Omega-3 (ω-3) and omega-6 (ω-6) polyunsaturated fatty acids (PUFAs) are nowadays desirable components of oils with special dietary and functional properties. Their therapeutic and health-promoting effects have already been established in various chronic inflammatory and autoimmune diseases through various mechanisms, including modifications in cell membrane lipid composition, gene expression, cellular metabolism, and signal transduction. The application of ω-3 and ω-6 PUFAs in most common skin diseases has been examined in numerous studies, but their results and conclusions were mostly opposing and inconclusive. It seems that combined ω-6, gamma-linolenic acid (GLA), and ω-3 long-chain PUFAs supplementation exhibits the highest potential in diminishing inflammatory processes, which could be beneficial for the management of inflammatory skin diseases, such as atopic dermatitis, psoriasis, and acne. Due to significant population and individually-based genetic variations that impact PUFAs metabolism and associated metabolites, gene expression, and subsequent inflammatory responses, at this point, we could not recommend strict dietary and supplementation strategies for disease prevention and treatment that will be appropriate for all. Well-balanced nutrition and additional anti-inflammatory PUFA-based supplementation should be encouraged in a targeted manner for individuals in need to provide better management of skin diseases but, most importantly, to maintain and improve overall skin health.

https://www.mdpi.com/1422-0067/21/3/741/pdf

Omega-3 Versus Omega-6 Polyunsaturated Fatty Acids in the Prevention and Treatment of Inflammatory Skin Diseases.

OBJECTIVE\nTo determine the effect of dietary supplementation with omega-3 fish oils with or without copper on disease activity in systemic lupus erythematosus (SLE). Fish oil supplementation has a beneficial effect on murine models of SLE, while exogenous copper can decrease the formation of lupus erythematosus cells in rats with a hydralazine-induced collagen disease.\n\n\nMETHODS\nA double blind, double placebo controlled factorial trial was performed on 52 patients with SLE. Patients were randomly assigned to 4 treatment groups. Physiological doses of omega-3 fish oils and copper readily obtainable by dietary means were used. One group received 3 g MaxEPA and 3 mg copper, another 3 g MaxEPA and placebo copper, another 3 mg copper and placebo fish oil, and the fourth group received both placebo capsules. Serial measurements of disease activity using the revised Systemic Lupus Activity Measure (SLAM-R) and peripheral blood samples for routine hematological, biochemical, and immunological indices were taken at baseline, 6, 12, and 24 weeks.\n\n\nRESULTS\nThere was a significant decline in SLAM-R score from 6.12 to 4.69 (p < 0.05) in those subjects taking fish oil compared to placebo. No significant effect on SLAM-R was observed in subjects taking copper. Laboratory variables were unaffected by either intervention.\n\n\nCONCLUSION\nIn the management of SLE, dietary supplementation with fish oil may be beneficial in modifying symptomatic disease activity.

The clinical effect of dietary supplementation with omega-3 fish oils and/or copper in systemic lupus erythematosus.

The rapid international spread of severe acute respiratory syndrome coronavirus 2 responsible for coronavirus disease 2019 (COVID-19) has posed a global health emergency in 2020. It has affected over 52 million people and led to over 1.29 million deaths worldwide, as of November 13th, 2020. Patients diagnosed with COVID-19 present with symptoms ranging from none to severe and include fever, shortness of breath, dry cough, anosmia, and gastrointestinal abnormalities. Severe complications are largely due to overdrive of the host immune system leading to "cytokine storm". This results in disseminated intravascular coagulation, acute respiratory distress syndrome, multiple organ dysfunction syndrome, and death. Due to its highly infectious nature and concerning mortality rate, every effort has been focused on prevention and creating new medications or repurposing old treatment options to ameliorate the suffering of COVID-19 patients including the immune dysregulation. Omega-3 fatty acids are known to be incorporated throughout the body into the bi-phospholipid layer of the cell membrane leading to the production of less pro-inflammatory mediators compared to other fatty acids that are more prevalent in the Western diet. In this article, the benefits of omega-3 fatty acids, especially eicosapentaenoic acid and docosahexaenoic acid, including their anti-inflammatory, immunomodulating, and possible antiviral effects have been discussed.

/pdf/omega-3-fatty-acids-and-covid-19-a-comprehensive-review-3rebqivm0c.pdf

Omega 3 Fatty Acids and COVID-19: A Comprehensive Review

The interaction between nutrition and the immune system is very complex. In particular, at every stage of the immune response, specific micronutrients, including vitamins and minerals play a key role and often synergistic, and the deficiency of only one essential nutrient may impair immunity. An individual's overall nutrition status and pattern of dietary intake (comprised of nutrients and non-nutritive bioactive compounds and food) and any supplementation with nutraceuticals including vitamins and minerals, can influence positively or negatively the function of the immune system. This influence can occur at various levels from the innate immune system and adaptive immune system to the microbiome. Although there are conflicting evidence, the current results point out that dietary supplementation with some nutrients such as vitamin D and zinc may modulate immune function. An update on the complex relationship between nutrition, diet, and the immune system through gut microbiota is the aim of this current review. Indeed, we will provide the overview of the link among immune function, nutrition and gut microbiota, paying particular attention at the effect of the Mediterranean diet on the immune system, and finally we will speculate the possible role of the main one functional supplements on immune function.

Nutrition and immune system: from the Mediterranean diet to dietary supplementary through the microbiota.

Nonalcoholic fatty liver disease (NAFLD) is present in approximately 25% of the population worldwide. It is characterized by the accumulation of triacylglycerol in the liver, which can progress to steatohepatitis with different degrees of fibrosis, stages that lack approved pharmacological therapies and represent an indication for liver transplantation with consistently increasing frequency. In view that hepatic steatosis is a reversible condition, effective strategies preventing disease progression were addressed using combinations of natural products in the preclinical high-fat diet (HFD) protocol (60% of fat for 12 weeks). Among them, eicosapentaenoic acid (C20:5n-3, EPA) and docosahexaenoic acid (C22:5n-3, DHA), DHA and extra virgin olive oil (EVOO), or EPA plus hydroxytyrosol (HT) attained 66% to 83% diminution in HFD-induced steatosis, with the concomitant inhibition of the proinflammatory state associated with steatosis. These supplementations trigger different molecular mechanisms that modify antioxidant, antisteatotic, and anti-inflammatory responses, and in the case of DHA and HT co-administration, prevent NAFLD. It is concluded that future studies in NAFLD patients using combined supplementations such as DHA plus HT are warranted to prevent liver steatosis, thus avoiding its progression into more unmanageable stages of the disease.

https://www.mdpi.com/2072-6643/12/2/499/pdf

Impact of the Co-Administration of N-3 Fatty Acids and Olive Oil Components in Preclinical Nonalcoholic Fatty Liver Disease Models: A Mechanistic View.

The recognition of ω-3 polyunsaturated acids (PUFAs) as essential fatty acids to normal growth and health was realized more than 80 years ago. However, the awareness of the long-term nutritional intake of ω-3 PUFAs in lowering the risk of a variety of chronic human diseases has grown exponentially only since the 1980s (1, 2). Despite the overwhelming epidemiological evidence, many attempts of using fish-oil supplementation to intervene human diseases have generated conflicting and often ambiguous outcomes; null or weak supporting conclusions were sometimes derived in the subsequent META analysis. Different dosages, as well as the sources of fish-oil, may have contributed to the conflicting outcomes of intervention carried out at different clinics. However, over the past decade, mounting evidence generated from genetic mouse models and clinical studies has shed new light on the functions and the underlying mechanisms of ω-3 PUFAs and their metabolites in the prevention and treatment of rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis, and type 1 diabetes. In this review, we have summarized the current understanding of the effects as well as the underlying mechanisms of ω-3 PUFAs on autoimmune diseases.

/pdf/therapeutic-potential-of-o-3-polyunsaturated-fatty-acids-in-47axuohlpc.pdf

Therapeutic Potential of ω-3 Polyunsaturated Fatty Acids in Human Autoimmune Diseases.

Adiponectin is an adipocyte-secreted cytokine that enhances insulin sensitivity and attenuates inflammation. Although circulating adiponectin level is often inversely associated with several malignancies, its role in the development of nasopharyngeal carcinoma (NPC) remains unclear. Here, we investigated the clinical association between circulating adiponectin level and NPC, and examined the impact of adiponectin, as well as the underlying mechanisms, on NPC growth both in vitro and in vivo.The association between circulating adiponectin level and the risk of developing NPC was assessed in two different cohorts, including a hospital-based case-control study with 152 cases and 132 controls, and a nested case-control study with 71 cases and 142 controls within a community-based NPC screening cohort. Tumor xenograft model, cell proliferation and cycle assays were applied to confirm the effects of adiponectin on NPC growth in cultured cells and in xenograft models. We also investigated the underlying signaling mechanisms with various specific pharmacological inhibitors and biochemistry analysis.High adiponectin levels were associated with a monotonic decreased trend of NPC risk among males in both the hospital-based case-control study and a nested case-control study. In vitro, recombinant human full-length adiponectin significantly inhibited NPC cell growth and arrested cell cycle, which were dependent on AMPK signaling pathway. The growth of xenograft of NPC tumor was sharply accelerated in the nude mice carrying genetic adiponectin deficiency. An adiponectin receptor agonist, AdipoRon, displayed strong anti-tumor activity in human xenograft models.These findings demonstrated for the first time that circulating adiponectin is not only inversely associated with NPC, but also controls the development of NPC via AMPK signaling pathway. Stimulation of adiponectin function may become a novel therapeutic modality for NPC. 

/pdf/adiponectin-suppresses-tumor-growth-of-nasopharyngeal-25ho1tij.pdf

Adiponectin suppresses tumor growth of nasopharyngeal carcinoma through activating AMPK signaling pathway

Obesity is one of the major risk factors for cancer. Clinical studies have demonstrated that circulating levels of adiponectin are inversely correlated, not only with the extent of adiposity, but also with the incidence of several types of cancer, particularly endometrial cancer (EC). However, thus far, adiponectin remains a correlative factor, without definitive evidence to show a causal effect in EC and the potential mechanism(s) involved. To address this issue, we introduced an Apn‐null mutation into Pten haploid‐deficient (Pten+/−) mice. The Pten heterozygous mutation alone led to the development of EC in less than 30% of female mice; however, when combined with the Apn‐null mutation, the incidence of endometrial lesions rose to at least two‐thirds. Although Apn deficiency did not further potentiate the Akt activation caused by the Pten mutation, it elevated the phosphorylation of mitogen‐activated protein kinase (MAPK) p42/44, indicating activation of the MAPK signaling pathway. Treatment of Apn−/−;Pten+/− mice with a MEK inhibitor blocked the development of EC. Finally, xenografts of a PTEN‐proficient human EC cell line grew faster in Apn‐deficient mice, whereas an adiponectin receptor agonist reduced xenograft growth of a PTEN‐deficient human EC cell line. Thus, reduction of adiponectin activity promotes EC development, at least in the context of Pten mutation, by activating MAPK. © 2022 The Pathological Society of Great Britain and Ireland.

Adiponectin deficiency promotes endometrial carcinoma pathogenesis and development via activation of mitogen‐activated protein kinase

New findings What is the central question of this study? What is the protective benefit of n-3 polyunsaturated fatty acids (PUFAs) on liver fibrosis and what are the relevant signalling pathways in a transgenic mouse model overexpressing the mfat-1 enzyme? What is the main finding and its importance? n-3 PUFA elevation strongly prevented carbon tetrachloride (CCl4 )-induced hepatic damage and inhibited the activation of hepatic stellate cells. n-3 PUFAs suppressed CCl4 -induced activation of mTOR, elevated Bcl-2 expression, and reduced Bax level, suggesting that n-3 PUFAs can render strong protective effects against liver fibrosis and point to the potential of mfat-1 gene therapy as a treatment modality. Abstract Liver fibrosis is a reversible wound healing response with excessive accumulation of extracellular matrix proteins. It is a globally prevalent disease with ultimately severe pathological consequences. However, very few current clinical therapeutic options are available. Nutritional addition of n-3 polyunsaturated fatty acids (PUFAs) can delay and lessen the development of liver fibrosis. Herein, this study examined the protective benefit of n-3 PUFAs on liver fibrosis and the relevant signalling pathways using a transgenic mouse model overexpressing the mfat-1 enzyme that converts n-6 to n-3 PUFAs. Male C57BL/6 wild-type and mfat-1 transgenic mice were administered carbon tetrachloride (CCl4 ) or control corn oil by intraperitoneal injection. Blood alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were subsequently measured. CCl4 -induced hepatic damage and fibrosis were assessed using haematoxylin-eosin and Masson's trichrome staining. Western blot assays were used to detect and quantify fibrosis-related proteins and mechanistic target of rapamycin (mTOR) and B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) signalling components. The direct effect of docosahexaenoic acid (DHA) on primary hepatic stellate cells (HSCs) was also investigated in a co-culture experiment. n-3 PUFAs, as a result of mfat-1 activity, had a strong protective effect on liver fibrosis. The elevation of ALT and AST induced by CCl4 was significantly lessened in the mfat-1 mice. Histological determination revealed the protective effects of n-3 PUFAs on liver inflammation and collagen deposition. Co-incubation with DHA reduced the expression of profibrogenic factors in the primary HSCs. Moreover, mfat-1 transgenic mice showed significant reduction of proteins that are involved in mTOR and Bcl-2/Bax signalling pathways. Collectively, these results suggest that n-3 PUFA elevation strongly prevents CCl4 -induced hepatic damage by directly inhibiting the activation of HSCs and regulating the basal activity of the mTOR and Bcl-2/Bax signalling pathways. Gene therapy applying mfat-1 and elevating n-3 PUFAs represents a promising treatment strategy to prevent liver fibrosis.

Endogenous production of n-3 polyunsaturated fatty acids protects mice from carbon tetrachloride-induced liver fibrosis by regulating mTOR and Bcl-2/Bax signalling pathways.

Shuai Wang

Papers

Therapeutic Potential of ω-3 Polyunsaturated Fatty Acids in Human Autoimmune Diseases.

Adiponectin suppresses tumor growth of nasopharyngeal carcinoma through activating AMPK signaling pathway

Adiponectin deficiency promotes endometrial carcinoma pathogenesis and development via activation of mitogen‐activated protein kinase

Endogenous production of n-3 polyunsaturated fatty acids protects mice from carbon tetrachloride-induced liver fibrosis by regulating mTOR and Bcl-2/Bax signalling pathways.