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Engineering in Life Sciences May 2022()-(+)-perillyl alcohol is widely used in agricultural and anticarcinogenic fields. Microbial production of ()-(+)-perillyl alcohol was investigated in this study. We...
()-(+)-perillyl alcohol is widely used in agricultural and anticarcinogenic fields. Microbial production of ()-(+)-perillyl alcohol was investigated in this study. We optimized biosynthesis of ()-(+)-perillyl alcohol in by using neryl pyrophosphate synthase and NADPH regeneration. Engineering neryl pyrophosphate (NPP)-supplied pathway resulted in a 4-fold improvement of ()-(+)-perillyl alcohol titer. Subsequently, combined engineering of p-cymene monooxygenase () expression and module for NADPH regeneration exhibited a 15.4-fold increase of titer over the initial strain S02. Finally, 453 mg/L ()-(+)-perillyl alcohol was achieved in fed-batch fermentation, which is the highest ()-(+)-perillyl alcohol titer in .
PubMed: 35573132
DOI: 10.1002/elsc.202100135 -
Frontiers in Bioengineering and... 2022()-(+)-perillyl alcohol is a much valued supplemental compound with a wide range of agricultural and pharmacological characteristics. The aim of this study was to...
()-(+)-perillyl alcohol is a much valued supplemental compound with a wide range of agricultural and pharmacological characteristics. The aim of this study was to improve ()-(+)-perillyl alcohol production using a whole-cell catalytic formula. In this study, we employed plasmids with varying copy numbers to identify an appropriate strain, strain 03. We demonstrated that low levels of alKL provided maximal biocatalyst stability. Upon determination of the optimal conditions, the ()-(+)-perillyl alcohol yield reached 130 mg/L. For cofactor regeneration, we constructed strain 10, expressing FDH from , and achieved ()-(+)-perillyl alcohol production of 230 mg/L. As a result, 1.23 g/L ()-(+)-perillyl alcohol was transformed in a 5 L fermenter. Our proposed method facilitates an alternative approach to the economical biosynthesis of ()-(+)-perillyl alcohol.
PubMed: 35547170
DOI: 10.3389/fbioe.2022.900800 -
AMB Express Apr 2022Optimized recombinant whole cells of E. coli bearing CYP153A6 were employed for catalyzing the hydroxylation of different monoterpene derivatives. In most cases, high...
Optimized recombinant whole cells of E. coli bearing CYP153A6 were employed for catalyzing the hydroxylation of different monoterpene derivatives. In most cases, high selectivity was observed with exclusive hydroxylation of the allylic methyl group bound to the aliphatic ring. In the case of (R)- and (S)-carvone, hydroxylation occurred also on the other allylic methyl group, although to a lesser extent. Biotransformations carried out in fed-batch mode on (S)-limonene and α-terpineol showed that recombinant whole cells retained activity for at least 24 h, allowing for the recovery of 3.25 mg mL of (S)-perillyl alcohol and 5.45 mg mL of 7-hydroxy-α-terpineol, respectively.
PubMed: 35478304
DOI: 10.1186/s13568-022-01389-8 -
Non-coding RNA Research Mar 2022Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play critical roles in the pathogenesis and progression of pulmonary artery...
BACKGROUND
Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play critical roles in the pathogenesis and progression of pulmonary artery hypertension (PAH). LncRNA H19, myocardial infarction-associated transcript (MIAT), miR-29a, and miR-33a have been suggested as potential targets for treating arterial hypertension. We explored the expression pattern of non-coding RNAs H19, MIAT, miR-29a, and miR-33a in monocrotaline (MCT)-induced PAH rats. Moreover, we investigated whether perillyl alcohol (PA) and quercetin (QS), two plant derivatives with beneficial effects on PAH-induced abnormalities, act through regulating the expression of these non-coding RNAs.
METHODS
Male Wistar rats ( = 30) were divided into five groups. MCT (60 mg/kg) was injected subcutaneously to induce PAH. PA (50 mg/kg daily) and QS (30 mg/kg daily) were administered three weeks after induction of PAH. H&E staining and qRT-PCR were performed to assess arteriole wall thickness and gene expression, respectively.
RESULTS
Right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) increased in MCT and MCT + Veh. groups compared to the control group (in both < 0.001). QS and PA decreased RVSP and RVH significantly. Wall thickness and fibrosis score in the MCT group (score 3) increased compared to the control group (score 0). PA and QS ameliorated wall thickness and fibrosis to score 1 (mild). Also, the expression of miR-29a and miR-33a decreased in the PAH group (in both, < 0.001). Treatment with PA and QS decreased the expression of H19 ( < 0.001) and MIAT ( < 0.01) and increased the expression of miR-29a ( < 0.01) and miR-33a significantly ( < 0.05 for QS and < 0.001 for PA).
CONCLUSIONS
The beneficial effects of PA and QS on PAH-induced abnormalities were exerted through returning the dysregulated expression of H19, MIAT, miR-29a, and miR-33a to normal levels in rats with MTC-induced PAH. This study emphasized the therapeutic potential of PA and QS in PAH. However, more detailed investigations are needed to clarify the underlying molecular mechanisms.
PubMed: 35155877
DOI: 10.1016/j.ncrna.2022.01.005 -
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 -
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