Clinical application progress

In recent years, n-3 PUFA have shown significant effects in the prevention and treatment of various diseases (Table 1), particularly in CVD and neurological disorders.^{(Reference Rodriguez, Lavie and Elagizi17–Reference von Schacky21)}. In CVD, n-3 PUFA reduce the risk of heart attacks and strokes through multiple mechanisms, including lowering blood lipid levels, reducing triglycerides, inhibiting platelet aggregation and decreasing atherosclerosis and vascular inflammation^{(Reference Sherratt, Libby and Budoff22–Reference Sala-Vila, Fleming and Kris-Etherton25)}. In addition, n-3 PUFA can lower blood pressure in hypertensive patients by regulating ion channels in the blood vessels^{(Reference Musazadeh, Kavyani and Naghshbandi26)}. In neurological disorders, n-3 PUFA, especially DHA, are crucial for brain health^{(Reference DiNicolantonio and O’Keefe27)}. Multiple studies have shown that n-3 PUFA can improve neural conduction, alleviate symptoms of depression, protect nerve cells, enhance memory and learning abilities and slow down cognitive decline in Alzheimer’s disease^{(Reference Zuo, Wu and Xiang28–Reference Lu, Qiao and Mi32)}.

Table 1. Clinical applications of n-3 PUFA in common diseases

The therapeutic potential of n-3 PUFA in ophthalmic diseases, allergic conditions and liver diseases is also gradually being recognised^{(Reference Jump, Lytle and Depner33–Reference Li, Li and Cao35)}. In ophthalmic diseases, n-3 PUFA alleviate dry eye symptoms by improving the ocular lipid layer and slowing down tear evaporation^{(Reference Downie, Ng and Lindsley36)}; n-3 PUFA also slow the progression of age-related macular degeneration by promoting the survival and repair of retinal nerve cells, as well as protecting the retina from oxidative damage^{(Reference Jiang, Shi and Fan37)}; In addition, n-3 PUFA have shown some potential in controlling myopia^{(Reference Pan, Zhao and Xie38)}. In allergic diseases, n-3 PUFA can effectively alleviate symptoms of allergic rhinitis by inhibiting the production of pro-inflammatory cytokines. Additionally, n-3 PUFA have a relieving effect on airway inflammation, helping to improve lung function in asthma patients and thereby effectively alleviating their symptoms^{(Reference Heras, Gomi and Young39,Reference Wake and Kobayashi40)} . In liver diseases, n-3 PUFA can reduce hepatic fat accumulation, improve liver function, regulate inflammatory responses and slow down liver damage^{(Reference Jump, Lytle and Depner33,Reference Shama and Liu41)} .

Additionally, although the potential of n-3 PUFA in cancer treatment has garnered widespread attention, their therapeutic efficacy remains somewhat controversial^{(Reference Manson, Cook and Lee42,Reference Lee, Seong and Kim43)} . Some studies indicate that n-3 PUFA exert their effects through multi-target mechanisms^{(Reference D’Angelo, Motti and Meccariello44,Reference Liput, Lepczyński and Ogłuszka45)} , such as inhibiting cell proliferation, promoting apoptosis, suppressing angiogenesis, reducing inflammation, lowering metastasis and regulating epigenetic abnormalities. These actions may inhibit the growth of various types of tumours, including breast cancer^{(Reference Fabian, Kimler and Hursting46)}, colon cancer^{(Reference D’Angelo, Motti and Meccariello44)} and prostate cancer^{(Reference Liang, Henning and Grogan47)}.

In addition to the therapeutic effects in the aforementioned diseases, the application of n-3 PUFA in the field of orthopaedics is also gaining increasing attention^{(Reference Li, Lu and Qi48–Reference Huang, Vi and Zong52)} (Fig. 2). With the changes in modern lifestyle, the incidence of orthopaedic diseases, particularly osteoarthritis (OA)^{(Reference Allen, Thoma and Golightly53,Reference Bijlsma, Berenbaum and Lafeber54)} and osteoporosis (OP)^{(Reference Ayers, Kansagara and Lazur55)}, has been rising year by year, significantly affecting patients’ quality of life and posing a major challenge to the healthcare system. Therefore, exploring the application of n-3 PUFA in the field of orthopaedics holds important research value and practical significance.

Figure 2. Application of n-3 PUFA in the field of orthopaedics.

Research progress of n-3 PUFA in osteoarthritis

In recent years, research on the application of n-3 PUFA in OA has gradually increased^{(Reference Cordingley and Cornish56,Reference Shawl, Geetha and Burnett57)} .OA^{(Reference Bijlsma, Berenbaum and Lafeber54)} is a chronic and degenerative disease, commonly linked with joint inflammation and cartilage degeneration. The clinical manifestations primarily include joint pain, stiffness, swelling and limited mobility, significantly affecting patients’ quality of life. n-3 PUFA play a role in the prevention and treatment of OA through various mechanisms^{(Reference Calder58–Reference Gutiérrez, Svahn and Johansson62)}, primarily including altering the lipid composition of cell membranes, inhibiting pro-inflammatory signalling pathways, promoting the production of anti-inflammatory mediators and regulating immune responses.

Alteration of the lipid composition of cell membranes

n-6 PUFA, especially arachidonic acid (AA), occupy a crucial position in the phospholipid components of cell membranes^{(Reference Das63)}. AA is converted into prostaglandin E₂ (PGE₂) via the cyclooxygenase-2 pathway and into leukotriene B₄ via the 5-lipoxygenase pathway. Both of these pro-inflammatory molecules regulate immune responses by chemotactically attracting immune cells to the site of injury, promoting the onset and maintenance of inflammation^{(Reference Pang, Liu and Zhao64–Reference Hoxha66)}. Therefore, the excessive accumulation of n-6 PUFA in the body is closely associated with many inflammation-related diseases.

In contrast, n-3 PUFA, particularly DHA and EPA, can competitively bind to cell membrane phospholipids with n-6 PUFA, thereby increasing the content of n-3 PUFA in the membrane and maintaining a healthy balance of lipid signalling in the body. This shift reduces the proportion of AA, thereby decreasing the production of pro-inflammatory substances such as PGE₂ and leukotriene B₄ derived from n-6 PUFA and mitigating the extent of the inflammatory response^{(Reference Peña-de-la-Sancha, Muñoz-García and Espínola-Zavaleta67)} (Fig. 3).

Figure 3. n-3 PUFA reduce inflammatory responses by competitively binding to cell membrane phospholipids with n-6 PUFA.

Inhibition of pro-inflammatory signalling pathways

The NF-κB signalling pathway is a central pathway in many inflammatory responses (Fig. 4), playing a crucial role in inflammation-related diseases such as OA^{(Reference Yao, Wu and Tao68)}. The NF-κB signalling pathway can activate the synthesis of pro-inflammatory cytokines, including TNF-α and IL-1β, promoting the initiation and persistence of inflammation^{(Reference Zhong, Liang and Zhang69)}. DHA can inhibit the degradation of key proteins in the NF-κB pathway, thereby preventing the nuclear translocation of NF-κB, reducing its activity in the nucleus and decreasing the release of pro-inflammatory cytokines, ultimately alleviating the inflammatory response^{(Reference Liu, Zhang and Yang59,Reference Jiang, Zeng and He70)} . This mechanism is of significant importance in orthopaedic diseases such as OA. Jin et al. ^{(Reference Jin, Dong and Sun71)} found through animal models that a diet rich in n-3 PUFA inhibits the expression of the NF-κB signalling pathway, demonstrating anti-inflammatory and anti-OA effects. Zhang et al. ^{(Reference Zhang, Dai and Zhang72)} also found that edible oils with a low n-6/n-3 PUFA ratio can delay the progression of OA by inhibiting the NF-κB pathway.

Figure 4. Classical NF-κB signalling pathway. This figure illustrates the main process of the classical NF-κB signalling pathway: pro-inflammatory cytokines and pathogen-associated molecular patterns bind to cell surface receptors, activating the IκB kinase complex. The IκB kinase complex phosphorylates IκB proteins, leading to their degradation and the release of NF-κB (p65/p50). Subsequently, NF-κB translocates to the nucleus, where it binds to specific DNA sequences and initiates the transcription of target genes. These target genes include matrix metalloproteinases, ADAMTS4/5, Runx2 and HIF2α, which are involved in important biological processes such as inflammation, extracellular matrix degradation, osteogenesis and hypoxic response.

Promotion of anti-inflammatory lipid mediator production

After metabolism, n-3 PUFA not only reduce the production of pro-inflammatory molecules but also promote the generation of active anti-inflammatory lipid mediators such as resolvins, protectins and maresins^{(Reference Dyall, Balas and Bazan73,Reference Chiang and Serhan74)} (Table 2). These active anti-inflammatory lipids have shown potential in inhibiting cartilage degradation and promoting joint tissue repair, particularly playing an important role in inflammation resolution and tissue regeneration^{(Reference Oppedisano, Bulotta and Maiuolo75–Reference Shih, Tao and Gilpin77)}. Park et al. ^{(Reference Park, Roh and Pan78)} found through animal models that resolvins can reduce the release of inflammatory factors (such as TNF-α, IL-1β, etc.) by binding to specific receptors on inflammatory cells in both neurogenic and inflammatory pain models, thereby alleviating the inflammatory response. Zhao et al. ^{(Reference Zhao, Wang and Wang79)} demonstrated through a rat model that protectins possess pro-resolving properties, promoting autophagy to accelerate the clearance of damaged cells, thereby exerting anti-inflammatory effects. Lu et al. ^{(Reference Lu, Feng and Zhang80)} similarly found through a rat model that maresins activate the PI3K/Akt pathway and inhibit the NF-κB pathway, reducing the secretion of matrix metalloproteinase-13, which increases type II collagen in cartilage, thereby exerting anti-inflammatory effects and protecting cartilage.

Table 2. Active anti-inflammatory lipid mediators derived from n-3 PUFA metabolism

MMP13, matrix metalloproteinase-13.

Regulation of immune responses

n-3 PUFA can also modulate immune responses and alleviate chronic inflammation in OA^{(Reference Poggioli, Hirani and Jogani81,Reference Coniglio, Shumskaya and Vassiliou82)} (Fig. 5). Dietary supplementation with n-3 PUFA effectively increases cell membrane fluidity, thereby modulating immune cell function, particularly the function of T cells and macrophages^{(Reference Gutiérrez, Svahn and Johansson62)}. Studies have found that T cells play a crucial role in immune suppression and tissue repair. n-3 PUFA can alter the ratio of T cell subsets, promote the activity of anti-inflammatory T cells (such as Th2, Treg) and inhibit the activation of pro-inflammatory T cells (such as Th1, Th17), helping to reduce immune-mediated inflammatory responses in OA^{(Reference Hou, McMurray and Chapkin83–Reference Perez-Hernandez, Chiurchiù and Perruche85)}. In addition, n-3 PUFA can modulate macrophage polarisation, promoting their transformation into anti-inflammatory M2 macrophages^{(Reference Schwager, Bompard and Raederstorff86,Reference Videla, Valenzuela and Del Campo87)} . Numerous studies have shown that M2 macrophages play a key role in immune suppression and tissue repair. They alleviate inflammatory damage to joints and cartilage tissue and slow the progression of OA by secreting anti-inflammatory cytokines such as IL-10 and TGF-β ^{(Reference Lu, Zhang and Pan88–Reference Zhou, Yang and Shi90)}.

Figure 5. The regulatory role of n-3 PUFA in immune responses.

Research progress of n-3 PUFA in rheumatoid arthritis

Rheumatoid arthritis (RA)^{(Reference Gravallese and Firestein91)} is a chronic, systemic autoimmune disease characterised by chronic inflammation, swelling, pain and dysfunction of the joints. RA typically affects symmetrical joints, particularly those in the hands, feet, knees, wrists and elbows. As the disease progresses, RA can lead to joint structural damage, resulting in joint deformities and loss of function^{(Reference Brown, Pratt and Hyrich92)}. The current treatment strategies for RA mainly rely on immunosuppressants, anti-inflammatory drugs and biologics^{(Reference Hwang, Rim and Nam93,Reference Smolen94)} . However, in recent years, an increasing number of studies have found that n-3 PUFA, as natural anti-inflammatory agents, demonstrate potential therapeutic value in the treatment of RA^{(Reference Nikiphorou and Philippou95,Reference Vadell, Bärebring and Hulander96)} .

Analogous to its effects in OA, n-3 PUFA can also exert anti-inflammatory effects through multiple mechanisms, alleviating the inflammatory response in RA^{(Reference Poggioli, Hirani and Jogani81,Reference Coniglio, Shumskaya and Vassiliou82)} (Table 3). Raad et al. ^{(Reference Raad, Griffin and George97)} demonstrated through clinical samples that n-3 PUFA can significantly reduce the production of pro-inflammatory cytokines, such as TNF-α and IL-6, thereby helping to alleviate symptoms such as joint swelling, pain and morning stiffness caused by inflammation. Similarly, Navarini et al. ^{(Reference Navarini, Afeltra and Gallo Afflitto98)} also demonstrated through animal experiments and clinical trials that n-3 PUFA reduce the levels of arachidonic acid (AA) in immune cells, inhibiting the production of pro-inflammatory mediators like PGE₂. Moreover, they promote the production of anti-inflammatory cannabinoids and cytokines, such as IL-10, while suppressing the levels of pro-inflammatory cytokines (e.g. TNF-α, IL-1β and IL-6), thus overall modulating immune responses and reducing the inflammatory symptoms of RA. Additionally, Jin et al. ^{(Reference Jin, Sun and Ling99)} first demonstrated in a collagen antibody-induced arthritis model that protectin DX (PDX), produced from n-3 PUFA metabolism, significantly inhibits the production of Th17 cells and pro-inflammatory mediators through the miR-20a-NLRP3 inflammasome pathway. This promotes Treg cells and anti-inflammatory cytokines, slows joint damage and improves the progression of RA. Furthermore, as persistent inflammation and joint destruction are major features of RA^{(Reference Deng, Zhang and He100)}, Su et al. ^{(Reference Su, Han and Choi101)} found that lipid mediators produced from DHA exhibit significant anti-inflammatory effects. In the collagen antibody-induced arthritis mouse model, lipid mediators significantly alleviated arthritis, cartilage erosion and bone destruction by downregulating osteoclast-related gene expression, inhibiting the NF-κB pathway, reducing the production of pro-inflammatory cytokines and increasing IL-10 levels, thereby demonstrating potential for mitigating RA symptoms.

Table 3. Mechanisms of anti-inflammatory effects of n-3 PUFA in rheumatoid arthritis

AA, arachidonic acid.

Research progress of n-3 PUFA in gout

Gout^{(Reference Dalbeth, Gosling and Gaffo102)} is a condition caused by abnormal purine metabolism, typically characterised by joint inflammation, pain and swelling. It is triggered by hyperuricaemia, which results in high levels of uric acid in the blood. Uric acid crystals accumulate in the joints and surrounding tissues, particularly in areas such as the toes, ankles and knees, leading to acute inflammatory responses^{(Reference Danve, Sehra and Neogi103,Reference Zhang, Chen and Yuan104)} (Fig. 6).

Figure 6. Pathogenesis and progression of gout. The pathogenesis and progression of gout begin with increased uric acid intake and decreased renal excretion capacity, leading to elevated blood uric acid levels and resulting in hyperuricaemia. As the uric acid concentration continues to rise, urate crystals accumulate in the joints and surrounding tissues, triggering an immune response and causing acute arthritis. Without treatment, this process can persist, ultimately leading to chronic gout, causing joint damage and long-term inflammation.

It is generally believed that seafood may have an adverse impact on individuals with hyperuricaemia^{(Reference Clebak, Morrison and Croad105,Reference Li, Yu and Li106)} . Because seafood is rich in purine compounds, which are metabolised into uric acid in the body. Excessive uric acid accumulation is a major trigger of gout. However, Zeng et al. ^{(Reference Zeng, You and Ye107)}, analysing data from 12 505 participants in the 2007–2016 NHANES database, found that seafood with low n-3 PUFA content is associated with a higher risk of gout, while seafood rich in n-3 PUFA does not carry this risk and may even counteract the negative effects of purines on gout through its anti-inflammatory properties. Similarly, Zhang et al. ^{(Reference Zhang, Zhang and Terkeltaub108)} confirmed this finding in a clinical study of 724 gout patients. Those who consumed at least two servings of n-3 PUFA-rich fish had a 26 % reduced risk of gout flare-ups compared with those who had not consumed such fish in the past 48 h.

Besides their excellent anti-inflammatory effects, n-3 PUFA have also been shown by Saito et al. ^{(Reference Saito, Toyoda and Takada109)} through cell models to inhibit renal urate transporter 1, which is responsible for the reabsorption of urate into the bloodstream. By inhibiting urate transporter 1, n-3 PUFA increase uric acid excretion and thereby reduce serum urate levels, alleviating gout symptoms.

In conclusion, moderate consumption of seafood rich in n-3 PUFA or supplementation with n-3 PUFA through dietary supplements may provide an effective dietary intervention strategy for gout patients, helping to alleviate symptoms and significantly reduce the frequency of gouty arthritis flare-ups.

Research progress of n-3 PUFA in osteoporosis

OP^{(Reference Wen, Xu and Zhang110)} is a chronic metabolic bone disease characterised by a significant decrease in bone density and destruction of bone microstructure, resulting in fragile bones and an increased risk of fractures. It is often referred to as a ‘silent disease’ because patients typically do not exhibit noticeable clinical symptoms until a fracture occurs^{(Reference Zhou, Huang and Chen111)}. The pathogenesis of OP is closely related to multiple factors, including an imbalance in bone remodelling, loss of minerals (particularly calcium) and abnormal regulation of the processes of bone formation and bone resorption^{(Reference Ayers, Kansagara and Lazur55,Reference Wen, Xu and Zhang110)} . n-3 PUFA, in addition to their anti-inflammatory effects, regulate bone metabolism through various mechanisms, promoting bone health^{(Reference Sharma and Mandal112,Reference Abshirini, Ilesanmi-Oyelere and Kruger113)} (Table 4).

Table 4. Application of n-3 PUFA in osteoporosis

BMSC, bone marrow stromal cells; OPG:RANKL, osteoprotegerin: receptor activator of NF-κB ligand.

Research progress of n-3 PUFA in fracture

Fracture^{(Reference Tai and Chen122)} refers to the rupture or breakage of bone continuity, typically caused by direct or indirect external forces. It not only affects the structural integrity of the bone but may also be accompanied by soft tissue damage, haematoma and nerve injuries^{(Reference Tai and Chen122–Reference Casas and Gonzalez124)}. The treatment for fractures varies depending on the nature, location and severity of the fracture^{(Reference Steinmetz, Brgger and Chauveau125–Reference Herterich, Baumbach and Kaiser131)}. The preventive effect of n-3 PUFA on fractures primarily involves promoting bone formation and inhibiting bone resorption as part of anti-OP therapy. Several studies have verified this preventive effect^{(Reference Sadeghi, Djafarian and Ghorabi132,Reference Martyniak, Wei and Ballesteros133)} . In fracture treatment, the application of n-3 PUFA is generally used as an adjunctive therapy. Research by Kafadar et al. ^{(Reference Halil Kafadar, Yalçın and Çakar134)} indicated that the combined use of n-3 PUFA and vitamin D₃ had a positive effect on fracture healing.

In mechanistic studies, Chen et al. ^{(Reference Chen, Cao and Sun135)} found that in a mouse femur fracture repair model, n-3 PUFA promote fracture healing by enhancing the expression of insulin-like growth factors, reducing the formation of PGE₂, increasing calcium absorption and decreasing the release of inflammatory factors from osteoclasts. Huang et al. ^{(Reference Huang, Vi and Zong52)} demonstrated through animal experiments that treatment with n-3 PUFA-derived MaR1 significantly improved tibial fracture healing, which was manifested by reduced cartilage formation and increased bone deposition, thereby enhancing the stiffness of the bone structure. In the early stages of treatment, MaR1 reduced the number of pro-inflammatory macrophages in the callus and lowered the levels of inflammatory biomarkers. Subsequently, it promoted osteoblast differentiation and enhanced the osteogenic activity of bone marrow stromal cells.

In addition, n-3 PUFA also have certain effects on fracture-related complications. Zhang et al. ^{(Reference Zhang, Terrando and Xu136)} found through clinical studies that specialised pro-resolving mediators derived from DHA can promote the resolution of acute inflammation and effectively inhibit neuropathic pain caused by tibial fractures. Zheng et al. ^{(Reference Zheng, Jia and Li137)} also demonstrated through clinical research that daily supplementation of n-3 PUFA can reduce the risk of pulmonary embolism and symptomatic deep vein thrombosis after fracture surgery, without increasing the risk of bleeding.

Research progress of n-3 PUFA in sarcopenia

Sarcopenia^{(Reference Cruz-Jentoft and Sayer138)} is a chronic condition characterised by the loss of muscle mass and strength, which is age-related and commonly observed in elderly populations. Patients with sarcopenia often experience mobility difficulties, which can significantly affect their daily lives. Early identification and active interventions, such as exercise, nutritional support and pharmacological treatments, can significantly improve the progression of sarcopenia and enhance the quality of life for the elderly^{(Reference Sayer and Cruz-Jentoft139–Reference Sayer, Cooper and Arai141)}. In recent years, n-3 PUFA have garnered increasing attention in the treatment and prevention of sarcopenia. Their anti-inflammatory properties, ability to promote muscle synthesis and enhance muscle strength make them an effective adjunctive therapy^{(Reference Jimenez-Gutierrez, Martínez-Gómez and Martínez-Armenta142–Reference Bird, Troesch and Warnke144)}. The specific mechanisms of action are summarised in Table 5.

Table 5. Mechanisms of n-3 PUFA in sarcopenia

mTOR, mammalian target of rapamycin.

Research progress of n-3 PUFA in spinal degenerative diseases

Spinal degenerative diseases (SDD)^{(Reference Zhao, Ma and Han163)}refer to a group of conditions involving the gradual degeneration of the spine and its components, including intervertebral discs, vertebrae and spinal joints. These diseases typically develop with age and may be influenced by genetic, environmental and lifestyle factors. The symptoms of SDD vary depending on the specific location and severity of degeneration but usually include pain, stiffness and limited range of motion. As the disease progresses, nerves may be compressed, leading to radicular symptoms. In severe cases, compression of the spinal cord may occur, causing symptoms such as sensory loss, limb weakness, incontinence and even paralysis^{(Reference Bumann, Nüesch and Loske164–Reference Witiw and Fehlings167)}.

Currently, research on the application of n-3 PUFA in SDD is relatively limited. However, some preliminary studies suggest that n-3 PUFA may have a positive effect on the treatment of intervertebral disc degeneration. A study by NaPier et al. ^{(Reference NaPier, Kanim and Arabi168)} found through a rat model that n-3 PUFA dietary supplements can reduce systemic inflammation by lowering the AA:EPA ratio in serum, potentially offering protective effects against the progression of intervertebral disc degeneration. Similarly, Shang et al. ^{(Reference Shang, Ma and Zhang169)} verified this effect through cell experiments and found that the protective role of DHA on the intervertebral disc may be exerted by regulating the expression of long non-coding RNA nuclear-enriched abundant transcript 1, thereby exerting its anti-inflammatory effects and reducing extracellular matrix degradation in nucleus pulposus cells caused by oxidative stress, ultimately slowing the pathological progression of intervertebral disc degeneration.

The dorsal root ganglion is a key pathway for sensing external stimuli. In the case of lumbar disc prolapse, degenerated nucleus pulposus tissue compresses the nerve root, leading to increased and prolonged infiltration of macrophages in the dorsal root ganglion. This can alter the function of neurons, causing excessive neural activation, which ultimately results in persistent pain or sensory abnormalities^{(Reference Naratadam, Mecklenburg and Shein170,Reference Lu, Chen and Jiang171)} . A study by Manzhulo et al. ^{(Reference Manzhulo, Ogurtsova and Lamash172)} using an animal model concluded that DHA can effectively alleviate neurogenic pain in SDD by inhibiting the response of satellite glial cells in the dorsal root ganglion, reducing the expression of the pro-apoptotic protein p53 and promoting neuroprotective effects in the dorsal root ganglion. Additionally, a study by Wang et al. ^{(Reference Wang, Li and Wang173)} using an lumbar disc prolapse rat model showed that mechanical and thermal hypersensitivity, increased inflammatory cytokines IL-1β and IL-18 levels and nerve root pain induced by activation of the NLRP3 inflammasome caused by nucleus pulposus exposure could all be significantly reversed by MaR1 produced from n-3 PUFA metabolism. This indicates that n-3 PUFA not only alleviate the early damage caused by lumbar disc prolapse-induced changes but also promote long-term nerve repair and functional recovery.

In summary, the application of n-3 PUFA in SDD holds great promise, particularly in alleviating inflammation, oxidative stress and promoting nerve repair. These potential benefits highlight the therapeutic value of n-3 PUFA in the management of SDD and related conditions.