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Phytomedicine : International Journal... Mar 2022Rheumatoid arthritis is a chronic and idiopathic autoimmune disorder. Perillyl alcohol (POH) is a monoterpene which can be extracted from widely available essential oils...
Perillyl alcohol attenuates rheumatoid arthritis via regulating TLR4/NF-κB and Keap1/Nrf2 signaling pathways: A comprehensive study onin-vitro and in-vivo experimental models.
BACKGROUND
Rheumatoid arthritis is a chronic and idiopathic autoimmune disorder. Perillyl alcohol (POH) is a monoterpene which can be extracted from widely available essential oils and is known for its strong anti-inflammatory and anti-oxidant properties.
HYPOTHESIS/PURPOSE
Recent studies have been proven that inhibitors of farnesyltransferase enzyme showed significant anti-arthritic activity. POH is one such natural molecule having anti-inflammatory and anti-oxidant properties by inhibiting farnesyltransferase enzyme which further down regulates NF-κB and Nrf2 via Ras/Raf/MAPK pathway. Also, the effect of POH against rheumatoid arthritis is not known yet. Hence, the present research was intended to assess the anti-arthritic potential of POH in-vitro and in-vivo.
METHODS
The in-vitro effects of POH on RAW 264.7 cells stimulated with LPS 1 µg/ml were investigated to its potential therapeutic effects. CFA 100 µl was intradermally administered to rats for the induction of arthritis. POH 100 mg/kg and 200 mg/kg administered topically from day 1 to day 28. Paw volumes measured, radiography analysis, anti-oxidant status, Gene expression studies, western blot analysis and histological analysis were performed to check the effects of POH.
RESULTS
Our in-vitro findings suggested that POH inhibits inflammation by suppressing reactive oxygen species (ROS), NF-кB and Nrf2 signaling axis. Besides this, POH also rescinded the nitrate levels, pro-inflammatory cytokine levels like IL-1β, IL-6 and TNF-α also PGE2 and COX-2 levels induced by LPS in murine macrophages. Additionally, our in-vivo results revealed that POH conscientiously alleviated CFA induced inflammation by restoring arthritis index, body weight, nitrosative, lipid peroxidation assays. Macroscopically through measuring paw volumes and X-ray, it was evidenced that POH has decreased inflammation and bone erosion. Not only in-vitro but also in-vivo, POH has abridged cytokine levels IL-1β, IL-6, and TNF-α. Histopathological evaluation presented POH treatment alleviated joint inflammation, pannus formation, and bone erosion significantly. Moreover, POH suppressed the protein expression of NF-кB, COX-2, iNOS and improved Nrf2, and SOD2 levels in paw tissues estimated by western blotting.
CONCLUSION
POH was effective in ameliorating LPS stimulation mediated oxidative stress and pro-inflammatory cytokines in RAW 264.7 cells in-vitro and FCA induced arthritis in rats in-vivo through its anti-inflammatory effects via regulating TLR4/NF-κB and Keap1/Nrf2 signaling pathways..
Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Cytokines; Inflammation; Kelch-Like ECH-Associated Protein 1; Lipopolysaccharides; Mice; Models, Theoretical; Monoterpenes; NF-E2-Related Factor 2; NF-kappa B; Rats; Signal Transduction; Toll-Like Receptor 4
PubMed: 35030388
DOI: 10.1016/j.phymed.2022.153926 -
ACS Omega Dec 2021In this contribution, the thermodynamic analysis of α- and β-pinene epoxide isomerization over Fe and Cu supported on MCM-41 is presented using computational chemistry...
In this contribution, the thermodynamic analysis of α- and β-pinene epoxide isomerization over Fe and Cu supported on MCM-41 is presented using computational chemistry and group contribution methods (GCMs). Some physical-chemical data ( , , , , ω, , ) and thermodynamic (°, , , Δ , Δ , Δ , Δ , ) properties obtained by different GCMs are reported for several monoterpenes and monoterpenoids, which significantly contribute to the knowledge of the properties of these compounds. Density functional theory (DFT), PBE-D3/6-311G(d,p), was employed for determining the Gibbs free energy and the heat of reaction associated with the transformation of monoterpene epoxides into aldehydes, ketones, and related oxygenated compounds in the presence of different solvents and at several temperatures. The calculations were compared with available data reported and the experimental results of the catalytic reactions. The transformation of α- and β-pinene epoxides into aldehydes appears to be more spontaneous and favorable than their transformations into alcohols in a wide range of temperatures. These results are in agreement with the experiments over Fe/MCM-41 and Cu/MCM-41, where α-pinene epoxide isomerization yields campholenic aldehyde (50-80% selectivity) as the main product. The 1.7Fe/MCM-41 material was more active in all solvents than 1.3Cu/MCM-41 for both α- and β-pinene epoxide isomerization. However, perillyl alcohol (20-70% selectivity) was the most favored for the isomerization reaction, except when ethyl acetate was the solvent. Enthalpy and Gibbs free energy of the studied reactions estimated by both GCMs and DFT calculations did not show large differences for most of the reactions at evaluated temperatures.
PubMed: 34963907
DOI: 10.1021/acsomega.1c03049 -
Pharmaceutics Dec 2021Perillyl alcohol (POH) is a naturally occurring monoterpenoid related to limonene that is present in the essential oils of various plants. It has diverse applications... (Review)
Review
Perillyl alcohol (POH) is a naturally occurring monoterpenoid related to limonene that is present in the essential oils of various plants. It has diverse applications and can be found in household items, including foods, cosmetics, and cleaning supplies. Over the past three decades, it has also been investigated for its potential anticancer activity. Clinical trials with an oral POH formulation administered to cancer patients failed to realize therapeutic expectations, although an intra-nasal POH formulation yielded encouraging results in malignant glioma patients. Based on its amphipathic nature, POH revealed the ability to overcome biological barriers, primarily the blood-brain barrier (BBB), but also the cytoplasmic membrane and the skin, which appear to be characteristics that critically contribute to POH's value for drug development and delivery. In this review, we present the physicochemical properties of POH that underlie its ability to overcome the obstacles placed by different types of biological barriers and consequently shape its multifaceted promise for cancer therapy and applications in drug development. We summarized and appraised the great variety of preclinical and clinical studies that investigated the use of POH for intranasal delivery and nose-to-brain drug transport, its intra-arterial delivery for BBB opening, and its permeation-enhancing function in hybrid molecules, where POH is combined with or conjugated to other therapeutic pharmacologic agents, yielding new chemical entities with novel mechanisms of action and applications.
PubMed: 34959448
DOI: 10.3390/pharmaceutics13122167 -
Frontiers in Oncology 2021Drug resistance remains a serious challenge to rituximab therapy in B-NHL (B cell non-Hodgkin's lymphoma). CDC (complement-dependent cytotoxicity) has been proposed as a...
BACKGROUND
Drug resistance remains a serious challenge to rituximab therapy in B-NHL (B cell non-Hodgkin's lymphoma). CDC (complement-dependent cytotoxicity) has been proposed as a major antitumor mechanism of rituximab, and direct abrogation of CD59 function partially restores rituximab sensitivity with high efficacy. However, universal blockade of CD59 may have deleterious effects on normal cells. Sp1 regulates constitutive CD59 expression, whereas NF-κB and CREB regulate inducible CD59 expression.
METHODS
Immunohistochemistry (IHC) assay was used to detect the expression levels of CD59 and other related molecules. Quantitative Real-time PCR (RT-PCR) analysis was used to explore the levels of transcripts in the original and resistant cells. We chose LY8 cells to test the effects of NF-κB and CBP/p300 inhibition on CD59 expression using flow cytometry (FACS). Immunoblotting analysis was employed to detect the effects of curcumin and POH. The and experiments were used to evaluate the toxicity and combined inhibitory effect on tumor cells of curcumin and POH.
RESULTS
We demonstrated that herbal (curcumin and perillyl alcohol) blockade of NF-κB specifically suppresses the expression of inducible CD59 but not CD20, thus sensitizing resistant cells to rituximab-mediated CDC. Moreover, activation of NF-κB and CREB is highly correlated with CD59 expression in B-NHL tissues.
CONCLUSIONS
Our findings suggest the potential of CD59 expression as a predictor of therapeutic efficacy of NF-κB inhibitors in clinical application as well as the rationality of a NF-κB inhibitor-rituximab regimen in B-NHL therapy.
PubMed: 34956875
DOI: 10.3389/fonc.2021.751904 -
International Immunopharmacology Feb 2022Psoriasis is a chronic inflammatory and proliferative skin disease characterized by pathological skin lesions which significantly impact the quality of life. Recent...
Psoriasis is a chronic inflammatory and proliferative skin disease characterized by pathological skin lesions which significantly impact the quality of life. Recent studies have been proven that inhibitors of farnesyltransferase enzyme showed significant anti-psoriatic activity. Perillyl alcohol (POH) is one such natural molecule having anti proliferative, anti-inflammatory and anti-oxidant properties by inhibiting farnesyltransferase enzyme which further down regulates NF-κB and STAT3 via Ras/Raf/MAPK pathway. Hence, in the current study we aimed to find the effect of POH on human keratinocytes (HaCat) cells in in-vitro and IMQ induced psoriatic like skin inflammation model in mice. POH significantly decreased the intracellular ROS levels and inhibited the phosphorylation of NF-κB and STAT3 in in-vitro. It was found that POH (200 mg/kg, topical application) has reduced the epidermal hyperplasia, psoriasis area and severity index (PASI) scoring; splenomegaly in imiquimod (IMQ) induced psoriatic mice. Further, POH treatment has decreased the pro-inflammatory serum cytokine levels such as IL-6, IL-12/23, TNF-α and IL-1β and also reduced the expression levels of various inflammatory proteins, COX-2, iNOS, IL-17A, IL-22, NF-кB and STAT3 evidenced by Immunoblotting studies from skin samples. The levels of endogenous antioxidants like glutathione GSH, SOD, Nrf2 were restored to normal levels upon POH treatment. POH downregulated the proteins levels of TLR7, TLR8, CyclinD1 and mRNA expression of Bcl-2 in the skin samples when compared to the IMQ group. POH has ameliorated the hyper-keratosis and acanthosis which was evidenced by histopathology. Collectively, our results suggest that POH has a promising therapeutic application for ameliorating psoriasis-like skin inflammation.
Topics: Animals; Anti-Inflammatory Agents; Cell Proliferation; Cells, Cultured; Humans; Inflammation; Keratinocytes; Male; Mice; Mice, Inbred ICR; Monoterpenes; NF-kappa B; Psoriasis; STAT3 Transcription Factor; Signal Transduction; Skin
PubMed: 34929480
DOI: 10.1016/j.intimp.2021.108436 -
ACS Chemical Neuroscience Jan 2022NLRP3 activation plays a key role in the initiation and progression of a variety of neurodegenerative diseases. However, understanding the molecular mechanisms involved...
NLRP3 activation plays a key role in the initiation and progression of a variety of neurodegenerative diseases. However, understanding the molecular mechanisms involved in the bidirectional signaling required to activate the NLRP3 inflammasomes is the key to treating several diseases. Hence, the present study aimed to investigate the role of lipopolysaccharide (LPS) and hydrogen peroxide (HO) in activating NLRP3 inflammasome-driven neurodegeneration and elucidated the neuroprotective role of perillyl alcohol (PA) in in vitro and in vivo models of Parkinson's disease (PD). Initial priming of microglial cells with LPS following treatment with HO induced NF-κB translocation to the nucleus with a robust generation of free radicals that act as signal 2 in augmenting NLRP3 inflammasome assembly and its downstream targets. PA treatment suppresses the nuclear translocation of NF-κB, enhances PARKIN translocation into the mitochondria, and maintains cellular redox homeostasis in both mouse and human microglial cells that limit NLRP3 inflammasome activation along with processing of active caspase-1, IL-1β, and IL-18. To further correlate the in vitro study with the in vivo MPTP model, treatment with PA also inhibited the nuclear translocation of NF-κB and downregulated the NLRP3 inflammasome activation. PA administration upregulated various antioxidant enzymes' levels and restored the level of dopamine and other neurotransmitters in the striatum of the mouse brain, subsequently improving the behavioral activities. Therefore, we conclude that NLRP3 inflammasome activation required a signal from damaged mitochondria for its activation. Further pharmacological scavenging of free radicals restricts microglia activation and simultaneously supports neuronal survival via targeting the NLRP3 inflammasome pathway in PD.
Topics: Animals; Dopaminergic Neurons; Hydrogen Peroxide; Inflammasomes; Mice; Monoterpenes; NLR Family, Pyrin Domain-Containing 3 Protein; Parkinson Disease
PubMed: 34904823
DOI: 10.1021/acschemneuro.1c00550 -
Molecules (Basel, Switzerland) Nov 2021Cyclic oxyterpenes are natural products that are mostly used as fragrances, flavours and drugs by the cosmetic, food and pharmaceutical industries. However, only a few...
Cyclic oxyterpenes are natural products that are mostly used as fragrances, flavours and drugs by the cosmetic, food and pharmaceutical industries. However, only a few cyclic oxyterpenes are accessible via chemical syntheses, which are far from being ecofriendly. We report here the synthesis of six cyclic oxyterpenes derived from ß-pinene while respecting the principles of green and sustainable chemistry. Only natural or biosourced catalysts were used in mild conditions that were optimised for each synthesis. A new generation of ecocatalysts, derived from Mn-rich water lettuce, was prepared via green processes, characterised by MP-AES, XRPD and TEM analyses, and tested in catalysis. The epoxidation of ß-pinene led to the platform molecule, ß-pinene oxide, with a good yield, illustrating the efficacy of the new generation of ecocatalysts. The opening ß-pinene oxide was investigated in green conditions and led to new and regioselective syntheses of myrtenol, 7-hydroxy-α-terpineol and perillyl alcohol. Successive oxidations of perillyl alcohol could be performed using no hazardous oxidant and were controlled using the new generation of ecocatalysts generating perillaldehyde and cuminaldehyde.
Topics: Benzaldehydes; Bicyclic Monoterpenes; Catalysis; Cymenes; Elements; Green Chemistry Technology; Monoterpenes; Principal Component Analysis; Terpenes; X-Ray Diffraction
PubMed: 34885776
DOI: 10.3390/molecules26237194 -
ACS Bio & Med Chem Au Feb 2022Increased incidences of fungal infections and associated mortality have accelerated the need for effective and alternative therapeutics. Perillyl alcohol (PA) is a...
Increased incidences of fungal infections and associated mortality have accelerated the need for effective and alternative therapeutics. Perillyl alcohol (PA) is a terpene produced by the hydroxylation of limonene via the mevalonate pathway. In pursuit of an alternative antifungal agent, we studied the effect of PA on the biofilm community of and on different cellular pathways to decipher its mode of action. PA efficiently inhibited growth and eradicated biofilms by reducing carbohydrate and eDNA content in the extracellular matrix. PA reduced the activity of hydrolytic enzymes in the ECM of biofilm. The chemical profiling study has given insights into the overall mode of action of PA in and the marked involvement of the cell wall and membrane, ergosterol biosynthesis, oxidative stress, and DNA replication. The spectroscopic and RT-PCR studies suggested a strong interaction of PA with chitin, β-glucan, ergosterol, and efflux pump, thus indicating increased membrane fluidity in . Furthermore, the microscopic and flow cytometry analysis emphasized that PA facilitated the change in mitochondrial activity, increased Ca influx via overexpression of voltage-gated Ca channels, and enhanced cytochrome C release from mitochondria. In addition, PA interferes with DNA replication and thus hinders the cell cycle progression at the S-phase. All these studies together established that PA mitigates the biofilms by targeting multiple cellular pathways. Interestingly, PA also potentiated the efficacy of azole drugs, particularly miconazole, against and its clinical isolates. Conclusively, the study demonstrated the use of PA as an effective antifungal agent alone or in combination with FDA-approved conventional drugs for fungal biofilm eradication.
PubMed: 37102177
DOI: 10.1021/acsbiomedchemau.1c00034 -
Communications Biology Oct 2021Respiratory syncytial virus (RSV) is a leading cause of severe respiratory tract infections in children. To uncover new antiviral therapies, we developed a live...
Respiratory syncytial virus (RSV) is a leading cause of severe respiratory tract infections in children. To uncover new antiviral therapies, we developed a live cell-based high content screening approach for rapid identification of RSV inhibitors and characterized five drug classes which inhibit the virus. Among the molecular targets for each hit, there was a strong functional enrichment in lipid metabolic pathways. Modulation of lipid metabolites by statins, a key hit from our screen, decreases the production of infectious virus through a combination of cholesterol and isoprenoid-mediated effects. Notably, RSV infection globally upregulates host protein prenylation, including the prenylation of Rho GTPases. Treatment by statins or perillyl alcohol, a geranylgeranyltransferase inhibitor, reduces infection in vitro. Of the Rho GTPases assayed in our study, a loss in Rac1 activity strongly inhibits the virus through a decrease in F protein surface expression. Our findings provide new insight into the importance of host lipid metabolism to RSV infection and highlight geranylgeranyltransferases as an antiviral target for therapeutic development.
Topics: Antiviral Agents; Drug Discovery; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Virus Replication
PubMed: 34716403
DOI: 10.1038/s42003-021-02754-2 -
BMC Cancer Aug 2021D-limonene and its derivatives have demonstrated potential chemopreventive and anticancer activity in preclinical and clinical studies. The aim of this scoping review... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
D-limonene and its derivatives have demonstrated potential chemopreventive and anticancer activity in preclinical and clinical studies. The aim of this scoping review was to assess and critically appraise current literature on the effect of these bioactive citrus peel compounds on breast cancer in human trials and to identify knowledge gaps for exploration in future studies.
METHODS
This study followed a scoping review framework. Peer-reviewed journal articles were included if they reported the effect of d-limonene or its derivatives on breast cancer in human subjects. Articles were retrieved from academic databases - PubMed, EMBASE, CINAHL, Web of Science, and Cochrane reviews - and iteratively through review of bibliographies of relevant manuscripts. Titles and abstracts were appraised against the aforementioned inclusion criteria in a first round of screening. Through consensus meetings and full article review by authors, a final set of studies were selected. Results were reported according to the PRISMA extension for scoping reviews.
RESULTS
Our search strategy yielded 367 records. Following screening and adjudication, five articles reporting on phase 1(n = 2), phase 2 (n = 2) and both trial phases (n = 1) were included as the final dataset for this review. Trials evaluating the effect of d-limonene (n = 2) showed it was well tolerated in subjects. One study (n = 43 participants) showed d-limonene concentrated in breast tissue (mean 41.3 μg/g tissue) and reduction in tumor cyclin D1 expression, which is associated with tumor proliferation arrest. This study did not show meaningful change in serum biomarkers associated with breast cancer, except for a statistically significant increase in insulin-like growth factor-1 (IGF-I) levels. While elevation of IGF-I is associated with increased cancer risk, the clinical implication of this study remains uncertain given its short duration. Trials with perillyl alcohol (n = 3) showed low tolerance and no effect on breast cancer.
CONCLUSION
This review demonstrated a dearth of clinical studies exploring the effect of d-limonene and its derivatives on breast cancer. Limited literature suggests d-limonene is safe and tolerable in human subjects compared to its derivative, perillyl alcohol. Our review demonstrates the need for additional well-powered placebo-controlled trials that assess d-limonene's efficacy on breast cancer compared to other therapies.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Combined Modality Therapy; Drug Monitoring; Female; Humans; Limonene; Maximum Tolerated Dose; Middle Aged; Molecular Structure; Treatment Outcome
PubMed: 34362338
DOI: 10.1186/s12885-021-08639-1