Background
Omega-9 fatty acids represent one of the main mono-unsaturated fatty acids (MUFA) found in plant and animal sources. They are synthesized endogenously in humans, though not fully ...compensating all body requirements. Consequently, they are considered as partially essential fatty acids. MUFA represent a healthier alternative to saturated animal fats and have several health benefits, including anti-inflammatory and anti-cancer characters.
The main body of the abstract
This review capitalizes on the major omega-9 pharmacological activities in context of inflammation management for its different natural forms in different dietary sources. The observed anti-inflammatory effects reported for oleic acid (OA), mead acid, and erucic acid were directed to attenuate inflammation in several physiological and pathological conditions such as wound healing and eye inflammation by altering the production of inflammatory mediators, modulating neutrophils infiltration, and altering VEGF effector pathway. OA action mechanisms as anti-tumor agent in different cancer types are compiled for the first time based on its anti- and pro-carcinogenic actions.
Conclusion
We conclude that several pathways are likely to explain the anti-proliferative activity of OA including suppression of migration and proliferation of breast cancer cells, as well stimulation of tumor suppressor genes. Such action mechanisms warrant for further supportive clinical and epidemiological studies to confirm the beneficial outcomes of omega-9 consumption especially over long-term intervention.
Nitro fatty acids (NO2–FAs) are biologically active compounds produced from the reaction of unsaturated fatty acids with reactive nitrogen species (RNS). Due to their electrophilic nature, these ...endogenously produced metabolites can react with nucleophilic targets, producing a spectrum of modulatory and protective effects. Determination of NO2–FAs in biological samples is challenging due to their low nanomolar to picomolar endogenous concentrations, indistinct metabolism, and distribution in many tissues and biofluids. Several attempts have been made to develop precise, standardized, and efficient methodologies for assessing physiological and pathophysiological processes to overcome the difficulties associated with their measurement. This review discusses those approaches utilizing liquid chromatography tandem mass spectrometry (LC‒MS/MS) and gas chromatography tandem mass spectrometry (GC‒MS/MS) for the quantification of NO2–FAs, in addition to a summary of their laboratory synthesis and extraction from biological samples. Clinical associations with different pathological conditions, including hyperlipidaemia, cardiac ischemia and herpes simplex type 2 viral infection (HSV-2), are also discussed.
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•LLE and SPE were reported to offer high recoveries of nitro fatty acids.•LC-MS/MS is a simpler technique, yet matrix effect hinders accurate quantification.•GC-MS/MS is the most sensitive way for endogenous nitro fatty acids quantification.•Plasma nitrated oleic and linoleic acids were reported to be in the nanomolar range.•Nitro oleic and linoleic acids increase in hyperlipidemia, ischemia and herpes simplex 2.
Discovery of novel biomarkers is critical for early diagnosis of acute coronary syndrome (ACS). Serum metabolite profiling of ST-elevation myocardial infarction (STEMI), unstable angina (UA) and ...healthy controls was performed using gas chromatography mass spectrometry (GC/MS), solid-phase microextraction coupled to gas chromatography mass spectrometry (SPME-GC/MS) and nuclear magnetic resonance (
H-NMR). Multivariate data analysis revealed a metabolic signature that could robustly discriminate STEMI patients from both healthy controls and UA patients. This panel of biomarkers consisted of 19 metabolites identified in the serum of STEMI patients. One of the most intriguing biomarkers among these metabolites is hydrogen sulfide (H
S), an endogenous gasotransmitter with profound effect on the heart. Serum H
S absolute levels were further investigated using a quantitative double-antibody sandwich enzyme-linked immunosorbent assay (ELISA). This highly sensitive immunoassay confirmed the elevation of serum H
S in STEMI patients. H
S level discriminated between UA and STEMI groups, providing an initial insight into serum-free H
S bioavailability during ACS. In conclusion, the current study provides a detailed map illustrating the most predominant altered metabolic pathways and the biochemical linkages among the biomarker metabolites identified in STEMI patients. Metabolomics analysis may yield novel predictive biomarkers that will potentially allow for an earlier medical intervention.
This study aimed to unravel the regulatory role of noncoding RNAs (ncRNA) on the nitric oxide (NO) machinery system in triple‐negative breast cancer (TNBC) patients and to further assess the ...influence of NO‐modulating ncRNAs on TNBC progression, immunogenic profile, and the tumor microenvironment (TME). The results revealed miR‐939‐5p and lncRNA HEIH as novel ncRNAs modulating NO machinery in TNBC. MiR‐939‐5p, an underexpressed microRNA (miRNA) in BC patients, showed an inhibitory effect on NOS2 and NOS3 transcript levels on TNBC cells. In contrast, HEIH was found to be markedly upregulated in TNBC patients and showed a modulatory role on miR‐939‐5p/NOS2/NO axis. Functionally, miR‐939‐5p was characterized as a tumor suppressor miRNA while HEIH was categorized as a novel oncogenic lncRNA in TNBC. Finally, knocking down of HEIH resulted in improvement of immunogenic profile of TNBC cells through inducing MICA/B and suppressing the immune checkpoint inhibitor PDL1. In the same context, knockdown of HEIH resulted in the alleviation of the immune‐suppressive TME by repressing interleukin‐10 and tumor necrosis factor‐α levels. In conclusion, this study identifies miR‐939‐5p as a tumor suppressor miRNA while HEIH as an oncogenic lncRNA exhibiting its effect through miR‐939‐5p/NOS2/NO axis. Therefore, repressing BC hallmarks, improving TNBC immunogenic profile, and trimming TME.
This study aimed to unravel the regulatory role of noncoding RNAs on the nitric oxide (NO) machinery system in triple‐negative breast cancer (TNBC) patients and to further assess the influence of NO‐modulating ncRNAs on TNBC progression, immunogenic profile, and the tumor microenvironment (TME).
Triple‐negative breast cancer (TNBC) represents an aggressive breast cancer subtype. Among young females, TNBC is the leading cause of cancer‐related mortalities. Recently, long noncoding RNAs ...(lncRNAs) are representing a promising pool of regulators for tuning the aggressiveness of several solid malignancies. However, this still needs further investigations in TNBC. The main aim of this study is to unravel the expression pattern of sONE lncRNA and its mechanistic role in TNBC. Results showed that sONE is restrictedly expressed in TNBC patients; its expression level is inversely correlated with the aggressiveness of the disease. sONE acts as a posttranscriptional regulator to endothelial nitric oxide synthase (eNOS) and thus affecting eNOS‐induced nitric oxide (NO) production from TNBC cells measured by Greiss reagent. Mechanistically, sONE is a potential tumor suppressor lncRNA in TNBC cells; repressing cellular viability, proliferation, colony‐forming ability, migration, and invasion capacities of MDA‐MB‐231. Furthermore, sONE effects were found to be extended to affect the maestro tumor suppressor TP53 and the oncogenic transcription factor c‐Myc. Knocking down of sONE resulted in a marked decrease in TP53 and increase in c‐Myc and consequently altering the expression status of their downstream tumor suppressor microRNAs (miRNAs) such as miR‐34a, miR‐15, miR‐16, and let‐7a. In conclusion, this study highlights sONE as a downregulated tumor suppressor lncRNA in TNBC cells acting through repressing eNOS‐induced NO production, affecting TP53 and c‐Myc proteins levels and finally altering the levels of a panel of tumor suppressor miRNAs downstream TP53/c‐Myc proteins.
sONE is a novel tumor suppressor long noncoding RNA (lncRNA) in triple‐negative breast cancer (TNBC). sONE lncRNA is restrictively expressed in TNBC patients. sONE expression level is inversely correlated with the aggressiveness of the disease. sONE expression level is almost diminished in young TNBC patients.
Ozonated olive oil (OL) combines the therapeutic effects of both ozone and olive oil. However, it suffers from limited water solubility and poor transdermal permeation, which hinder its application ...in melanoma treatment. Nanocarrier host molecules, such as niosomes, were used to improve the water solubility, transdermal permeation, and anticancer effect of hydrophobic compounds. This study aims to design and optimize a niosomal vesicular nanoplatform loaded with OL (OL/NSs) to improve OL’s skin permeation and anti-melanoma effect. In this regard, OL was prepared and characterized by evaluating its chemical properties (acid, peroxide, and iodine values) and fatty acid composition using gas chromatography. Then, OL/NSs were developed using the thin film hydration method employing cholesterol, Span 60, and Tween 60 at five different molar ratios. The optimized niosomes had an average diameter of 125.34 ± 13.29 nm, a surface charge of −11.34 ± 4.71 mV, and a spherical shape. They could entrap 87.30 ± 4.95% of the OL. OL/NSs showed a 75% sustained oil release over 24 h. The skin permeation percentage of OL/NSs was 36.78 ± 3.31 and 53.44 ± 6.41% at 12 and 24 h, respectively, three times higher than that of the free OL (11.50 ± 1.3 and 17.24 ± 2.06%, at 12 and 24 h, respectively). Additionally, the anticancer activity of the developed niosmal formulation, when tested on human melanoma cells (A375), was double that of the free OL; the IC50 of the OL/NSs was 8.63 ± 2.8 μg/mL, and that of the free OL was 17.4 ± 3.7 μg/mL. In conclusion, the encapsulation of ozonated olive oil in niosomes enhanced its water solubility, skin permeation, and anticancer activity and thus may represent potent natural chemotherapy in treating melanoma.
Triple-Negative Breast Cancer (TNBC) is one of the most aggressive and hot BC subtypes. Our research group has recently shed the light on the utility of natural compounds as effective ...immunotherapeutic agents. The aim of this study is to investigate the role of a methoxylated quercetin glycoside (MQG) isolated from
Cleome droserifolia
in harnessing TNBC progression and tuning the tumor microenvironment and natural killer cells cytotoxicity. Results showed that MQG showed the highest potency (IC
50
= 12 µM) in repressing cellular proliferation, colony-forming ability, migration, and invasion capacities. Mechanistically, MQG was found to modulate a circuit of competing endogenous RNAs where it was found to reduce the oncogenic MALAT-1 lncRNA and induce TP53 and its downstream miRNAs; miR-155 and miR-146a. Accordingly, this leads to alteration in several downstream signaling pathways such as nitric oxide synthesizing machinery, natural killer cells' cytotoxicity through inducing the expression of its activating ligands such as MICA/B, ULBP2, CD155, and ICAM-1 and trimming of the immune-suppressive cytokines such as TNF-α and IL-10. In conclusion, this study shows that MQG act as a compelling anti-cancer agent repressing TNBC hallmarks, activating immune cell recognition, and alleviating the immune-suppressive tumor microenvironment experienced by TNBC patients.
Ephedrine, a sympathomimetic amine that exhibits several adrenaline actions, is a plant alkaloid that is a common ingredient in several cold, asthma and narcolepsy treatment preparations, and in ...obesity management and sport medicine. Its principal action mechanism relies on its direct adrenergic actions as well as indirect role that involves the release of epinephrine and norepinephrine, thus increasing the activity of epinephrine and norepinephrine at the postsynaptic α and β receptors. Nevertheless, its serious side effects, including stroke, heart attack, drug abuse and interactions, have never been comprehensively reviewed. We conducted a systematic review of data on ephedrine, including its occurrence in functional foods, pharmacological aspects, metabolism, pharmaco/toxicokinetics and clinical features. Furthermore, a review of ephedrine natural structural analogues with regards to their differential adrenergic receptor binding affinities, food interaction, and their impact on the pharmacokinetics and effects relative to ephedrine are presented for the first time, and in comparison to its action when present in herbs.
Overview of the covered topics: action mechanisms for ephedrine stimulation of α and β adrenoceptor, impact of processing and combination on the pharmacokinetics of its ephedrine content, and key players in pharmacokinetics.
Abstract
N6-methyl-adenosine (m
6
A) is the most prevalent modification on mRNAs and long noncoding RNAs (lnRNAs) in higher eukaryotes. Modulation of m
6
A relies on m
6
A writers, erasers and ...readers. m
6
A modification contributes to diverse fundamental biological functions at the molecular, cellular, and physiological levels. The dysregulation of m
6
A modification has been implicated in various human diseases. Thus, m
6
A modification has now become a research hotspot for its potential therapeutic applications in the treatment of various cancers and diseases. The immune system is essential to provide defense against infections and cancers. This review summarizes the current knowledge about the roles of m
6
A in regulating immune cell functions and immune responses.
Triple negative breast cancer (TNBC) is an immunogenically hot tumor. The immune checkpoint blockades (ICBs) have been recently emerged as promising therapeutic candidates for several malignancies ...including TNBC. Yet, the development of innate and/or adaptive resistance by TNBC patients towards ICBs such as programmed death-ligand 1 (PD-L1) inhibitors (e.g. Atezolizumab) shed the light on importance of identifying the underlying mechanisms regulating PD-L1 in TNBC. Recently, it was reported that non-coding RNAs (ncRNAs) perform a fundamental role in regulating PD-L1 expression in TNBC. Hence, this study aims to explore a novel ncRNA axis tuning PD-L1 in TNBC patients and investigate its possible involvement in fighting Atezolizumab resistance.
In-silico screening was executed to identify ncRNAs that could potentially target PD-L1. Screening of PD-L1 and the nominated ncRNAs (miR-17–5p, let-7a and CCAT1 lncRNA) was performed in BC patients and cell lines. Ectopic expression and/or knockdown of respective ncRNAs were performed in MDA-MB-231. Cellular viability, migration and clonogenic capacities were evaluated using MTT, scratch assay and colony-forming assay, respectively.
PD-L1 was upregulated in BC patients, especially in TNBC patients. PD-L1 is positively associated with lymph node metastasis and high Ki-67 in recruited BC patients. Let-7a and miR-17–5p were nominated as potential regulators of PD-L1. Ectopic expression of let-7a and miR-17–5p caused a noticeable reduction in PD-L1 levels in TNBC cells. In order to investigate the whole ceRNA circuit regulating PD-L1 in TNBC, intensive bioinformatic studies were performed. The lncRNA, Colon Cancer-associated transcript 1 (CCAT1), was reported to target PD-L1 regulating miRNAs. Results showed that CCAT1 is an upregulated oncogenic lncRNA in TNBC patients and cell lines. CCAT1 siRNAs induced a noticeable reduction in PD-L1 levels and a marked increase in miR-17–5p level, building up a novel regulatory axis CCAT1/miR-17–5p/PD-L1 in TNBC cells that was tuned by the let-7a/c-Myc engine. On the functional level, co-treatment of CCAT-1 siRNAs and let-7a mimics efficiently relieved Atezolizumab resistance in MDA-MB-231 cells.
The present study revealed a novel PD-L1 regulatory axis via targeting let-7a/c-Myc/CCAT/miR-17–5p. Additionally, it sheds the light on the potential combinational role of CCAT-1 siRNAs and Let-7a mimics in relieving Atezolizumab resistance in TNBC patients.
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