The physicochemical and functional features of sea buckthorn berry pomace powder (PP) justify its usage as a fiber-rich dietary additive (16). PP had strong hydration qualities in addition to having a high protein content (21.09 g/100 g) such as 4.24 g/g and 9.98 mL/g of water-holding capacity and swelling capacity, respectively. The functional potential of the tested PP was determined by its in vitro hypoglycemic and hypolipidemic qualities, which were shown to be comparable to and, in some cases, superior to those of other dietary fiber powders made from by-products of the processing of fruits and vegetables. Berry PP had a cholesterol-binding capacity of 21.11 to 23.13 mg/g (16). Traditionally, sea buckthorn berries also serve as a Chinese medicine with multiple bioactivities (18). A recent bioassay-guided investigation applied to seek the hepatoprotective and hypolipidemic ingredients has been able to isolate three new (10 → 10’’)-biauronlignans (1–3), three new 10-(4’’-hydroxy-benzyl)-auronlignans (4–6), three new 10-O-β-D-glucopyranosyl-auronlignans (7–9), and eleven known auronlignan derivatives (10–20). Their structures have been established using lengthy and thorough infrared (IR), ultraviolet/visible (UV/Vis), nuclear magnetic resonance (NMR), and mass spectroscopy (MS) spectrum investigations, and these results have been compared with the published references. While compounds 2, 5, 8, and 12 displayed mild pancreatic lipase activity inhibition and reduced the moderately FFA-induced lipid accumulation in HepG2 liver cells, compounds 1, 4, 7, 11, 15, and 19 demonstrated moderate hepatoprotective activities against the damage in acetaminophen-induced HepG2 cells (37). In addition, structural data of a homogeneous polysaccharide from sea buckthorn (SBP-1-A) has recently been described, and it was discovered that SBP-1-A has a backbone of around 3,4).-β-l-Rhap-(1 → 4)-α-d-GalAp-(1 → with side chains made up of α-l-Araf, β-d-Galp, β-d-Glcp, and α-d-Glcp, of which the arabinose, glucose, and galactose residues have been identified as the primary monosaccharide compositions with a percentage surpassing 92%. Furthermore, the protein-free polysaccharide fraction (SBP-1) obtained after isolation of crude SBP showed an outstanding anti-obesity effect. According to the findings, consuming SBP-1 might increase the expression of peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1α), uncoupling protein 1 (UCP-1), and PR domain containing 16 (PRDM 16) in adipocytes, activate brown adipocytes, and boost thermogenesis, which would prevent fat buildup and weight gain. It is crucial to remember that the type of preparation, its chemical composition, and its concentration all appear to have an impact on how sea buckthorn preparations affect hemostasis. The sea buckthorn preparations seem to be excellent regulators of hemostasis, particularly blood platelet function, due to their high phytochemical contents, notably phenolic components. Additionally, it is still uncertain how much of these preparations should be used for prophylaxis and therapy, and recommendations for using sea buckthorn preparations are frequently based on sparse clinical investigations. Thus, more randomized clinical studies with bigger samples are required, particularly those including healthy volunteers and those with the greatest cardiovascular risk factors. Additionally, the effects of several sea buckthorn components on hemostasis, including fibrinolysis and coagulation systems as well as blood platelet activities, should be studied in these trials. Since there is currently no reliable information about the anti-hemorrhagic effectiveness of sea buckthorn preparations in either people or animals, it is also crucial to investigate the role of various sea buckthorn products in the prevention and treatment of cardiovascular disorders (50). Recently, phytoprostanes in sea buckthorn juices have been discovered, and their quantities are highly connected with the capacity to reduce inflammation through inhibition of the 15-lipoxygenase enzyme (23). Due to the presence of possible inhibitors of α-amylase, α-glucosidase (tocopherols, tocotrienols, and certain amino acids), and pancreatic lipase (xanthophylls), sea buckthorn juice can be an intriguing anti-diabetic and anti-obesity diet. Juices act more effectively in lowering neurological alterations due to the presence of phytoprostanes, phytofurans, tocopherols, tocotrienols, and amino acids, making them possible anti-aging agents in the prevention of Alzheimer’s disease, the most prevalent kind of dementia. Juice from sea buckthorn may be crucial in the body’s fight against diseases brought on by free radical assault (23). Sea buckthorn insoluble dietary fiber (IDF) can be modified to increase its in vitro hypoglycemic capacity. Examples of these modifications include IDF, milled insoluble dietary fiber, and co-modified insoluble dietary fiber. Ball milling, as well as ball milling coupled with cellulose treatment reportedly enhanced the characteristics of IDF which provide a foundation for the extensive utilization of sea buckthorn resources (27).

Maslinic acid functions via the nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and erythroid 2-related factor 2 (Nrf2) signaling pathways, whereas oleanolic and asiatic acids act via the NF-κB, mitogen-activated protein kinase (MAPK), and Nrf2 signaling pathways to exert anti-inflammatory effects on macrophages. These three substances can be employed as natural anti-inflammatory dietary supplements because they exhibited specific inhibitory effects on the LPS-induced inflammatory response in vitro. However, more research is necessary, including in vivo investigations, to encourage the usage of sea buckthorn-derived products (42). The active components of sea buckthorn that are responsible for the biological effects haven’t yet been fully identified. The flavonoids quercetin and isorhamnetin, a 3′-O-methylated metabolite of quercetin, are thought to be principally in charge. There is proof that isorhamnetin can prevent cells from proliferating (42), promote apoptosis and mitigate tumor development (51–53), suppress inflammatory processes (33, 42, 54), improve cognitive functions (54), and affect numerous metabolic processes (33). The anti-cancer (29, 55), cardioprotective (56), and anti-obesity (57) effects of quercetin have been reported, too. Presence of several flavonoids including isorhamnetin (54, 58), auronlignan (18), polysaccharides (37, 59), and dietary fibers (16, 27) indicate towards the anti-cholesterol and anti-obesity effects of sea buckthorn. Thus, a number of physiological and pathological processes can be targeted by sea buckthorn and its bioactive compounds. Nevertheless, a majority of the studies on sea buckhorn action were performed for medicinal purposes in pathological conditions, including on cancer cells. Therefore, obtained information could potentially be helpful for management of tumors, but the biological value of the information is limited due to the fact that whether and how the dietary consumption of sea buckwheat could affect healthy organism and its cells. Even the applicability of sea buckthorn for treatment of cancer is yet to be sufficiently demonstrated by clinical trials. Furthermore, sea buckthorn constituents responsible for the effect of the whole plant remains to be identified. The molecules, which might be responsible for sea buckhorn effect have been hypothesized on the basis of their presence in the plant and the similarity of their as well as whole plant effects. But there isn’t a single thorough experiment that has compared these impacts. Furthermore, there is no conclusive evidence of a functional connection from the similarities of the effects. Therefore, extensive research is needed to identify the components of sea buckthorn that are responsible for its biological and therapeutic effects.

Although the evidence for each of these processes is weak and the interactions between these mechanisms are poorly understood, extracellular and intracellular modes of action of sea buckthorn and its constituents on cells have been postulated. Nevertheless, it has been proposed that the ability of sea buckthorn to prevent and to treat infections and cancer (15) as mentioned previously can mainly be due to its antioxidant (29), anti-inflammatory (31), antiviral (32), antimicrobial (24, 33), and antibacterial (34, 35) properties. Numerous clinical disorders, including allergies, cancer, and many others, are mostly driven by inflammation. By stimulating Nrf2-dependent pathways, sea buckthorn’s anti-inflammatory effects may be mediated (60). An effective anti-inflammatory target, the heme oxygenase-1 (HO-1) axis, is known to be regulated in part by Nrf2. Nrf2 is essential for regulating the production of antioxidant genes, which in turn have anti-inflammatory effects (60). The protective action of sea buckthorn polysaccharide is linked to the activation of the Nrf-2/HO-1-SOD-2 signaling pathway (36). Recent investigations revealed a relationship between the production of additional inflammatory mediators including the NF-κB pathway and macrophage metabolism and the Nrf2/antioxidant response element system (60). It’s interesting to note that a sea buckthorn polysaccharide has been shown to protect the liver against acetaminophen (APAP)-induced liver damage in rats. Enzymes like alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been able to be reduced by it (36). The antioxidant qualities of sea buckthorn’s components have been used to describe a variety of its therapeutic benefits. In the liver, brain, and plasma, for instance, sea buckthorn supplementation elevated glutathione (GSH) and GSH-Px levels and the production of nitric oxide (NO) and the inducible nitric oxide synthase (iNOS), which was linked to lessened liver damage (36) and oxidative and nitrosative stress in liver and brain of rats (61). Antioxidant chemicals, especially phenolic components such as flavonoids kaempferol, isorhamnetin, and quercetin, are responsible for sea buckthorn’s antitumor action. These flavonoids defend against oxidative stress, which can cause cancer and genetic alterations in cells (50, 62). The formation of ROS was reduced along with the reduction in glioma cell viability after sea buckthorn extract treatment, at the very least (26). Masoodi et al. (63) has proposed that sea buckthorn reduces the production of a certain antigen and inhibits cellular growth in prostate cancer cells. Additionally, rat glioma cells’ fast multiplication was suppressed by sea buckthorn leaf extract, which is thought to have done so via causing the first stages of cell death. The increased expression of B-cell lymphoma 2/Bcl-2-associated X protein (Bcl-2/Bax) and acetaminophen-induced inhibition of c-Jun N-terminal kinase phosphorylation are further signs of sea buckthorn’s impact on cytoplasmic apoptosis (36). The pro-apoptotic Bax gene expression was increased by sea buckthorn extracts, and its localization, accumulation, and translocation in the nuclei were all encouraged (26). However, as demonstrated in human retinoblastoma cells, the quercetin-induced rise in cytochrome c levels together with the activation of caspase-3 and caspase-9 results in apoptosis in cancer cells (64). Additionally, it was shown previously that buckthorn procyanidins might cause cell death in a dose-dependent way (65). It is possible that these procyanidins might block intracellular fatty acid synthase (FAS) activity and cause human breast cancer cells to undergo apoptosis. At least, sea buckthorn procyanidins were discovered to restrict the proliferation of cancer cells, and FAS is a critical enzyme for de novo long-chain fatty acid production, which is present in high amounts in cancer cells (65). Several flavonoids (especially isorhamnetin) affecting a number of enzymes regulating fat synthesis and metabolism can be responsible for their hypolipidemic, cholesterol-lowering, and anti-obesity effects (58). In addition, the anti-obesity effects of sea buckthorn polysaccharides could be due to their stimulatory action on brown adipose tissue and thermogenesis inducing its “burning” (37). Finally, sea buckthorn’s anti-diabetic and anti-obesity effects can be attributed to the ability of its dietary fibers to reduce glucose production and metabolism via suppression of glucose adsorption, glucose diffusion inhibition, starch digestion inhibition, starch pasting interference, and α-amylase activity (27). Androgen receptors are the next potential mediator of sea buckthorn’s actions on tissues that are dependent on hormones. These receptors control the expression of androgen-responsive genes through ligand-dependent transcription factors. The target androgen responsive genes cannot be activated, and prostate cancer growth cannot be stopped if the androgen receptor is somehow kept in the cytoplasm and its shuttling into the nucleus is blocked. Prostate cancer cells’ androgen receptors have been shown to be affected by the administration of sea buckthorn leaf extracts, which was correlated with the suppression of genes that respond to androgens, cellular growth, and survival of these cells (63). The beneficial effects of sea buckthorn on spermatogenesis may be due to its effect on androgen receptors. By increasing spermatogonia proliferation, stem cell survival, and lowering sperm abnormalities, sea buckthorn therapy enhanced spermatogenesis and had a protective effect against the negative effects of gamma radiation (66). Available literature demonstrates a number of signaling molecules and mechanisms mediating sea buckthorn’s actions on various targets in the organism and/or their pathologies at a cellular level. Some of their mediators could be specific for particular target cells or organs (e.g., steroid hormones for steroid-dependent processes). Other mediators could be more pervasive, such as those that influence cell proliferation, apoptosis, and oxidative processes. Additionally, although they haven’t been fully explored yet, functional hierarchy linkages between the mediators of sea buckthorn’s effects are feasible. Last but not least, studies of the effects of sea buckthorn and its mediators have primarily used cell cultures. As a result, appropriate in vivo research should be used to confirm the findings gained using such models.

One of the most potent active components in sea buckthorn berries is isorhamnetin, a 3′-O-methylated metabolite of quercetin that has a wide range of pharmacological effects, including anti-cancer ones. The modulation of PI3K/AKT/PKB, NF-κB, MAPK, and other signaling pathways, as well as the production of associated cytokines and protein kinases involved in controlling cell apoptosis and proliferation, are all part of the mechanisms of action (53, 54). Through the activation of apoptotic genes and apoptosis and the downregulation of oncogenes, isorhamnetin can inhibit the development of cancer. Isorhamnetin has also been demonstrated to inhibit the PI3K-AKT-mTOR pathway (phosphatidylinositol 3-kinase, protein kinase B, and the mammalian target of rapamycin), which in turn inhibits the proliferation of cancer cells by inducing cell cycle arrest at the G2/M phase. Additionally, isorhamnetin can increase the production of cyclin B1 protein while decreasing the phosphorylation levels of AKT, phosph-p70S6 kinase, and phosph-4E-BP1 proteins (52). Additionally, isorhamnetin can enhance liver and kidney functioning by lowering blood levels of urea nitrogen, AST, and ALT. Additionally, by preventing the dimerization of the toll-like receptor 4, isorhamnetin can reduce infection-induced liver and kidney inflammation as well as inflammation-induced cell death (33). Some physiological actions of isorhamnetin could be mediated by an interplay of several intracellular signaling pathways. For example, isorhamnetin can mitigate the adverse effect of obesity on cognitive functions by suppression of neuroinflammation via downregulation of MAPK- and NFkB-dependent pathways (54). Quercetin is another ingredient that may contribute to the benefits of sea buckthorn. Quercetin’s ability to influence intracellular signaling pathways that regulate cell proliferation and apoptosis may be the cause of its anti-cancer effects (29, 55, 67). It can cause cell cycle arrest through suppression of its promoters cyclin B1 and MAPK/ERK1/2 and activation of transcription factor p53. It can also prolong DNA repair and promote apoptosis through inhibition of survivin, activation of transforming growth factor-β (TGF-β), PI3K/AKT/mTOR, Wnt/-catenin, NOTCH, sonic hedgehog signaling pathway (SHH), Janus kinas Additionally, quercetin can inhibit tumorigenesis by controlling VEGF and its receptors, which are the factors that stimulate tumor vascularization (55). The presence of quercetin, tannins, and other polyphenolic flavonoids in sea buckthorn extract, as well as their radical scavenging and anti-inflammatory properties, may be responsible for the protection of spermatozoa (66), and cardiomyocytes (56, 57). Some possible mechanisms of action of sea buckthorn and its bioactive components on cancer cells are summarized in Figure 2 . In fine, the literature concerning the mechanisms and/or mediators of action of sea buckhorn compounds isorhamnetin and quercetin indicate an existence of multiple pathways of these molecules on target cells. The key mechanisms of their action (e.g., related to cell proliferation, apoptosis, or oxidative stress) are like mechanisms of sea buckthorn whole plant’s effects. Nevertheless, it remains to be investigated whether the effects of the whole plant and its mechanisms

of action could be explained by the presence of only isorhamnetin and quercetin, or other constituents and their mechanisms of action could be involved in mediating sea buckthorn’s effects. Furthermore, the data concerning these mediators, which were obtained predominantly by in vitro experiments, require verification by corresponding in vivo studies.

There is no evidence accessible in scientific databases about the effects of entire sea buckthorn on ovarian functions. Dietary sea buckthorn oil did not influence bovine ovarian folliculogenesis, oocyte quality, or embryo developmental ability (68). Nonetheless, some physiologically active sea buckthorn elements have been shown to influence female reproductive processes. However, the direct impact of quercetin on fundamental ovarian cell processes (proliferation, apoptosis, and hormone release) may vary depending on the species (69). Quercetin also inhibits the development of human metastatic ovarian cancer cells and affects the intrinsic apoptotic mechanism (70–73). Isorhamnetin, another sea buckthorn component, can stimulate ovarian cell proliferation and estrogen release (52, 70), and suppress estrogen-dependent ovarian cancer development (70, 73). Other physiologically active components of sea buckhorn have also been proven to be advantageous to ovarian cancer cells. Apigenin, myricetin, and luteolin have been shown to cause apoptosis, decrease cell proliferation, limit cell invasion, and stop the cell cycle of ovarian cancer. Furthermore, apigenin, myricetin, and luteolin have been recommended as prospective ovarian cancer preventative and adjuvant therapy options (70, 74). Another sea buckthorn ingredient that can inhibit ovarian cancerogenesis is kaempherol. In cultivated ovarian cancer cells, it can at least trigger apoptosis and halt the cell cycle (70, 73, 75–77). Furthermore, kaempherol can inhibit angiogenesis in ovarian tumors (76). As a result, sea buckthorn components may influence ovarian cell proliferation, death, and hormone release. In ovarian cancer cells, on the other hand, sea buckthorn components can cause apoptosis, decrease cell proliferation, and stop the cell cycle. Nonetheless, the relevance of the collected data is restricted by the fact that the claimed effects on ovarian functions are primarily the product of in vitro investigations, with majority of these tests being done on ovarian cancer cells rather than healthy cells. There is a need for more information on the entire sea buckthorn’s activity on ovarian functions (including dysfunctions and malignant transformation) both in vitro and in vivo.

Traditionally, sea buckthorn has been used to treat gynecological diseases such as uterine inflammation and endometriosis. Its oil helps reduce the symptoms of endometriosis and uterine inflammation. These effects might be linked to the carotenoid, sterol, and hypericin content of the plant (55). Consumption of sea buckthorn extract or oil may also be beneficial in the avoidance of vaginal difficulties during menopause, which is associated with vaginal atrophy and the thinning and drying of the vaginal mucosa. Menopausal women who used sea buckthorn oil had better vaginal epithelial integrity and a higher vaginal health score. It has been proposed as an alternative to estrogen replacement therapy for postmenopausal women’s vaginal health (78). Furthermore, a novel vaginal gel containing sea buckthorn oil (Meclon Idra Alfasigma) has recently been registered. It appears to be a viable option as a local agent for alleviating symptoms of vulvovaginal atrophy (vaginal dryness, itching, and burning feeling) and enhancing sexual function in postmenopausal women (79). Sea buckthorn also has a high concentration of vitamins C and E. Infertile or subfertile women undergoing controlled ovarian stimulation may benefit from vitamin C and E supplementation in terms of uterine features, endometrial thickness, and endometrial blood flow. Furthermore, the antioxidant and anticoagulant properties of vitamins C and E are assumed to be responsible for the increase in fertility (80). In contrast to its effect on the ovary, sea buckthorn, and its components have been shown to have a therapeutic effect on the management of gynecological problems such as uterine inflammation, endometriosis, and signs of vulvovaginal atrophy in postmenopausal women. We summarized the important effects in Table 2 . However, the effect of sea buckthorn on the healthy vagina and uterus has not been thoroughly established. Furthermore, the components of sea buckthorn that affect these organs are mainly unknown. Even the role of vitamins in mediating the benefits of sea buckthorn is more or less theoretical and requires scientific validation.