Medicinal plants' proposed nanocomposites for the management of endocrine disorders.

In addition to the various ailments and physiological disorders that can disturb the balance of thyroid hormones, it is good to highlight that continuous exposure to specific environmental factors such as pesticides, herbicides, fungicides, and insecticides are considered serious risk factors for triggering thyroid diseases. This is due to the disruptions in the endocrine system, inhibition of thyroidal iodine uptake, interference in thyroid hormone receptors, blockage in transport proteins, interruptions in iodothyronine deiodinases activity, acceleration in thyroid hormone clearance, weakening the thyroid hormone uptake and its activity in the target cells ( Nagarathna and Jha, 2013 ). Hence, researchers are currently highly attentive to phytochemicals which act as natural thyroid hormone analogs or even as modulators for the nuclear receptors, to replace or support synthetic compounds. This exploration of agonists, antagonists, ligands, co-repressors, and co-activators components is a promising therapeutic target for managing thyroid disorders ( Taïbi et al., 2021 ). Moreover, it has been recommended to be utilized as a concoction of natural products in combination with chemical drugs, in order to optimize the therapeutic effects ( Abderrahim et al., 2019 ). Nigella sativa is the furthermost medicinal plant cited as an anti-hypothyroidism agent, owing to the main bioactive ingredient of its essential oil thymoquinone. According to a recent animal study, this mixture of essential oils might be beneficial as adjuvant therapy for improving thyroid hormone levels by reducing oxidative stress due to the potent antioxidant effect of thymoquinone. This compound is responsible for normalizing the abnormalities of thyroid hormones in both hypothyroidism and hyperthyroidism models. It has significantly amplified the total antioxidant capacity, reduced nitric oxide, and elevated total triiodothyronine (TT3) levels in hypothyroidism. On the other hand, it has declined TT3 levels in the hyperthyroidism animal group ( Avci et al., 2021 ). Besides, another recent study reported that this essential oil's therapeutic effects against thyroid damage were induced by aluminum chloride. Treatment with N. sativa seed oil has facilitated stimulating the regeneration of the epithelial cells surrounding the thyroid gland follicles, and improved TT3 levels as well as the histological features of the thyroid gland impaired by aluminum chloride ( Mekkey, 2021 ). It was also reported that the daily consumption of N. sativa was effective against hypothyroidism in Hashimoto’s thyroiditis patients due to the potent antioxidant properties of this plant ( Farhangi et al., 2016 ). It is noteworthy that, thymoquinone, the main bioactive component of N. sativa, is also found in Thymus vulgaris ( Taborsky et al., 2012 ) and Origanum ( Ahmad et al., 2019 ) which also were suggested as potential therapeutic choices for hypothyroidism. Nonetheless, thymoquinone’s poor bioavailability has limited this plant’s clinical application. Consequently, nanotechnology was suggested to overcome this problem and it has been utilized to treat various other diseases ( Hannan et al., 2021 ). The main bioactive component, thymoquinone (TQ), was investigated using several nanoparticle formulations to test its potential against different diseases. For instance, oral administration of glycyrrhizin with polymeric nanoparticles in combination with TQ loaded into polymeric nanocapsules displayed a significant anti-hyperglycaemic effect. However, these nanoformulations when applied independently failed to display any encouraging pattern in the diabetes parameters being studied ( Rani et al., 2019 ). Several other nanoparticles formulations have also demonstrated promising therapeutic benefits of TQ in the treatment of different cancers ( Bhattasharya et al., 2020 ; Fathy, 2020 ; Nasri et al., 2020 ; Ramzy et al., 2020 ), as a wound-healing agent ( Negi et al., 2020 ), as an anti-epilepsy agent ( Ahmad et al., 2020 ) and to treat depression ( Alam et al., 2020 ; Fahmy et al., 2020 ). Yet, none of those formulations was investigated against hypothyroidism. Hence, evaluating the effectiveness of nanoformulations in hypothyroidism experimental models is highly recommended. Citrus flavanones such as naringenin and hesperetin are the main active components in these plants. It has been reported that naringenin increased the serum thyroid-stimulating hormone (TSH) in old-aged rats, showing more potency compared with hesperetin within the pituitary-thyroid axis. Nevertheless, both compounds maintained the capacity of the thyroid gland to produce thyroxine (T 4 ) which is reduced in old-aged rats ( Miler et al., 2017 ). The large hydrophobic ring structure of naringenin is the reason for its minimal bioavailability and low solubility. This problem has inquired the development of innovative naringenin nanoparticle strategies. oOne of these promising applications has used a simple nanoprecipitation procedure with a hydrophilic carrier, polyvinylpyrrolidone (PVP), enabling the usage of a lower dose of naringenin with improved bioavailability ( Kumar and Abraham, 2016 ). On the other hand, gold ( Krishnan et al., 2017 ) and silver ( Trendafilova et al., 2020 ) nanoparticles were also used to enhance the effect of hesperetin by solving the bioavailability problem related to the instability and low solubility, and were evaluated in many experimental models such as cancer ( Ersoz et al., 2019 ), inflammation ( Abdou and Elkader, 2021 ), and Alzheimer’s disease ( Babylon et al., 2021 ), while the thyroidal effect of these nanoparticle formulations remains to be investigated. Costus pictus, also known as insulin plant, fiery Costus , and spiral flag ( Selvakumarasamy et al., 2021 ) is widely used in the traditional management of diabetes, and its methanolic extract has shown synergistic antidiabetic effect with metformin in the alloxan-induced diabetic model ( Naik et al., 2022 ). The main active compounds in this plant are alpha and beta amyrin. Moreover, it has been revealed that C. pictus extract has potentially restored thyroid hormone levels in hypothyroidism rats induced by propylthiouracil. This animal model is usually associated with high rates of plasma total cholesterol. However, treatment with the plant leaf extract significantly reduced plasma levels of cholesterol as well as the inflammatory markers, blocked oxidative stress in the tissues, and inhibited renal and hepatic damage often observed in hypothyroidism. It is found that alpha and beta amyrins are the main active compounds thought to be responsible for the therapeutic effects ( Ashwini et al., 2017 ). Interestingly, silver nanoparticles of C. pictus methanolic extracts have shown a surge in phenolic and flavonoid contents and increased antioxidant activity ( Selvakumarasamy et al., 2021 ). Therefore, evaluating the nanoformulations on the hypothyroidism animal model is recommended. The most active compounds in ashwagandha are withanolides, alkaloids, organic acids, and fatty acids ( Abdel-Wahhab et al., 2019 ). It was revealed that the high contents of antioxidant compounds of ashwagandha methanolic extract significantly contributed to improving the tissue in propylthiouracil induced hypothyroidism, elevating the levels of thyroid hormones, and reducing oxidative stress. This was shown by a significant decrease in the serum levels of TSH levels and an increase in T 3 , free T 3 , and free T 4 , as well as total T 4 hormones versus the untreated hypothyroidism rat group. In addition, the hypothyroidism rat group treated with ashwagandha extract exhibited lower serum concentrations of glucose and Il-6 and higher levels of blood haemoglobin, GPx, GSH, and Na + /K + -ATPase. However, this plant was also reported to have a beneficial effect on hyperthyroidism, which might indicate its modulatory effects on thyroid hormones ( Abdel-Wahhab et al., 2019 ). According to a recent promising study, nanoparticle-based technology was applied to achieve a higher efficacy of this plant against cancer by employing nanoparticles using an anti-mortalin antibody (MotAb) and folic acid ( Wang, 2021 ). This might open the door for similar applications of nanoformulae to modulate thyroidal hormones. The crude polysaccharides fraction and lactones fraction of Atractylodes macrocephala rhizome were found to be the most potent components of the plant. A. macrocephala rhizome was recommended for hypothyroidism treatment due to its effects in enhancing energy and substance metabolism, mostly by interacting with the signalling pathway of thyroid hormone, tricarboxylic acid (Krebs) cycle, glycolysis/gluconeogenesis, and fatty acid metabolism. Therefore, A. macrocephala rhizome directly affects thyroid hormone receptors A and B, increases the levels of T 3 and T 4 , promotes glycolysis, and triggers the Krebs cycle to stimulate energy metabolism, as well as fatty acid metabolism in hypothyroidism rats as a suggested pathway for hypothyroidism treatment ( Chen et al., 2021 ). The effect of nanostructured particles lipid carriers of polysaccharides of A. macrocephala was investigated in vitro on bone marrow, showing a greater immunological stimulatory effect ( Liu et al., 2018 ). However, to date, none have reported any findings concerning nanoformulations of this plant against thyroid hormone disorders. Recently, Scutellaria baicalensis was proposed to suppress T 3 , T 4 , as well as the adrenergic activity in levothyroxine-induced hyperthyroid in animal models by increasing serum TSH, downregulating deiodinase-1, and upregulating thyroxine-binding globulin expression. This regulatory effect of thyroid hormone is thought to be responsible for S. baicalensis efficacy in the treatment of cardiovascular and anxiety disorders ( Kim and Lee, 2019 ). Interestingly, S. baicalensis is one of the main herbs of Ahnjeonbaekho-tang (AJBHT) which is clinically reported as an effective medicinal plant in the treatment of Graves’ disease ( Kim et al., 2005 ) by controlling the expression of cyclic AMP. This anti-thyroid effect of AJBHT is attributed mainly to the compounds daidzein and baicalein which are considered the most active components. On the other hand, zinc oxide nanoparticles have shown a potent scavenging activity ( Chen et al., 2019 ). However, such a formulation against thyroid gland dysfunction is not discovered yet and should be explored. Lycopus europaeus extracts decreased thyroid gland weight, and reduced the TSH leading to a reduction in the levels of T 3 and T 4 , in addition to increasing iodine absorption and storage and inhibiting the progress of goiter in animal models; with a blocking effect on adenylate cyclase, resulting in an inhibitory effect to the extreme thyroid stimulation. This extract has also reduced the luteinizing hormone levels. This confirms the central action nature of this plant. This effect is justified by the presence of rosmarinic acid as a major active compound ( Al-Snai, 2019 ). On the other hand, L. virginicus extract has been recommended as a potent anti-thyroidal medicinal plant to control hyperthyroidism. It has been reported to have a remarkable inhibitory effect on the progress of Grave’s disease, by reducing thyroid hormone and TSH levels. It also inhibited the conversion of T 4 in the target tissues ( Kaplan and Dosiou, 2021 ). This effect is most probably due to the presence of phenolic compounds such as rosmarinic acid, chlorogenic acid, and luteolin-7β-glucuronide, which are the active constituents of this plant extract ( Winterhoff et al., 1988 ). Also, a very recent noteworthy study has used rosmarinic acid in gold-based nano-formulation to treat anaplastic thyroidal carcinoma, showing promising results ( Amaral et al., 2021 ). The extract of Annona squamosa seeds has been highlighted for its likely therapeutic effects in managing hyperthyroidism in the animal model not only by reducing the serum levels of T 3 and T 4 and inhibiting the activity of both 5’-mono-deiodinase and hepatic G-6-Pase enzymes, but also by reducing the hepatic lipid peroxidation and improving the activities of superoxide dismutase as well as catalase. This indicates the safety and antiperoxidative efficacy of this plant, which is mostly related to the presence of the main active component, quercetin ( Panda and Kar, 2007 ). However, to date, the nanoformulation of this plant extract was only investigated against cancer ( Fadholly et al., 2020 ). It was reported by animal and in vitro studies that the aqueous extract of rosemary has a remarkable suppressive effect on the thyroid gland leading to lower secretion of T 4 and T 3 serum levels. This is due to the direct effect of rosmarinic acid which has the ability to block the immunoglobin effects on TSH receptors, decreasing the peripheral conversion of thyroid hormones, reversing the hyperplastic changes of the thyroid parenchyma, in addition to the anti-oxidative activity of this plant extract which is mostly attributed to phenolic diterpenes, carnosic acid and carnosol ( Kasim et al., 2020 ). However, these phenolic compound molecules are highly susceptible to degradation by enzymatic activities, heat, light, oxidants, pH, and water. Hence, it was suggested that their stability should be maintained by being protected via encapsulation in silk fibroin nanoparticles before its application. This method has augmented the antioxidant activity of rosemary, owing to the efficacy of the encapsulation in stabilizing the phenolic compounds and improving their delivery ( Hcini et al., 2021 ).

Endocrine disorders, especially diabetes mellitus, and thyroidal and hormonal imbalances, are gaining more scientific attention because of their critical complications and rising prevalence. Treatments of such ailments are mainly focused on the use of synthesised small molecules and hormone-replacement therapies which can manage or limit further impediments. The search for novel plant-derived treatments has been seen to have similar pharmacological effects, and sometimes better, besides the reduced cytotoxicity and adverse effects of the conventional treatments. Despite that, some extracts of medicinal plants or their isolated secondary metabolites were effective in preventing such diseases or impeding their progress. These medicinal plants are found to have numerous potential pharmacological effects by acting on diabetes mellitus type-1 and -2, insulin resistance, hyper and hypogonadism, polycystic ovarian syndrome, dysmenorrhea, male and female fertility, and hyper- or hypothyroidism. To our knowledge, not all the covered medicinal plants have been proceeded with in vivo or clinical studies. Thus, more scientific research is required to scrutinize the effects of these plants, plus, other species of the same genera, which might have similar or more potent activities. Moreover, we examined some nano-formulated extracts and isolated natural products which have been reported either for the discussed disorders or other types of diseases. Similarly, these nanoformulations require further studies on their targeted biological systems which in turn can lead to better future studies and prospects.

All authors listed have significantly contributed to the development and the writing of this article. Dr. Raghdaa Hamdan Al Zarzour was supported by 10.13039/501100002385 Ministry of Higher Education , Malaysia [FRGS/1/2021/SKK0/USM/02/27]. No data was used for the research described in the article. The authors declare no conflict of interest. No additional information is available for this paper.

Nowadays endocrine disorders have become a more prevalent complex global health problem which increases the economic burden on governments worldwide due to their serious complications. According to a recent study published in 2020, 10% of the worldwide population are suffering from diabetes mellitus, around 5% suffers from hypothyroidism, 0.2–1.3% are affected by hyperthyroidism, in addition to more than 200 million females are diagnosed with osteoporosis ( Pal and Bhadada, 2020 ). On the other hand, although the therapeutic agents managing endocrine disorders are overlooked, they are vital elements within the protective measures for patients suffering from diabetes mellitus, thyroid disorders, infertility, and adrenal gland diseases. In addition to the conventional approaches in this field, medicinal plants acquire exceptional consideration from professionals to develop potent phytomedicine for optimizing curative outcomes. Therefore, the rising interests of researchers in nutrition and natural products are fast rising to the frontier of research priorities. Herein, this review provides examples of the most effective medicinal plants used for the management of common endocrine diseases taking into account the green-formulated nanoparticles, which are more effective than the crude extracts. Their higher efficacy can be attributed to their higher surface area and better solubility, which in turn enhance the therapeutic activity and thus overcome the limitations of insolubility, low bioavailability, and incapability to reach their sites of action ( Desai et al., 2012 ). A profound summary about these medicinal palnts, their active constituents, and reported nanoformulations can be found in Table S1 (Supplementary Materials).