Understanding the Role of Polyunsaturated Fatty Acids in the Development and Prevention of Cancer.

Polyunsaturated fatty acids (PUFAs), notably omega-3 (n-3) and omega-6 (n-6), have received much attention owing to their multifaceted effects not only in the management of diverse pathological conditions but also in the maintenance of overall health of an individual. A disproportionately high n-6 to n-3 ratio contributes to the development of various disorders including cancer, which ranks as a leading cause of death worldwide with profound social and economic burden. Epidemiological studies and clinical trials combined with the animal and cell culture models have demonstrated the beneficial effects of n-3 PUFAs in reducing the risk of various cancer types including breast, prostate and colon cancer. The anti-cancer actions of n-3 PUFAs are mainly attributed to their role in the modulation of a wide array of cellular processes including membrane dynamics, apoptosis, inflammation, angiogenesis, oxidative stress, gene expression and signal transduction pathways. On the contrary, n-6 PUFAs have been shown to exert pro-tumor actions; however, the inconsistent findings and controversial data emphasize upon the need to further investigation. Nevertheless, one of the biggest challenges in future is to optimize the n-6 to n-3 ratio despite the genetic predisposition, age, gender and disease severity. Moreover, a better understanding of the potential risks and benefits as well as the cellular and molecular mechanisms of the basic actions of these PUFAs is required to explore their role as adjuvants in cancer therapy. All these aspects will be reviewed in this chapter.

Correlation of meniscus tear type with synovial inflammation and the therapeutic potential of docosapentaenoic acid.

BACKGROUND: Synovitis, characterized by inflammation of the synovial membrane, is commonly induced by meniscus tears. However, significant differences in inflammatory responses and the key inflammatory mediators of synovium induced by different types of meniscal tears remain unclear. METHODS: Magnetic resonance imaging (MRI) was employed to identify the type of meniscus tear, and the quantification of synovial inflammation was assessed through H&E staining assay. Transcription and expression levels of IL-1ß and IL-6 were evaluated using bioinformatics, ELISA, RT-qPCR, and IHC of CD68 staining assays. The therapeutic potential of Docosapentaenoic Acid (DPA) was determined through network pharmacology, ELISA, and RT-qPCR assays. The safety of DPA was assessed using colony formation and EdU staining assays. RESULTS: The results indicate that both IL-1ß and IL-6 play pivotal roles in synovitis pathogenesis, with distinct expression levels across various subtypes. Among tested meniscus tears, oblique tear and bucket handle tear induced the most severe inflammation, followed by radial tear and longitudinal tear, while horizontal tear resulted in the least inflammation. Furthermore, in synovial inflammation induced by specific meniscus tears, the anterior medial tissues exhibited significantly higher local inflammation than the anterior lateral and suprapatellar regions, highlighting the clinical relevance and practical guidance of anterior medial tissues' inflammatory levels. Additionally, we identified the essential omega-3 fatty acid DPA as a potential therapeutic agent for synovitis, demonstrating efficacy in blocking the transcription and expression of IL-1ß and IL-6 with minimal side effects. CONCLUSION: These findings provide valuable insights into the nuanced nature of synovial inflammation induced by various meniscal tear classifications and contribute to the development of new adjunctive therapeutic agents in the management of synovitis.

Overcoming biological barriers BBB/BBTB by designing PUFA functionalised lipid-based nanocarriers for glioblastoma targeted therapy.

A major obstacle for chemotherapeutics in Glioblastoma (GB) is to reach the tumour cells due to the presence of the blood-brain barrier (BBB) and chemoresistance of anticancer drugs. The present study reports two polyunsaturated fatty acids, gamma-linolenic acid (GLA) and alpha-linolenic acid (ALA) appended nanostructured lipid carriers (NLCs) of a CNS negative chemotherapeutic drug docetaxel (DTX) for targeted delivery to GB. The ligand appended DTX-NLCs demonstrated particle size < 160 nm, PDI < 0.29 and a negative surface charge. The successful linkage of GLA (41 %) and ALA (30 %) ligand conjugation to DTX- NLCs was confirmed by diminished surface amino groups on the NLCs, lower surface charge and FTIR profiling. Fluorophore labelled GLA-DTX-NLCs and ALA-DTX-NLCs permeated the in-vitro 3D BBB model with Papp values of 1.8 × 10-3 and 1.9 × 10-3 cm/s respectively. Following permeation, both formulations showed enhanced uptake by GB immortalised cells while ALA-DTX-NLCs showed higher uptake in patient-derived GB cells as evidenced in an in-vitro 3D blood brain tumour barrier (BBTB) model. Both surface functionalised formulations showed higher internalisation in GB cells as compared to bare DTX-NLCs. ALA-DTX-NLCs and GLA-DTX-NLCs showed 13.9-fold and 6.8-fold higher DTX activity respectively at 24 h as indicated by IC50 values when tested in patient-derived GB cells. ALA-DTX-NLCs displayed better efficacy than GLA-DTX-NLCs when tested against 3D tumour spheroids and patient-derived cells. These novel formulations will contribute widely to overcoming biological barriers for treating glioblastoma.

A randomised, double-blinded, controlled trial to determine the efficacy of combined therapy of oclacitinib and marine oil extract PCSO-524 in dogs with atopic dermatitis.

BACKGROUND: Polyunsaturated fatty acids (PUFA) can be beneficial in the management of canine atopic dermatitis (cAD). A commercial product PCSO-524 containing PUFA has demonstrated anti-inflammatory effects in dogs. HYPOTHESIS/OBJECTIVES: To evaluate the efficacy of PCSO-524, in combination with oclacitinib in dogs with cAD. ANIMALS: Seventeen client-owned dogs with cAD. MATERIALS AND METHODS: A randomised, double-blinded, controlled trial. All dogs were treated with oclacitinib (0.4-0.6 mg/kg) twice a day for 14 days, then once a day until Day (D)42. They were randomly divided into two groups: PCSO-524 (n = 9) and sunflower oil (n = 8). Clinical status was assessed by Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) and pruritus Visual Analog Scale (pVAS) at baseline (D0), D14, D28 and D42. Trans epidermal water loss (TEWL) was measured at the same time points. RESULTS: CADESI scores decreased significantly after treatment and there was a significant difference between the PCSO-524 and the control group at D28 (p = 0.04) and D42 (p = 0.03). The PCSO-524 group also demonstrated a significantly decreased pVAS on D28 and D42 (p < 0.001 and p < 0.001) compared to D0, while significant differences were observed in the control group at D14 and D28 (p < 0.01 and p = 0.04) and not at D42 (p = 0.12). The mean TEWL showed a significant decrease at D28 and D42 in the PCSO-524 group, compared to the control group (p = 0.002 and p < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: The combination of PCSO-524 and oclacitinib may help to alleviate the rebound effect that occurs when tapering down the dosage of oclacitinib, as compared to using oclacitinib alone for the management of cAD.

Radiation therapy promotes unsaturated fatty acids to maintain survival of glioblastoma.

Radiation therapy (RT) is essential for the management of glioblastoma (GBM). However, GBM frequently relapses within the irradiated margins, thus suggesting that RT might stimulate mechanisms of resistance that limits its efficacy. GBM is recognized for its metabolic plasticity, but whether RT-induced resistance relies on metabolic adaptation remains unclear. Here, we show in vitro and in vivo that irradiated GBM tumors switch their metabolic program to accumulate lipids, especially unsaturated fatty acids. This resulted in an increased formation of lipid droplets to prevent endoplasmic reticulum (ER) stress. The reduction of lipid accumulation with genetic suppression and pharmacological inhibition of the fatty acid synthase (FASN), one of the main lipogenic enzymes, leads to mitochondrial dysfunction and increased apoptosis of irradiated GBM cells. Combination of FASN inhibition with focal RT improved the median survival of GBM-bearing mice. Supporting the translational value of these findings, retrospective analysis of the GLASS consortium dataset of matched GBM patients revealed an enrichment in lipid metabolism signature in recurrent GBM compared to primary. Overall, these results demonstrate that RT drives GBM resistance by generating a lipogenic environment permissive to GBM survival. Targeting lipid metabolism might be required to develop more effective anti-GBM strategies.

The Beneficial Effects of Pine Nuts and Its Major Fatty Acid, Pinolenic Acid, on Inflammation and Metabolic Perturbations in Inflammatory Disorders.

Inflammatory disorders such as atherosclerosis, diabetes and rheumatoid arthritis are regulated by cytokines and other inflammatory mediators. Current treatments for these conditions are associated with significant side effects and do not completely suppress inflammation. The benefits of diet, especially the role of specific components, are poorly understood. Polyunsaturated fatty acids (PUFAs) have several beneficial health effects. The majority of studies on PUFAs have been on omega-3 fatty acids. This review will focus on a less studied fatty acid, pinolenic acid (PNLA) from pine nuts, which typically constitutes up to 20% of its total fatty acids. PNLA is emerging as a dietary PUFA and a promising supplement in the prevention of inflammatory disorders or as an alternative therapy. Some studies have shown the health implications of pine nuts oil (PNO) and PNLA in weight reduction, lipid-lowering and anti-diabetic actions as well as in suppression of cell invasiveness and motility in cancer. However, few reviews have specifically focused on the biological and anti-inflammatory effects of PNLA. Furthermore, in recent bioinformatic studies on human samples, the expression of many mRNAs and microRNAs was regulated by PNLA indicating potential transcriptional and post-transcriptional regulation of inflammatory and metabolic processes. The aim of this review is to summarize, highlight, and evaluate research findings on PNO and PNLA in relation to potential anti-inflammatory benefits and beneficial metabolic changes. In this context, the focus of the review is on the potential actions of PNLA on inflammation along with modulation of lipid metabolism and oxidative stress based on data from both in vitro and in vivo experiments, and human findings, including gene expression analysis.

Novel proresolving lipid mediator mimetic 3-oxa-PD1n-3 docosapentaenoic acid reduces acute and chronic itch by modulating excitatory and inhibitory synaptic transmission and astroglial secretion of lipocalin-2 in mice.

ABSTRACT: Specialized proresolving mediators (SPMs) have demonstrated potent analgesic actions in animal models of pathological pain. The actions of SPMs in acute and chronic itch are currently unknown. Recently, n-3 docosapentaenoic acid (DPA) was found to be a substrate for the biosynthesis of several novel families of SPMs and 3-oxa-PD1 n-3 DPA (3-oxa-PD1) is an oxidation-resistant metabolic stable analogue of the n-3 DPA-derived protectin D1 (PD1). In this article, we demonstrate that 3-oxa-PD1 effectively reduces both acute and chronic itch in mouse models. Intrathecal injection of 3-oxa-PD1 (100 ng) reduced acute itch induced by histamine, chloroquine, or morphine. Furthermore, intrathecal 3-oxa-PD1 effectively reduced chronic itch, induced by cutaneous T-cell lymphoma (CTCL), allergic contact dermatitis with dinitrofluorobenzene, and psoriasis by imiquimod. Intratumoral injection of 3-oxa-PD1 also suppressed CTCL-induced chronic itch. Strikingly, the antipruritic effect lasted for several weeks after 1-week intrathecal 3-oxa-PD1 treatment. Whole-cell recordings revealed significant increase in excitatory postsynaptic currents in spinal dorsal horn (SDH) neurons of CTCL mice, but this increase was blocked by 3-oxa-PD1. 3-oxa-PD1 further increased inhibitory postsynaptic currents in SDH neurons of CTCL mice. Cutaneous T-cell lymphoma increased the spinal levels of lipocalin-2 (LCN2), an itch mediator produced by astrocytes. 3-oxa-PD1 suppressed LCN2 production in CTCL mice and LCN2 secretion in astrocytes. Finally, CTCL-induced anxiety was alleviated by intrathecal 3-oxa-PD1. Our findings suggest that 3-oxa-PD1 potently inhibits acute and chronic itch through the regulation of excitatory or inhibitory synaptic transmission and astroglial LCN2 production. Therefore, stable SPM analogs such as 3-oxa-PD1 could be useful to treat pruritus associated with different skin injuries.

THE ROLE OF DIET IN MULTIPLE SCLEROSIS.

Multiple sclerosis (MS) is a disease of the central nervous system (CNS), characterized by chronic inflammation associated with autoimmune damage to myelin and axons leading to neurodegeneration. Although the etiology is not fully understood, some factors that increase the risk of disease have been identified. One of the key elements of multidisciplinary approach to the management of MS is a properly balanced diet, e.g. Swank diet. Its main assumption is to reduce the supply of animal fats in favor of fats of plant origin, which contain polyunsaturated fatty acids omega-3. One of the factors influencing the course of the disease is vitamin D deficiency. In 80-90% it is synthesized by exposure to the sun, while the other 10-20% may be supplied with ingested food. Although elevated plasma homocysteine levels have been demonstrated in MS patients, there is no need to modify the supply of B vitamins. Further studies are necessary to show the correlation between the supply of B vitamins and the course of the disease. Due to the antioxidant effect, it is recommended to include products that are sources of vitamin A, E and C, glutathione, coenzyme Q10. It is also beneficial to include compounds from the polyphenol group: quercetin, resveratrol and curcumin. Through proper nutrition model it is also possible to reduce side effects of applied medications, such as constipation, what improves patients' quality of life. Diet therapy is a key element supporting pharmacotherapy in patients with multiple sclerosis.

Adipocyte-Derived Exosomal MTTP Suppresses Ferroptosis and Promotes Chemoresistance in Colorectal Cancer.

Obesity is closely related to a poor prognosis in patients with advanced colorectal cancer (CRC), but the mechanisms remain unclear. Ferroptosis is a form of nonapoptotic cell death characterized by lipid reactive oxygen species (ROS) accumulation and iron dependency and is associated with the chemoresistance of tumors. Here, it is shown that adipose-derived exosomes reduce ferroptosis susceptibility in CRC, thus promoting chemoresistance to oxaliplatin. It is found that microsomal triglyceride transfer protein (MTTP) expression is increased in the plasma exosomes of CRC patients with a high body fat ratio, serving as an inhibitor of ferroptosis and reducing sensitivity to chemotherapy. Mechanistically, the MTTP/proline-rich acidic protein 1 (PRAP1) complex inhibited zinc finger E-box binding homeobox 1 expression and upregulated glutathione peroxidase 4 and xCT, leading to a decreased polyunsaturated fatty acids ratio and lipid ROS levels. Moreover, experiments are carried out in organoids, and a tumor implantation model is established in obese mice, demonstrating that the inhibition of MTTP increases the sensitivity to chemotherapy. The results reveal a novel intracellular signaling pathway mediated by adipose-derived exosomes and suggest that treatments targeting secreted MTTP might reverse oxaliplatin resistance in CRC.

Effects of omega-3 supplementation on quality of life, nutritional status, inflammatory parameters, lipid profile, exercise tolerance and inhaled medications in chronic obstructive pulmonary disease.

BACKGROUND: The omega-3 polyunsaturated fatty acids (PUFAs) have an anti-inflammatory effect, beneficial for allergies, asthma, chronic obstructive pulmonary disease (COPD), reduce cholesterol and triglyceride levels and blood inflammatory parameters [C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α)]. The aim of our cross-sectional study was to monitor omega-3 supplementation in patients with severe COPD and assess its association with quality of life, nutritional status, inflammatory parameters, lipid profile, comorbidities, exercise tolerance and inhaled medications. METHODS: Our questionnaire on dietary supplement habits and our validated self-completion questionnaires were filled in by 400 patients with COPD at the National Koranyi Institute of Pulmonology, Hungary, mean age 67 [61-73] years; forced expiratory volume in one second (FEV1) (ref%): 46 [34-58]; 47.5% male, 52.5% female. We used the disease-specific COPD Assessment Test (CAT) questionnaire to measure quality of life. RESULTS: More than half of the study participants (61%) did not consume fish or oilseeds at all. Nineteen patients (4.75%) took omega-3 supplementation regularly, mainly on medical advice (0.5 g/day). We observed significantly lower serum CRP levels [6.0 (1-7.3) vs. 9.7 (7.4-14.4); P=0.044], more favourable lipid profile [triglycerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol] with higher mean body mass index (BMI) [28.1 (22.0-35.3) vs. 24.7 (24.5-30.1); P=0.118], better quality of life {CAT: 25 [21-30.5] vs. 26 [20-31]; P=0.519}, lower inhaled short-acting bronchodilators use [short-acting beta-agonists (SABAs): 6 (31.58) vs. 209 (54.86); P=0.047], lower number of exacerbations in the previous half year [0 (0-1) vs. 1 (0-2); P=0.023], and higher 6-minute walking distance (6MWD) {300 [177-387] vs. 251 [150-345]; P=0.120} in the group with omega-3 supplementation. CONCLUSIONS: PUFAs are anti-inflammatory and affect the immune system. Our study shows that omega-3 intake of COPD patients is insufficient, and there is an urgent need to develop new anti-inflammatory strategies because only one drug (such as corticosteroids) cannot ease the chronically progressive inflammatory process of COPD.

Cytochrome P450 oxidase 2J inhibition suppresses choroidal neovascularization in mice.

INTRODUCTION: Choroidal neovascularization (CNV) in age-related macular degeneration (AMD) leads to blindness. It has been widely reported that increased intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) diets reduce CNV. Of the three major pathways metabolizing ω-3 (and ω-6 LCPUFA), the cyclooxygenase and lipoxygenase pathways generally produce pro-angiogenic metabolites from ω-6 LCPUFA and anti-angiogenic ones from ω-3 LCPUFA. Howevehr, cytochrome P450 oxidase (CPY) 2C produces pro-angiogenic metabolites from both ω-6 and ω-3 LCPUFA. The effects of CYP2J2 products on ocular neovascularization are still unknown. Understanding how each metabolic pathway affects the protective effect of ω-3 LCPUFA on retinal neovascularization may lead to therapeutic interventions. OBJECTIVES: To investigate the effects of LCPUFA metabolites through CYP2J2 pathway and CYP2J2 regulation on CNV both in vivo and ex vivo. METHODS: The impact of CYP2J2 overexpression and inhibition on neovascularization in the laser-induced CNV mouse model was assessed. The plasma levels of CYP2J2 metabolites were measured by liquid chromatography and tandem mass spectroscopy. The choroidal explant sprouting assay was used to investigate the effects of CYP2J2 inhibition and specific LCPUFA CYP2J2 metabolites on angiogenesis ex vivo. RESULTS: CNV was exacerbated in Tie2-Cre CYP2J2-overexpressing mice and was associated with increased levels of plasma docosahexaenoic acids. Inhibiting CYP2J2 activity with flunarizine decreased CNV in both ω-6 and ω-3 LCPUFA-fed wild-type mice. In Tie2-Cre CYP2J2-overexpressing mice, flunarizine suppressed CNV by 33 % and 36 % in ω-6, ω-3 LCPUFA diets, respectively, and reduced plasma levels of CYP2J2 metabolites. The pro-angiogenic role of CYP2J2 was corroborated in the choroidal explant sprouting assay. Flunarizine attenuated ex vivo choroidal sprouting, and 19,20-EDP, a ω-3 LCPUFA CYP2J2 metabolite, increased sprouting. The combined inhibition of CYP2J2 with flunarizine and CYP2C8 with montelukast further enhanced CNV suppression via tumor necrosis factor-α suppression. CONCLUSIONS: CYP2J2 inhibition augmented the inhibitory effect of ω-3 LCPUFA on CNV. Flunarizine suppressed pathological choroidal angiogenesis, and co-treatment with montelukast inhibiting CYP2C8 further enhanced the effect. CYP2 inhibition might be a viable approach to suppress CNV in AMD.

Methylsulfonylmethane and Sesame Seed Oil Improve Dyslipidemia and Modulate Polyunsaturated Fatty Acid Metabolism in Two Mouse Models of Diabetes.

The objective of this study was to identify alterations in lipids and polyunsaturated fatty acid (PUFA) metabolism in both the streptozotocin (STZ)-induced type 1 diabetic (T1D) mouse and the mutant db/db type 2 diabetic (T2D) mouse to establish a biological signature for the evaluation of natural products with purported lipid-altering activity. Eight-week-old male C57BL/6J mice were randomized to nondiabetic group or STZ-induced diabetic groups (n = 10/group). STZ-induced diabetic mice and 6-week-old male db/db mice (n = 10/group) were randomized to the following groups: (1) diabetic control, no treatment, (2) methylsulfonylmethane (MSM) treatment, (3) sesame seed oil (SSO) treatment, and (4) MSM+SSO combination treatment. Clinical parameters measured included weights, blood glucose, serum lipid panels, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) detection of free fatty acids in serum, liver, brain, and eyes. Blood glucose significantly decreased after 4 weeks of MSM treatment in T1D mice. Serum PUFA levels were significantly reduced in T2D mice compared with control mice. In contrast, treatment with SSO reversed this effect in T2D mice, exhibiting serum PUFA levels comparable to control mice. Serum triglycerides were significantly increased in both diabetic models compared to nondiabetic control, mimicking diabetes in people. High-density lipoprotein (HDL) was significantly increased in T1D receiving MSM+SSO and all T2D treatment groups. A corresponding significant decrease in non-HDL cholesterol was seen in T2D mice in all treatment groups. MSM+SSO treatment's effects on HDL and non-HDL cholesterol and PUFA metabolism could lead to improved clinical outcomes in diabetics by improving the lipid profile.

2-Hexyl-4-Pentylenic Acid (HPTA) Stimulates the Radiotherapy-induced Abscopal Effect on Distal Tumor through Polarization of Tumor-associated Macrophages.

OBJECTIVE: The aim of this study was to explore the effects of 2-hexyl-4-pentylenic acid (HPTA) in combination with radiotherapy (RT) on distant unirradiated breast tumors. METHODS: Using a rat model of chemical carcinogen (7,12-dimethylbenz[a]anthracene,DMBA)-induced breast cancer, tumor volume was monitored and treatment response was evaluated by performing HE staining, immunohistochemistry, immunofluorescence, qRT-PCR, and western blot analyses. RESULTS: The results demonstrated that HPTA in combination with RT significantly delayed the growth of distant, unirradiated breast tumors. The mechanism of action included tumor-associated macrophage (TAM) infiltration into distant tumor tissues, M1 polarization, and inhibition of tumor angiogenesis by IFN-γ. CONCLUSION: The results suggest that the combination of HPTA with RT has an abscopal effect on distant tumors via M1-polarized TAMs, and HPTA may be considered as a new therapeutic for amplifying the efficacy of local RT for non-targeted breast tumors.The graphical abstract was available in the web of www.besjournal.com.

Beneficial effects of natural compounds on experimental liver ischemia-reperfusion injury.

Liver ischemia-reperfusion injury (IRI) is a phenomenon inherent to hepatic surgery that severely compromises the organ functionality, whose underlying mechanisms involve cellular and molecular interrelated processes leading to the development of an excessive inflammatory response. Liver resident cells and those recruited in response to injury generate pro-inflammatory signals such as reactive oxygen species, cytokines, chemokines, proteases and lipid mediators that contribute to hepatocellular necrosis and apoptosis. Besides, dying hepatocytes release damage-associated molecular patterns that actívate inflammasomes to further stimulate inflammatory responses leading to massive cell death. Since liver IRI is a complication of hepatic surgery in man, extensive preclinical studies have assessed potential protective strategies, including the supplementation with natural compounds, with the objective to downregulate nuclear factor-κB functioning, the main effector of inflammatory responses. This can be accomplished by either the activation of peroxisome proliferator-activated receptor-α, G protein-coupled receptor 120 or antioxidant signaling pathways, the synthesis of specific pro-resolving mediators, downregulation of Toll-like receptor 4 activity or additional contributory mechanisms that are beginning to be understood. The latter aspect is a crucial issue to be accomplished in preclinical studies, in order to establish adequate conditions for the supplementation with natural products before major liver surgeries in man involving warm IR, such as hepatic trauma or resection of large intrahepatic tumors.

Unsaturated fatty acids as a co-therapeutic agents in cancer treatment.

Chemotherapy is standard treatments for many malignancies. However, in most cases, this method is not able to induce apoptosis and in many cases, with cancer recurrence, leads to patient death. There are several procedure to control and suppress malignant cells, but among these methods, administration of É·-3 fatty acids and É·-6 fatty due to their destructive effects on cancer cells is more prominent. Many clinical studies have shown beneficial effects of É·-3 and É·-6 fatty acids in cardiovascular disorders, asthma, rheumatoid arthritis, osteoporosis and in most cancers such as colon, breast, prostate and other malignancies. Studies showed that polyunsaturated fatty acids (PUFAs) have a toxic effect on cancer cells. However, the exact mechanism of how É·- fatty acids affect cancer cells is still unknown. In this review alternative issues of malignancies co-treatments agents such as PUFAs have been studied. Also, the latest known PUFAs mechanisms on malignancies have been described.

Clinical presentation and molecular characterization of a novel patient with variant POC1A-related syndrome.

Biallelic pathogenic variants in POC1A result in SOFT (Short-stature, Onychodysplasia, Facial-dysmorphism, and hypoTrichosis) and variant POC1A-related (vPOC1A) syndromes. The latter, nowadays described in only two unrelated subjects, is associated with a restricted spectrum of variants falling in exon 10, which is naturally skipped in a specific POC1A mRNA. The synthesis of an amount of a POC1A isoform from this transcript in individuals with vPOC1A syndrome has been believed as the likely explanation for such a genotype-phenotype correlation. Here, we illustrate the clinical and molecular findings in a woman who resulted to be compound heterozygous for a recurrent frameshift variant in exon 10 and a novel variant in exon 9 of POC1A. Phenotypic characteristics of this woman included severe hyperinsulinemic dyslipidemia, acanthosis nigricans, moderate growth restriction, and dysmorphisms. These manifestations overlap the clinical features of the two previously published individuals with vPOC1A syndrome. RT-PCR analysis on peripheral blood and subsequent sequencing of the obtained amplicons demonstrated a variety of POC1A alternative transcripts that resulted to be expressed in the proband, in the healthy mother, and in controls. We illustrate the possible consequences of the two POC1A identified variants in an attempt to explain pleiotropy in vPOC1A syndrome.

Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis.

Rationale: Psoriasis is a chronic inflammatory disease caused by a complex interplay between the immune and nervous systems with recurrent scaly skin plaques, thickened stratum corneum, infiltration and activation of inflammatory cells, and itch. Despite an increasing availability of immune therapies, they often have adverse effects, high costs, and dissociated effects on inflammation and itch. Activation of sensory neurons innervating the skin and TRPV1 (transient receptor potential vanilloid 1) are emerging as critical components in the pathogenesis of psoriasis, but little is known about their endogenous inhibitors. Recent studies have demonstrated that resolvins, endogenous lipid mediators derived from omega-3 fatty acids, are potent inhibitors of TRP channels and may offer new therapies for psoriasis without known adverse effects. Methods: We used behavioral, electrophysiological and biochemical approaches to investigate the therapeutic effects of resolvin D3 (RvD3), a novel family member of resolvins, in a preclinical model of psoriasis consisting of repeated topical applications of imiquimod (IMQ) to murine skin, which provokes inflammatory lesions that resemble human psoriasis. Results: We report that RvD3 specifically reduced TRPV1-dependent acute pain and itch in mice. Mechanistically, RvD3 inhibited capsaicin-induced TRPV1 currents in dissociated dorsal root ganglion (DRG) neurons via the N-formyl peptide receptor 2 (i.e. ALX/FPR2), a G-protein coupled receptor. Single systemic administration of RvD3 (2.8 mg/kg) reversed itch after IMQ, and repeated administration largely prevented the development of both psoriasiform itch and skin inflammation with concomitant decreased in calcitonin gene-related peptide (CGRP) expression in DRG neurons. Accordingly, specific knockdown of CGRP in DRG was sufficient to prevent both psoriasiform itch and skin inflammation similar to the effects following RvD3 administration. Finally, we elevated the translational potential of this study by showing that RvD3 significantly inhibited capsaicin-induced TRPV1 activity and CGRP release in human DRG neurons. Conclusions: Our findings demonstrate a novel role for RvD3 in regulating TRPV1/CGRP in mouse and human DRG neurons and identify RvD3 and its neuronal pathways as novel therapeutic targets to treat psoriasis.

Associations between diet quality, blood pressure, and glucose levels among pregnant women in the Asian megacity of Jakarta.

BACKGROUND: The prevalence of gestational hypertension and diabetes in pregnancy is increasing worldwide. Diet is a modifiable factor that may influence these conditions, but few studies have examined the association between diet quality and blood pressure and glucose profiles among pregnant women. Data are especially scarce for women in low- and middle-income countries (LMICs), where 90% of global pregnancies occur, and in urban settings. We, therefore, assessed these associations among 174 pregnant women in the Asian megacity of Jakarta in a cross-sectional study of the Brain Probiotic and LC-PUFA Intervention for Optimum Early Life (BRAVE) project. METHODS: Trained field-enumerators collected socio-demographic characteristics, measured Mid-Upper Arm Circumference (MUAC), and assessed diet by two 24-hour recalls, which were used to calculate the Alternate Healthy Eating Index for Pregnancy (AHEI-P). Blood pressure was measured by automated sphygmomanometer, and fasting blood glucose by capillary glucometer. General linear models were used to identify associations. RESULTS: The median AHEI-P score was 47.4 (IQR 19.1-76.6). The middle tertile of the AHEI-P score (39.59-56.58) was associated with a 0.4 SD (standardized effect size, 95% CI -0.7 to -0.06; p = 0.02) lower diastolic blood pressure compared with the lowest tertile (<39.59), after adjustment for level of education, smoking status, MUAC, gestational age, history of hypertension, and family history of hypertension. However, no associations were found between the AHEI-P score and systolic blood pressure and blood glucose. CONCLUSION: Higher diet quality was associated with lower diastolic blood pressure among pregnant women in an urban LMIC community, but not with systolic blood pressure and blood glucose. A behavioral change intervention trial would be warranted to confirm the influence of diet quality on blood pressure and glucose levels and among pregnant women, and even before pregnancy.

2-hexyl-4-pentynoic acid, a potential therapeutic for breast carcinoma by influencing RPA2 hyperphosphorylation-mediated DNA repair.

Breast carcinoma is one of the most common malignancies in women. Previous studies have reported that 500 µM valproic acid can sensitize breast tumor cells to the anti-neoplastic agent hydroxyurea. However, the dose requirements for valproic acid is highly variable due to the wide inter-individuals clinical characteristics. High therapeutic dose of valproic acid required to induce anti-tumor activity in solid tumor was associated with increased adverse effects. There are attempts to locate suitably high-efficient low-toxicity valproic acid derivatives. We demonstrated that lower dose of 2-hexyl-4-pentynoic acid (HPTA; 15 µM) has similar effects as 500 µM VPA in inhibiting breast cancer cell growth and sensitizing the tumor cells to hydroxyurea on MCF7 cells, EUFA423 cells, MCF7 cells with defective RPA2-p gene and primary culture cells derived from tissue-transformed breast tumor cells. We discovered HPTA resulted in more DNA double-strand breaks, the homologous recombination was inhibited through the interference of the hyperphosphorylation of replication protein A2 and recombinase Rad51. Our data postulate that HPTA may be a potential novel sensitizer to hydroxyurea in the treatment of breast carcinoma.

Immunomodulatory Effects of Diet and Nutrients in Systemic Lupus Erythematosus (SLE): A Systematic Review.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement, including the skin, joints, kidneys, lungs, central nervous system and the haematopoietic system, with a large number of complications. Despite years of study, the etiology of SLE remains unclear; thus, safe and specifically targeted therapies are lacking. In the last 20 years, researchers have explored the potential of nutritional factors on SLE and have suggested complementary treatment options through diet. This study systematically reviews and evaluates the clinical and preclinical scientific evidence of diet and dietary supplementation that either alleviate or exacerbate the symptoms of SLE. For this review, a systematic literature search was conducted using PubMed, Scopus and Google Scholar databases only for articles written in the English language. Based on the currently published literature, it was observed that a low-calorie and low-protein diet with high contents of fiber, polyunsaturated fatty acids, vitamins, minerals and polyphenols contain sufficient potential macronutrients and micronutrients to regulate the activity of the overall disease by modulating the inflammation and immune functions of SLE.