltiorrhiza inhibited TNF-α, IL-6 production and promoted the production of IL-10 in vivo in mice and in vitro in the macrophage cell line RAW264.7. NF-κB and MAPKs kinase phosphorylation were also suppressed by PAI in vivo and in vitro, indicating that PAI exhibited an anti-inflammatory effect. CONCLUSION: These findings suggest that the aerial parts of Salvia miltiorrhiza extract may serve as potential protective agents for inflammatory.

[6]-Gingerol Ameliorates Cisplatin-Induced Pica by Regulating the TPH/MAO-A/SERT/5-HT/5-HT3 Receptor System in Rats.

PURPOSE: [6]-gingerol is a bioactive compound extracted from ginger, a traditional anti-emetic herb in Chinese medicine. Previous studies have demonstrated that [6]-gingerol can ameliorate chemotherapy-induced pica in rats, although the underlying mechanism has not been elucidated. This study is designed to investigate [6]-gingerol's antiemetic mechanism focusing on the 5-hydroxytryptamine (serotonin, 5-HT) system by evaluating the synthesis, metabolism and reuptake of 5-HT, as well as the mechanism of 5-hydroxytryptamine type 3 receptor (5-HT3 receptor), in a cisplatin-induced pica model of rats. METHODS: Rats were randomly divided into control group (vehicle + saline, Con), [6]-gingerol control group (50 mg/kg [6]-gingerol + saline, G-con), ondansetron control group (2.6 mg/kg ondansetron + saline, O-con), cisplatin model group (vehicle + cisplatin, Model), ondansetron-treated group (2.6 mg/kg ondansetron + cisplatin, O-treated), high dosage of [6]-gingerol-treated group (100 mg/kg [6]-gingerol + cisplatin, GH-treated), and low dosage of [6]-gingerol-treated group (50 mg/kg [6]-gingerol + cisplatin, GL-treated). The rats were administered with [6]-gingerol, ondansetron, and vehicle (3% Tween-80) by gavage twice (7:00 AM and 7:00 PM). One hour after the first treatment (8:00 AM), rats in groups Model, O-treated, GH-treated and GL-treated were injected intraperitoneally (i.p.) with 6 mg/kg cisplatin, and the other groups were injected i.p. with saline of equal volume. The consumption of kaolin of the rats were measured. All the rats were anesthetized by i.p. injection of pentobarbital sodium at 24 h post-cisplatin. After blood samples were taken, medulla oblongata and ileum were removed. The levels of 5-HT and its metabolite 5-HIAA in ileum, medulla oblongata and serum were determined using high-performance liquid chromatography with electrochemical detection (HPLC-ECD). The mRNA expression levels of 5-HT3 receptor, tryptophan hydroxylase (TPH), monoamine oxidase A (MAO-A) and serotonin reuptake transporter (SERT) were detected by real-time PCR. The protein expression levels and distribution of 5-HT3 receptor, TPH and MAO-A in the medulla oblongata and ileum were measured by Western blotting and immunohistochemistry, respectively. RESULTS: [6]-gingerol treatment significantly reduced the kaolin ingestion and the increase in 5-HT concentration in rats induced by cisplatin. TPH, MAO-A, SERT, and 5-HT3 receptor are important in 5-HT metabolism, and cisplatin-induced alterations in the associated protein/mRNA levels were restored when treated with [6]-gingerol. CONCLUSION: This suggests that the antiemetic effect of [6]-gingerol against cisplatin-induced emesis may be due to 5-HT attenuation via modulating the TPH/MAO-A/SERT/5-HT/5-HT3 receptor system.

Inhibiting NF-κB-Mediated Inflammation by Catechol-Type Diphenylbutadiene via an Intracellular Copper- and Iron-Dependent Pro-Oxidative Role.

Chronic inflammation mediated by nuclear factor-κB (NF-κB) plays a crucial role in the development of cancer. As part of our continuous efforts placed on investigating anticancer mechanisms of dietary catechols, we further applied catechol-type diphenylbutadiene (3,4-DHB) as a model molecule to probe whether it inhibits inflammation by its pro-oxidative role. Employing lipopolysaccharide-stimulated RAW264.7 cells as a model of inflammation, we validated that benefiting from its catechol moiety, 3,4-DHB inhibited significantly the LPS-induced formation of NO (11.48 ± 0.39 µM) compared with the only LPS-stimulated group (31.8 ± 1.78 µM) with an inhibitory rate of 64% at 5 µM, expression of iNOS and COX-2 proteins, phosphorylation of IkB kinase and IkBα, and nuclear translocation of NF-κB. Noticeably, its inhibitory activity against the NF-κB-mediated inflammation can be obviously revised by pretreatment of the cells with dithiothreitol (a quencher of both electrophilic o-quinone and ROS), neocuproine (a specific chelating agent for copper ions), and deferoxamine (a specific chelating agent for iron ions). The above results support that depending on intracellular copper and iron ions, 3,4-DHB, a pro-electrophile, can be converted into its corresponding o-quinone electrophile together with the generation of ROS, a pro-oxidative event that mediates its inhibitory activity against NF-κB signaling and inflammation. The copper- and iron-dependent inhibition against inflammation supports that dietary catechols are probably pro-oxidative anti-inflammatory agents.

Fixed-dose combination therapy for Parkinson's disease with a spotlight on entacapone in the past 20 years: a reduced pill burden and a simplified dosing regime.

INTRODUCTION: Parkinson's disease (PD) is a progressive, chronic neurodegenerative disorder. The main neuropathological cause of the disease is the death of dopaminergic neurons in the substantia nigra. Unfortunately, there is no curative treatment yet. The gold-standard of the treatment is levodopa (LD). During the course of the disease, motor complications develop, which postulates the addition of entacapone (ENT) to the dopaminergic medication. Previous studies have suggested that patients have a better quality of life when entacapone is added in a combination with LD. AREAS COVERED: A systematic literature search was performed. Articles were identified through PubMed (MEDLINE), Web of Science, Ovid, and ClinicalTrials.gov databases. The following search terms were used: 'Levodopa' AND 'Carbidopa' OR 'Benserazide' AND 'Entacapone'. The search period was between 2000 and 2020. Twenty randomized and 10 non-randomized clinical trials (12,893 subjects) were included in the qualitative analysis. The systematic review was written in line with the PRISMA guideline. EXPERT OPINION: ENT administered in combination with LD resulted in a better quality of life compared to separate tablets. Therefore, in PD patients where impaired motor performance develops and the application of entacapone is necessary, it is suggested to be administered in a single tablet form.

Ultrasound-Augmented Phase Transition Nanobubbles for Targeted Treatment of Paclitaxel-Resistant Cancer.

Paclitaxel (PTX) resistance in most epithelial ovarian cancers (EOCs) with increasing membrane expression of mucin 16 (MUC16) is mediated by the Toll-like receptor-myeloid differentiation factor 2/myeloid differentiation factor 88 (TLR4-MD2/MyD88) signaling pathway. 6-Shogaol (6S), an α,ß-unsaturated carbonyl compound with lipophilic property, can block PTX-induced formation of the TLR4-MD2 complex that activates the MyD88/NF-κB signaling pathway. Herein, to improve the effectiveness of 6S, augment the sensibility of PTX, and enhance the targeting ability of PTX-resistant cancer therapies, we report a class of 6S-loaded phase transition nanobubbles conjugated with the MUC16 antibody (6S@NBs-MUC16A), which can enhance the sensitivity of PTX to EOC cells through ultrasound-controlled targeted-delivery of 6S. The 6S@NB-MUC16A could enhance the targeting efficiency and organizational distribution of 6S in MyD88+ EOC area, and the 1 MHz ultrasound can be used as an initiator to trigger the "explosion" of nanobubbles and promote the 6S release. Furthermore, in vivo assessment results indicate that ultrasound-augmented 6S@NB-MUC16A can significantly improve the response of EOC to PTX and the inhibition ratio of tumor growth compared to the control-treated with PTX alone, and exhibit less toxicity to the critical organs. The ultrasound-augmented 6S@NB-MUC16A with less cytotoxicity could be a potentially useful nanosystem to surmount PTX resistance in EOC, which provides potential possibilities for the applications in the biological field.

Optimized clinical management of Parkinson's disease with opicapone. Recommendations from Spanish experts. / Optimización del manejo clínico de opicapona en la enfermedad de Parkinson. Recomendaciones de expertos españoles.

Motor fluctuations are frequently seen in Parkinson disease patients on chronic treatment with levodopa. Management of motor fluctuation includes the addition of catechol-O-methyl transferase (COMT) inhibitors. Opicapone is a recent and selective third-generation COMT inhibitor which achieves marked increase in the bioavailability of levodopa. We present a consensus of a group of Spanish neurologists with extensive experience in the clinical management of motor fluctuations. The clinical experience of this group of experts is in line with clinical trials and confirms that opicapone is an effective drug in the control of motor fluctuations, regardless of the daily levodopa dose, or the use of other antiparkinsonian drugs. However, in the opinion of these experts, the ideal patient with Parkinson's disease to initiate treatment with opicapone is the one with mild motor fluctuations, since the ratio between clinical efficacy and adverse effects is more favorable. In general, it is an easy-to-use drug both in those first treated with a COMT inhibitor or those already on entacapone. In any case, the secondary side effects are easily managed.

TITLE: Optimización del manejo clínico de opicapona en la enfermedad de Parkinson. Recomendaciones de expertos españoles.Las fluctuaciones motoras constituyen una importante complicación en los pacientes con enfermedad de Parkinson tratados con levodopa. Entre las opciones terapéuticas para el manejo de las fluctuaciones motoras se cuenta con los inhibidores de la catecol-O-metil-transferasa (COMT), incluyendo la opicapona. La opicapona muestra una elevada afinidad por la COMT y consigue un aumento marcado de la biodisponibilidad de la levodopa. Se presenta el consenso de un grupo de expertos españoles en la enfermedad de Parkinson con experiencia en el tratamiento clínico de fluctuaciones motoras y el empleo de opicapona. La experiencia de este grupo de expertos, en consonancia con los ensayos clínicos, confirma que la opicapona es un fármaco eficaz en el control de las fluctuaciones motoras de la enfermedad de Parkinson, con independencia de la dosis de levodopa recibida o de la utilización de otros fármacos antiparkinsonianos. No obstante, a juicio de estos expertos, el paciente ideal para iniciar el tratamiento con opicapona es el que presenta fluctuaciones motoras leves, ya que muestra una mejor relación entre eficacia clínica y efectos adversos. En general, la opicapona es un fármaco de fácil manejo, tanto en pacientes que requieren opicapona como primer inhibidor de la COMT como en los previamente tratados con entacapona, o en los que están en tratamiento concomitante con otros fármacos antiparkinsonianos. En cualquier caso, los efectos secundarios son fácilmente corregibles.