4-Allyl-2-methoxyphenol modulates the expression of genes involved in efflux pump, biofilm formation and sterol biosynthesis in azole resistant Aspergillus fumigatus.

Introduction: Antifungal therapy for aspergillosis is becoming problematic because of the toxicity of currently available drugs, biofilm formation on host surface, and increasing prevalence of azole resistance in Aspergillus fumigatus. Plants are rich source of bioactive molecules and antimicrobial activity of aromatic bioactive compounds draws attention because of its promising biological properties. The present study elucidated the antibiofilm activity of 4-allyl-2-methoxyphenol (eugenol) against azole-resistant environmental A. fumigatus isolates. Methods: Soil samples were collected from agricultural fields across India; azole-resistant A. fumigatus (ARAF) were isolated followed by their molecular identification. Antibiofilm activity of eugenol was calculated via tetrazolium based-MTT assay. The expression of the multidrug efflux pumps genes MDR1, MDR4, transporters of the MFS gene, erg11A gene encoding 14α demethylase, and transcription regulatory genes, MedA, SomA and SrbA, involved in biofilm formation of A. fumigatus were calculated by quantitative real time PCR. Results: Out of 89 A. fumigatus isolates, 10 were identified as azole resistant. Eugenol exhibited antibiofilm activity against ARAF isolates, ranging from 312 to 500 µg/mL. Confocal laser scanning microscopy analysis revealed absence of extracellular matrix of ARAF biofilm after eugenol treatment. The gene expression indicated significantly low expression of efflux pumps genes MDR1, MDR4, erg11A and MedA in eugenol treated ARAF isolates when compared with untreated isolates. Conclusions: Our results demonstrate that eugenol effects the expression of efflux pump and biofilm associated genes as well as inhibits biofilm formation in azole resistant isolates of A. fumigatus.

Guaiacol augments quorum quenching potential of ciprofloxacin against Pseudomonas aeruginosa.

AIM: The present study aims to investigate the antimicrobial as well as antivirulence potential and the principle mechanism of action of guaiacol against Pseudomonas aeruginosa. METHODS AND RESULTS: Quorum sensing inhibition and membrane disruption studies were performed to check the effect of guaiacol on the virulence of P. aeruginosa. Production of various virulence factors and biofilm formation was studied at a sub-MIC concentration of guaiacol alone (1/8 MIC) and in combination with ciprofloxacin (1/2 FIC). Guaiacol exhibited synergistic interactions with ciprofloxacin and further reduced the production of all virulence factors and biofilm formation. Using crystal violet (CV) assay and quantification of exopolysaccharide, we observed weak biofilm formation, together with reduced motilities at sub-MIC, which was further visualized by confocal laser microscopy and Field Emission Scanning Electron Microscopy. The antibacterial activity of guaiacol against P. aeruginosa upon 2 × MIC exposure coincided with enhanced membrane permeability leading to disruption and release of cellular material as quantified by CV uptake assay and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The results demonstrated that sub-MICs of guaiacol in combination with ciprofloxacin can act as a potent alternate compound for attenuation of quorum sensing in P. aeruginosa. CONCLUSION: The study reports that guaiacol in combination with ciprofloxacin at 1/2 FIC significantly compromised the bacterial growth and motilities alongside inducing quorum quenching potential. This was accompanied by inhibition of biofilm which subsequently decreased EPS production at sub-MIC concentration. Furthermore, guaiacol in combination displayed a severe detrimental effect on bacterial membrane disruption, thereby enhancing cellular material release. NOVELTY IMPACT STATEMENT: For the first time, the potential of guaiacol in combination with ciprofloxacin in attenuation of virulence factors, and biofilm formation in Pseudomonas aeruginosa was described. Results corroborate how plant bioactive in synergism with antibiotics can act as an alternate treatment regime to tackle the menace of drug resistance.

The protective role of exogenous Ghrelin versus its combination with Zingerone on experimentally induced gastric ischemic-reperfusion in adult male albino rats.

Ghrelin is a gut hormone has stimulatory properties on food intake, fat deposition and growth hormone release. Zingerone is a component of ginger with multiple pharmacological activities. They were established that have protective roles against oxidative stress actions.  We planned this study to evaluate pretreatment exogenous Ghrelin alone and or accompanied with Zingerone on ischemia-reperfusion injury to gastric fundus wall. Fifty male albino rats were used and subdivided into control, ischemic- reperfusion, Ghrelin pretreated and Ghrelin Zingerone pretreated groups. Specimens from the stomach fundus were processed for histological, immunohistochemical study and gene expression using real time PCR. Morphometric and statistical analyses were also carried out in this research. In ischemic-reperfusion sections, there were deep erosion and distortion of the mucosa. Chief cells appeared with vacuolated cytoplasm and pyknotic nuclei. Congestion of blood vessels with extravasation and cellular infiltration was also noticed. There was a decrease in mucous secreted cells in PAS-stained sections. Sections from Ghrelin pretreated and Ghrelin Zingerone pretreated groups showed a great improvement. In addition, gastric tissues with the ischemia-reperfusion group showed a significant decrease in enos and nrf2 mRNA expression while there was a significant increase in HIF and VEGF, which is counteracted to Ghrelin pretreated and Ghrelin Zingerone pretreated groups. This study revealed the vital protective role of Ghrelin in concomitant with Zingerone than pretreated Ghrelin alone on attenuating the damage changes of fundus that occurred after experimentally induced gastric ischemia-reperfusion.

L-norvaline affects the proliferation of breast cancer cells based on the microbiome and metabolome analysis.

AIMS: The altered faecal metabolites and microbiota might be involved in the development of breast cancer. We aimed to investigate the effect of differential metabolites on the proliferative activity of breast cancer cells. METHODS AND RESULTS: We collected faecal samples from 14 breast cancer patients and 14 healthy subjects. Untargeted metabolomics analysis, short-chain fatty acid (SCFA) targeted analysis, and 16S rDNA sequencing was performed. The gut metabolite composition of patients changed significantly. Levels of norvaline, glucuronate and galacturonate were lower in the cancer group than in the Control (p < 0.05). 4-Methylcatechol and guaiacol increased (p < 0.05). Acetic acid and butyric acid were lower in the cancer group than in the control group (p < 0.05). Isobutyric acid and pentanoic acid were higher in the cancer group than in the control (p < 0.05). In the genus, the abundance of Rothia and Actinomyces increased in the cancer group, compared with the control group (p < 0.05). The differential microbiotas were clearly associated with differential metabolites but weakly with SCFAs. The abundance of Rothia and Actinomyces was markedly positively correlated with 4-methylcatechol and guaiacol (p < 0.05) and negatively correlated with norvaline (p < 0.05). L-norvaline inhibited the content of Arg-1 in a concentration-dependent manner. Compared with the L-norvaline or doxorubicin hydrochloride (DOX) group, the proliferation abilities of 4 T1 cells were the lowest in the L-norvaline combined with DOX (p < 0.05). The apoptosis rate increased (p < 0.05). CONCLUSIONS: Faecal metabolites and microbiota were significantly altered in breast cancer. Levels of differential metabolites (i.e. Norvaline) were significantly correlated with the abundance of differential microbiota. L-norvaline combined with DOX could clearly inhibit the proliferation activity of breast cancer cells. SIGNIFICANCE AND IMPACT OF STUDY: This might provide clues to uncover potential biomarkers for breast cancer diagnosis and treatment.

8-Shogaol inhibits rheumatoid arthritis through targeting TAK1.

Rheumatoid arthritis (RA) is a chronic immune-mediated disorder, mainly characterized by synovial inflammation and joint damage. If insufficiently treated, RA can lead to irreversible joint destruction and decreased life expectancy. While better understanding of the pathologies and the development of new antirheumatic drugs have improved the outcome of individuals with RA, many patients still cannot achieve remission and experience progressive disability. Fibroblast-like synoviocytes (FLS) have gained attention due to its pivotal role in RA pathogenesis and thus targeting FLS has been suggested as an attractive therapeutic strategy. To identify candidate molecules with strong inhibitory activity against FLS inflammation, we tested the effect of 315 natural extracts against IL-17-mediated IL-6 production. Zingiber officinale was found as the top hit and further analysis on the active compound responsible led to the discovery of 8-shogaol as a potent molecule against synovitis. 8-Shogaol displayed significant inhibitory effects against TNF-α-, IL-1ß-, and IL-17-mediated inflammation and migration in RA patient-derived FLS (RA-FLS) and 3D synovial culture system. 8-Shogaol selectively and directly inhibited TAK1 activity and subsequently suppressed IKK, Akt, and MAPK signaling pathways. Moreover, treatment with 8-shogaol reduced paw thickness and improved walking performance in the adjuvant-induced arthritic (AIA) rat model. 8-Shogaol also reversed pathologies of joint structure in AIA rats and decreased inflammatory biomarkers in the joints. Collectively, we report a novel natural compound that inhibits RA through reversing pathologies of the inflamed synovium via targeting TAK1.

Zingerone ameliorates non-alcoholic fatty liver disease in rats by activating AMPK.

This study was conducted to test the protective potential of Zingerone against a high-fat diet (HFD)-mediated non-alcoholic fatty liver disease (NAFLD) development in rats and examined in this protection is mediated modulating AMP-activated protein kinase (AMPK). Animals were segregated based on their diet and treatment into four groups (n = 6 each): (a) fed standard diet (STD), (b) treated with Zingerone (100 mg/kg), (c) fed HFD, (d) HFD + Zingerone (100 mg/kg), and (e) HFD + Zingerone (100 mg/kg) + compound c (CC) (an AMPK inhibitor) (0.2 mg/kg). The treatment with Zingerone attenuated the gain in final body weights, preserved liver structure, and downregulated the transcription of Bax and cleaved caspase-3. In the HFD and STD-fed rats, Zingerone reduced levels of fasting glucose and insulin and circulatory levels of cholesterol (CHOL) and triglycerides (TGs). Concomitantly, Zingerone enhanced glutathione (GSH) and superoxide dismutase (SOD) levels, depleted levels of malondialdehyde (MDA), and enhanced the nuclear levels of the nuclear factor erythroid 2-related factor 2 (Nrf2). In addition, it lowered the levels of inflammatory cytokines and the nuclear levels of the nuclear factor kappa beta p65 (NF-κB p65). All these biochemical changes were associated with an increment in the phosphorylation of AMPK (p-AMPK) (activation) and reduced mRNA levels of SREBP1 and SREBP2. All observed effects afforded by Zingerone were abolished by CC. In conclusion, Zingerone prevents hepatic oxidative stress, inflammation, and apoptosis by activating AMPK. PRACTICAL APPLICATIONS: The findings of this study identified Zingerone, isolated from ginger, as a very effective drug that not only can attenuate fasting hyperglycemia and hyperlipidemia, but also prevent hepatic deposition, steatosis, and oxidative damage induced by high-fat-fed rats by activating the AMPK/Nrf2 antioxidant axis and concomitant suppression of SREBP1, SREBp2, and NF-κB p65. These data list Zingerone as a potent stimulator of AMPK which suggests an effective strategy to treat and alleviate NAFLD and encourages further translational and clinical trials.

10-Dehydrogingerdione Attenuates Tramadol-Induced Nephrotoxicity by Modulating Renal Oxidative Stress, Inflammation and Apoptosis in Experimental Rats: Role of HO-1 Activation and TLR4/NF-κB/ERK Inhibition.

Tramadol represents a synthetic opioid analgesic especially for mild to severe pain. Its dose must be commonly monitored according to pain status and to alleviate the appearance of any adverse effects such as renal cellular damage during its excretion. Present work aimed mainly to study the effects of tramadol intake on renal tissues and 10-dehydrogingerdione (10-DHGD) potential as a protective agent. Tramadol administration induced an increase in serum levels of urea, creatinine, uric acid, the renal immune expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and caspase-3 which turned out to be decreased by 10-DHGD intake. Our results also recorded a significant increase in renal malondialdehyde (MDA), toll-like receptor 4 (TLR4), and extracellular signal-regulated protein kinase-1 (ERK1) along with glutathione (GSH), superoxide dismutase (SOD), and heme oxygenase-1 (HO-1) decrease due to tramadol intake, which were counteracted by 10-DHGD administration as illustrated and supported by the histopathological findings. Our conclusion refers to renoprotective potential of 10-DHGD against tramadol adverse effects.

Paradol Induces Cell Cycle Arrest and Apoptosis in Glioblastoma Cells.

Despite being the most common primary malignant tumor of the central nervous system, the prognosis of glioblastoma (GBM) is still remarkably poor. Paradol is a flavor phenolic constituent found in pepper and ginger, with anti-tumor, anti-inflammatory, and antioxidant activities. However, the effects of paradol on GBM cells remain unknown. In this study, we investigated the cytotoxicity of paradol on U-87 and U-251 GBM cells. Cell viability and Transwell assays revealed that paradol treatment markedly inhibited the viability and migration of GBM cells. Flow cytometry analysis showed G0/G1 cell cycle arrest, which was verified by the downregulation of CCNA and CCNB expression using western blotting. Paradol-induced cell apoptosis was confirmed by annexin V-FITC/PI staining and nuclear morphology. Furthermore, the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) was determined by western blotting. Collectively, our data revealed that paradol inhibited cell viability and migration of GBM cells by inducing G0/G1 phase arrest and apoptosis, and activating ERK and p38 MAPK signaling.

Gigantol inhibits proliferation and enhanced oxidative stress-mediated apoptosis through modulating of Wnt/ß-catenin signaling pathway in HeLa cells.

Cervical cancer is one of the leading malignant cancers that is the fourth prominent cause of malignancy-related mortality in women globally. There is a predominant validation to a beneficial target in Wnt/ß-catenin signaling in cervical carcinogenesis as they are very much deregulated in cancer. Previous studies reported Gigantol (GG) showed suppressive properties on the Wnt/ß-catenin pathway in other tumor cells, but no evidence is available regarding GG suppressing Wnt/ß-catenin signaling cervical tumor cells. Hence, the current research was planned to examine the suppressive effects of GG on HeLa cells and investigate the mechanism of action. HeLa cells were treated by GG in various doses and then appraising cell viability, oxidant/antioxidant levels, ∆Ñ°M status, reactive oxygen species (ROS) generation, apoptosis, and cell proliferation via Wnt/ß-catenin signaling. We observed that GG noticeably inhibits cell proliferation, increased ROS generation, lipid peroxidation, mitochondrial membrane depolarization (∆Ñ°M), and increased apoptotic morphological changes of nuclear fragmentation and condensation. Moreover, GG effectively enhances proapoptotic, decreased ∆Ñ°M and antioxidant amounts, and mitigated Wnt/ß-catenin signaling. Concisely, these findings proved that activating apoptosis and suppression of cell proliferation in GG treated HeLa cells was documented by the alleviation of Wnt/ß-catenin signaling. Therefore, this study suggested that GG might develop a therapeutic effect against cervical carcinogenesis.

A novel method for explaining the product inhibition mechanisms via molecular docking: inhibition studies for tyrosinase from Agaricus bisporus.

The present study aims to investigate the substrate (4-methyl catechol and catechol) specificity and inhibition mechanisms (l-ascorbic acid, citric acid, and l-cysteine) of the tyrosinase enzyme (TYR), which is held responsible for browning in foods and hyperpigmentation in the human skin, through kinetic and molecular docking studies. During the experimental studies, the diphenolase activities of TYR were determined, following which the inhibitory effects of the inhibitors upon the diphenolase activities of TYR. The inhibition types were determined as competitively for l-ascorbic acid and citric acid and noncompetitive for l-cysteine. The kinetic results showed that the substrate specificity was better for catechol while l-cysteine showed the best inhibition profile. As for the in silico studies, they also showed that catechol had a better affinity in line with the experimental results of this study, considering the interactions of the substrates with TYR's active site residues and their distance to CuB metal ion, which is an indicator of diphenolase activity. Besides, the inhibitory mechanisms of the inhibitor molecules were explained by the molecular modeling studies, considering the binding number of the inhibitors with the active site amino acid residues of TYR, the number and length of H bonds, negative binding energy values, and their distance to CuB metal ion. Based on our results, we suggest that the novel method used in this study to explain the inhibitory mechanism of l-cysteine may provide an affordable alternative to the expensive methods available for explaining the inhibitory mechanism of TYR and those of other enzymes. HighlightsThe best affinity for the tyrosinase enzyme occurred with catechol.l-Ascorbic acid, citric acid, l-cysteine inhibited the diphenolic activity of tyrosinase.In silico studies confirmed the best affinity shown by catechol.Product inhibition mechanism of l-cysteine explained by in silico for the first time.Communicated by Ramaswamy H. Sarma.

Investigating the Efficacy of Zingerone on Mesothelioma and the Role of TRPV1 in This Effect.

Mesothelioma is a highly lethal cancer developing in the lung, heart, and abdominal membranes. Zingerone, a capsaicin-like bioactive compound, has been shown to have anticancer properties. Transient Receptor Potential Vanilloid 1 (TRPV1) is an ion channel involving in the cytotoxicity of capsaicin. In the present study, we aimed at determining the cytotoxicity of zingerone on a mesothelioma cell line and to evaluate the role of TRPV1 in this effect. For this purpose, H2452 was used as the mesothelioma cell line and MTS was performed to calculate zingerone cytotoxicity. Moreover, TRPV1 was inhibited by capsazepeine while TRPV1 production was reduced through shRNA treatment. Besides, wound healing and clonogenic assays were performed to measure the migration and colony forming abilities, respectively. As a result, IC50 value of zingerone was calculated as 11.49 mM. Capsazepine treatment or lowered TRPV1 gene expression did not appear to affect zingerone cytotoxicity (p > 0.05) even though the migration rate and colony forming abilities of the zingerone treated cells decreased significantly compared to the control (p < 0.05). Therefore, we concluded that zingerone was less cytotoxic to H2452 cells than the most cancer types and TRPV1 did not seem to have a role in its cytotoxicity.

Cinnamophilin overcomes cancer multi-drug resistance via allosterically modulating human P-glycoprotein on both drug binding sites and ATPase binding sites.

Cancer multi-drug resistance (MDR) caused by P-glycoprotein (P-gp) efflux is a critical unresolved clinical concern. The present study analyzed the effect of cinnamophilin on P-gp inhibition and MDR reversion. The effect of cinnamophilin on P-gp was investigated through drug efflux assay, ATPase assay, MDR1 shift assay, and molecular docking. The cancer MDR-reversing ability and mechanisms were analyzed through cytotoxicity and combination index (CI), cell cycle, and apoptosis experiments. P-gp efflux function was significantly inhibited by cinnamophilin without influencing the drug's expression or conformation. Cinnamophilin uncompetitively inhibited the efflux of doxorubicin and rhodamine 123 and exhibited a distinct binding behavior compared with verapamil, the P-gp standard inhibitor. The half maximal inhibitory concentration of cinnamophilin for doxorubicin and rhodamine 123 efflux was 12.47 and 11.59 µM, respectively. In regard to P-gp energy consumption, verapamil-stimulated ATPase activity was further enhanced by cinnamophilin at concentrations of 0.1, 1, 10, and 20 µM. In terms of MDR reversion, cinnamophilin demonstrated synergistic cytotoxic effects when combined with docetaxel, vincristine, or paclitaxel. The CI was < 0.7 in all experimental combination treatments. The present study showed that cinnamophilin possesses P-gp-modulating effects and cancer MDR resensitizing ability.

Anti-Osteoporotic Effects of n-trans-Hibiscusamide and Its Derivative Alleviate Ovariectomy-Induced Bone Loss in Mice by Regulating RANKL-Induced Signaling.

Osteoporosis is characterized by the deterioration of bone structures and decreased bone mass, leading to an increased risk of fracture. Estrogen deficiency in postmenopausal women and aging are major factors of osteoporosis and are some of the reasons for reduced quality of life. In this study, we investigated the effects of n-trans-hibiscusamide (NHA) and its derivative 4-O-(E)-feruloyl-N-(E)-hibiscusamide (HAD) on receptor activator of nuclear factor kappa-Β (NF-κB) ligand (RANKL)-induced osteoclast differentiation and an ovariectomized osteoporosis mouse model. NHA and HAD significantly inhibited the differentiation of osteoclasts from bone marrow-derived macrophages (BMMs) and the expression of osteoclast differentiation-related genes. At the molecular level, NHA and HAD significantly downregulated the phosphorylation of mitogen-activated protein kinase (MAPK) signaling molecules. However, Akt and NF-κB phosphorylation was inhibited only after NHA or HAD treatment. In the ovariectomy (OVX)-induced osteoporosis model, both NHA and HAD effectively improved trabecular bone structure. C-terminal telopeptide (CTX), a bone resorption marker, and RANKL, an osteoclast stimulation factor, were significantly reduced by NHA and HAD. The tartrate-resistant acid phosphatase (TRAP)-stained area, which indicates the osteoclast area, was also decreased by these compounds. These results show the potential of NHA and HAD as therapeutic agents for osteoporosis.

6-Gingerol and Semisynthetic 6-Gingerdione Counteract Oxidative Stress Induced by ROS in Zebrafish.

6-Gingerol (1) is one of the major components in ginger and developing new synthetic methodologies could bring semisynthetic analogs with improved therapeutic properties. Towards this, multigram scale isolation of 6-gingerol with excellent purity was optimized using a simple and robust extraction, followed by column purification. Synthesis of 6-gingerdione, 7 from 6-gingerol was then achieved through selective -OTBDMS protection, DMP oxidation and deprotection reaction sequence for the first time. Compounds 1, 7 and 8 (dehydrozingerone) exhibited excellent cell-free antioxidant properties in DPPH, ABTS, superoxide radical scavenging assay and H2 O2 assay at 10-50 µM concentrations. The hemolytic study suggests that up to 50 µM, all three compounds did not exhibit toxicity to human erythrocytes. When H2 O2 treated zebrafish larvae groups (96hpf) were exposed to compounds 1, 7 and 8, it increases the SOD (19, 19.1 and 18.7 U/mg protein), CAT (18.1, 16.5, and 15.8 µmol/mg levels and decreases the lipid peroxidation level (13, 15 and 18 nmol/mg protein), respectively. In vivo ROS levels and degree of cell death were studied using DCFDA and Acridine orange assays. Compounds 1, 7 and 8 decreases the ROS and cell death level significantly. Taken together, compounds 1, 7 and 8 exhibit excellent antioxidant properties, counteract H2 O2 induced oxidative stress, reduces cell death in zebrafish larvae.

Ginger, a Possible Candidate for the Treatment of Dementias?

As the human life expectancy increases, age-linked diseases have become more and more frequent. The worldwide increment of dementia cases demands medical solutions, but the current available drugs do not meet all the expectations. Recently the attention of the scientific community was attracted by natural compounds, used in ancient medicine, known for their beneficial effects and high tolerability. This review is focused on Ginger (Zingiber officinale) and explore its properties against Alzheimer's Disease and Vascular Dementia, two of the most common and devastating forms of dementia. This work resumes the beneficial effects of Ginger compounds, tested in computational in vitro and in vivo models of Alzheimer's Disease and Vascular Dementia, along with some human tests. All these evidences suggest a potential role of the compounds of ginger not only in the treatment of the disease, but also in its prevention.

Tetrahexyldecyl Ascorbate (THDC) Degrades Rapidly under Oxidative Stress but Can Be Stabilized by Acetyl Zingerone to Enhance Collagen Production and Antioxidant Effects.

Tetrahexyldecyl Ascorbate (THDC) is an L-ascorbic acid precursor with improved stability and ability to penetrate the epidermis. The stability and transdermal penetration of THDC, however, may be compromised by the oxidant-rich environment of human skin. In this study, we show that THDC is a poor antioxidant that degrades rapidly when exposed to singlet oxygen. This degradation, however, was prevented by combination with acetyl zingerone (AZ) as a stabilizing antioxidant. As a standalone ingredient, THDC led to unexpected activation of type I interferon signaling, but this pro-inflammatory effect was blunted in the presence of AZ. Moreover, the combination of THDC and AZ increased expression of genes associated with phospholipid homeostasis and keratinocyte differentiation, along with repression of MMP1 and MMP7 expression, inhibition of MMP enzyme activity, and increased production of collagen proteins by dermal fibroblasts. Lastly, whereas THDC alone reduced viability of keratinocytes exposed to oxidative stress, this effect was completely abrogated by the addition of AZ to THDC. These results show that AZ is an effective antioxidant stabilizer of THDC and that combination of these products may improve ascorbic acid delivery. This provides a step towards reaching the full potential of ascorbate as an active ingredient in topical preparations.

Ginger: A complementary approach for management of cardiovascular diseases.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. Inflammation and oxidative stress play critical roles in progression of various types of CVD. Broad pharmacological properties of ginger (the rhizome of Zingiber officinale) and its bioactive components have been reported, suggesting that they can be a therapeutic choice for clinical use. Consistent with its rich phenolic content, the anti-inflammatory and antioxidant properties of ginger have been confirmed in many studies. Ginger modifies many cellular processes and in particular was shown to have potent inhibitory effects against nuclear factor kappa B (NF-κB); signal transducer and activator of transcription; NOD-, LRR-, and pyrin domain-containing proteins; toll-like receptors; mitogen-activated protein kinase; and mammalian target of rapamycin signaling pathways. Ginger also blocks pro-inflammatory cytokines and the activation of the immune system. Ginger suppresses the activity of oxidative molecules such as reactive oxygen species, inducible nitric oxide synthase, superoxide dismutase, glutathione, heme oxygenase, and GSH-Px. In this report, we summarize the biochemical pathologies underpinning a variety of CVDs and the effects of ginger and its bioactive components, including 6-shogaol, 6-gingerol, and 10-dehydrogingerdione. The properties of ginger and its phenolic components, mechanism of action, biological functions, side effects, and methods for enhanced cell delivery are also discussed. Together with preclinical and clinical studies, the positive biological effects of ginger and its bioactive components in CVD support the undertaking of further in vivo and especially clinical studies.

Development of edible Thai rice film fortified with ginger extract using microwave-assisted extraction for oral antimicrobial properties.

This study aimed to investigate microwave-assisted extraction (MAE) of dried ginger and to develop a rice-based edible film incorporating ginger extract. The optimal MAE conditions of 400 W microwave power and an extraction time of 1 min were determined using a 32 full factorial design. The optimized extract showed total phenolic compounds (TPC, 198.2 ± 0.7 mg gallic acid equivalent/g), antioxidant activity measured by DPPH (91.4 ± 0.6% inhibition), ABTS (106.4 ± 3.1 mg Trolox/g), and FRAP (304.6 ± 5.5 mg Trolox/g), and bioactive compounds including 6-gingerol (71.5 ± 3.6 mg/g), 6-shogaol (12.5 ± 1.0 mg/g), paradol (23.1 ± 1.1 mg/g), and zingerone (5.0 ± 0.3 mg/g). Crude extract of dried ginger showed antimicrobial activity against Streptococcus mutans DMST 18777, with a minimum inhibitory concentration and minimum bactericidal concentration of 0.5 and 31.2 mg/mL, respectively. The rice-based edible film incorporating 3.2% (w/v) ginger extract tested against S. mutans DMST 18777 had a mean zone of inhibition of 12.7 ± 0.1 mm. Four main phenolic compounds, 6-gingerol, 6-shogaol, paradol, and zingerone, and six volatile compounds, α-curcumene, α-zingiberene, γ-muurolene, α-farnesene, ß-bisabolene, and ß-sesquiphellandrene, were found in rice film fortified with crude ginger extract.

10-Dehydrogingerdione ameliorates renal endoplasmic reticulum/oxidative stress and apoptosis in alcoholic nephropathy induced in experimental rats.

BACKGROUND: Chronic alcoholism induces kidney injury (KI), leading to increased mortality in alcoholic hepatitis patients. Endoplasmic reticulum stress (ER) represents the main initiator of kidney diseases and alcoholic nephropathy. AIMS: We used alcoholic nephropathy rat model followed by 10-dehydrogingerdione (10-DHGD) intake as potential modulator. This is to focus on ER/oxidative stress/inflammatory and apoptotic pathways involvement. MAIN METHOD: Alcoholic nephropathy was induced by alcohol administration (3.7 g/kg/body weight) orally and daily for 45 days. 10-DHGD (10 mg/kg/day) was administered either alone or along with alcohol. KEY FINDINGS: Our results demonstrated significant increase in kidney function parameters like f creatinine, urea, uric acid, and blood urea nitrogen (BUN) levels. Renal ER/oxidative stress markers such as cytochrome P450 family two subfamily E member 1 (CYP2E1), C/EBP homologous protein (CHOP), and endoplasmic glucose-regulated protein 78 (GRP-78) demonstrated also significant increase. Inflammatory mediators like nuclear factor-kappa B (NF-kB), tumor necrosis factor-α (TNF-α), and transforming growth factor-ß (TGF-ß along with apoptotic marker caspase-3 behaved similarly. Antioxidant molecules like reduced glutathione (GSH), superoxide dismutase (SOD), and catalase demonstrated marked decrease. SIGNIFICANCE: 10-DHGD administration resulted in significant modulation represented by an enhancement in the kidney functions and the histopathological patterns in a conclusion of its potential to ameliorate the pathological changes (kidney injury) induced by alcohol intake.

4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis.

BACKGROUND: Multiple sclerosis (MS) is a progressive autoimmune disease characterized by the accumulation of pathogenic inflammatory immune cells in the central nervous system (CNS) that subsequently causes focal inflammation, demyelination, axonal injury, and neuronal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established murine model that mimics the key features of MS. Presently, the dietary consumption of foods rich in phenols has been reported to offer numerous health benefits, including anti-inflammatory activity. One such compound, 4-ethylguaiacol (4-EG), found in various foods, is known to attenuate inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects on modulating the CNS inflammatory immune responses remains unknown. Thus, in this study, we assessed the therapeutic effect of 4-EG in EAE using both chronic and relapsing-remitting animal models and investigated the immunomodulatory effects of 4-EG on neuroinflammation and Th1/Th17 differentiation in EAE. METHODS: Chronic C57BL/6 EAE and relapsing-remitting SJL/J EAE were induced followed by 4-EG treatment. The effects of 4-EG on disease progression, peripheral Th1/Th17 differentiation, CNS Th1/Th17 infiltration, microglia (MG) activation, and blood-brain barrier (BBB) disruption in EAE were evaluated. In addition, the expression of MMP9, MMP3, HO-1, and Nrf2 was assessed in the CNS of C57BL/6 EAE mice. RESULTS: Our results showed that 4-EG not only ameliorated disease severity in C57BL/6 chronic EAE but also mitigated disease progression in SJL/J relapsing-remitting EAE. Further investigations of the cellular and molecular mechanisms revealed that 4-EG suppressed MG activation, mitigated BBB disruption, repressed MMP3/MMP9 production, and inhibited Th1 and Th17 infiltration in the CNS of EAE. Furthermore, 4-EG suppressed Th1 and Th17 differentiation in the periphery of EAE and in vitro Th1 and Th17 cultures. Finally, we found 4-EG induced HO-1 expression in the CNS of EAE in vivo as well as in MG, BV2 cells, and macrophages in vitro. CONCLUSIONS: Our work demonstrates that 4-EG confers protection against autoimmune disease EAE through modulating neuroinflammation and inhibiting Th1 and Th17 differentiation, suggesting 4-EG, a natural compound, could be potentially developed as a therapeutic agent for the treatment of MS/EAE.