Antioxidant effects of α-lipoic acid against epididymal oxidative damage in adult offspring rats exposed to maternal hypothyroidism stress.

It is well known that the epididymis promotes post-testicular sperm maturation events. However, its malfunction during congenital hypothyroidism is relatively less understood as compared to the testis. The present study evaluated the probable effect of α-lipoic acid on epididymal oxidative stress parameters in rats exposed to antithyroid drug, carbimazole during fetal period. Time-mated pregnant rats in unexposed and carbimazole (1.35 mg/Kg body weight exposed were allowed to deliver pups and weaned. At postnatal day 100, the F1 male pups were assessed for epididymal endpoints. Among the epididymal regions, significant elevation of lipid peroxidation levels, superoxide anion, and hydrogen peroxide contents with a concomitant reduction in the activity levels of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and reduced glutathione levels were observed in cauda epididymis of carbimazole exposed rats over controls. Significant elevation in sperm DNA fragmentation (comet assay), accelerated cauda epididymal sperm transit time and reduction in epididymal sialic acid content was observed in carbimazole exposed rats. RT-qPCR studies revealed that embryonic exposure to carbimazole resulted in down regulation of androgen receptor, nuclear factor eryrthoid 2 like 2, 5α-reducatse 1 mRNA levels, while up regulation of caspase 3 mRNA was observed in epididymal regions of rats. In addition, fetal exposure to carbimazole resulted in disorganization of cauda epididymal architecture in rats. Conversely, supplementation of α-lipoic acid (70 mg/Kg bodyweight) during PND 3 to 14 restored epididymal functions in carbimazole exposed rats and the ameliorative effects of lipoic acid could be attributed to its antioxidant and steroidogenic effects.

Metabolomic insights into the therapeutic mechanisms of costus (Saussurea costus (Falc.) Lipsch.) root extract in propylthiouracil-induced hypothyroidism rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Saussurea costus (Falc.) Lipschitz. is one of the most reputed medicinal plants as a traditional medicine in the Arab and Middle East regions in the treatment of thyroid disorders, however, more investigations are needed to fully understand its effectiveness and mechanism of action. AIM OF THE STUDY: The primary objective of the study was to assess the impact of Saussurea costus (COST) on the metabolic profiles of propylthiouracil (PTU)-induced hypothyroidism in rats. This involves a comprehensive examination of serum metabolites using UPLC/QqQ-MS analysis aiming to identify differential metabolites, elucidate underlying mechanisms, and evaluate the potential pharmacological effect of COST in restoring metabolic homeostasis. MATERIALS AND METHODS: Hypothyroidism was induced in female Sprague-Dawley rats by oral administration of propylthiouracil (PTU). UPLC/QqQ MS analysis of serum samples from normal, PTU, and PTU + COST rats was utilized for annotation of intrinsic metabolites with the aid of online Human metabolome database (HMDB) and extensive literature surfing. Multivariate statistical analyses, including orthogonal partial least squares discriminant analysis (OPLS-DA), discerned variations between the different groups. Serum levels of T3, T4 and TSH in addition to arachidonic acid (ARA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) levels in thyroid gland tissues; Phospholipase A2 group IIA (PLA2G2A), and lipoprotein lipase (LPL) in liver tissues were assessed by specific ELISA kits. Gene expression for key proteins of the primary evolved pathwayswere quantified by one-step qRT-PCR technique. Histopathological evaluation of thyroid gland tissue was performed by an investigator blinded to the experimental group using light microscope. RESULTS: Distinct clustering in multivariate statistical analysis models indicated significant variations in serum chemical profiles among normal, disease, and treated groups. VIP values guided the selection of differential metabolites, revealing significant changes in metabolite concentrations. Subsequent to COST treatment, 43 differential intrinsic metabolites exhibited a notable tendency to revert towards normal levels. Annotated metabolites, such as lysophosphatidylcholine (LPC), L-acetylcarnitine, gamma-glutamylserine, and others, showed differential regulation in response to PTU and subsequent S. costus treatment. Notably, 21 metabolites were associated with polyunsaturated fatty acids (PUFAs) biosynthesis, arachidonic acid (ARA) metabolism, and glycerophospholipid metabolism exhibited significant changes on conducting metabolic pathway analysis. CONCLUSIONS: COST improves PTU-induced hypothyroidism by regulating biosynthesis of PUFAs signified by n-3/n-6, ARA and glycerophospholipid metabolism. The study provides us a novel mechanism to explain the improvement of hypothyroidism and associated dyslipidemia by COST, depicts a metabolic profile of hypothyroidism, and gives us another point cut for further exploring the biomarkers and pathogenesis of hypothyroidism.

The Combined Effect of Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors on Thyroid Function.

Background: Recent successes with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the treatment of solid malignancies have paved the way for a new era of combined therapy. A common side effect seen with each of these classes of treatment is thyroid dysfunction, with rates estimated at 30-40% for TKI and 10-20% for ICI. However, little is known about the effect of combined ICI+TKI therapy on thyroid function. Therefore, this study evaluated the incidence, clinical features, and risk factors for developing thyroid abnormalities during ICI+TKI therapy and the relationship to cancer outcomes. Methods: We conducted a retrospective cohort study of patients treated with combination ICI+TKI cancer therapy at City of Hope Comprehensive Cancer Center from 2017 to 2023 who had pretreatment normal thyrotropin (TSH) levels. Primary analyses assessed the frequency, timing, and severity of thyroid function test abnormalities during ICI+TKI cancer therapy, and the requirement for thyroid hormone replacement. Secondary analyses evaluated risk factors for the development of thyroid dysfunction, including sex and drug regimen, and the association with cancer progression-free survival or overall survival. Univariable and multivariable models were used. Results: There were 106 patients who received ICI+TKI therapy with a median age of 63.5 years and a median follow-up of 12.8 months (interquartile range [IQR] 5.9-20.9). Notably, 63.2% (67/106) developed thyroid function abnormalities during ICI+TKI therapy, including 11 (10.4%) with hyperthyroidism, 42 (39.6%) with subclinical hypothyroidism (SCHypo), and 14 (13.2%) with overt hypothyroidism. The onset of thyroid dysfunction occurred at a median of 7 weeks (IQR 3.1-9.0) after start of ICI+TKI treatment for hyperthyroidism, 8.0 weeks (IQR 3.0-19.0) for SCHypo, and 8.1 weeks (IQR 5.9-9.1) for overt or worsening hypothyroidism. Hyperthyroidism resolved to hypothyroidism or normal TSH without intervention in all subjects, suggesting thyroiditis, and hypothyroidism was readily treated with thyroid hormone replacement. Conclusions: Thyroid dysfunction is a frequent adverse event in individuals treated with combination ICI+TKI therapy, with our data suggesting a rapid onset and higher incidence than previously seen with ICI or TKI therapy alone. Therefore, close monitoring of thyroid function during initial therapy and multidisciplinary care with endocrinology are recommended to facilitate early detection and initiation of thyroid hormone replacement in these patients.

Ameliorative effects of thiamin on learning behavior and memory dysfunction in a rat model of hypothyroidism: implication of oxidative stress and acetylcholinesterase.

Hypothyroidism causes learning and memory impairment. Considering the neuroprotective properties of thiamine (Vitamin B1), this study was conducted to investigate the effects of thiamine on acetylcholinesterase (AChE) activity, oxidative damage, and memory deficits in hypothyroid rats.In this study, 50 rats (21 days old) were randomly divided into 5 groups and treated with propylthiouracil (0.05% in drinking water) and thiamine (50, 100, and 200 mg/kg, oral) for 7 weeks. Following that, Morris water maze (MWM) and passive avoidance (PA) tests were performed. Finally, oxidative stress indicators and AChE activity were measured in brain tissue.Treatment of hypothyroid rats with thiamine, especially at 100 and 200 mg/kg, alleviated the ability to remember the location of the platform as reflected by less time spent and distance to reach the platform, during the MWM test (P < 0.05 to P < 0.001). In the PA test, the latency to enter the dark chamber and light stay time were increased in rats who received thiamine compared to the hypothyroid group (P < 0.05 to P < 0.001). In addition, thiamine increased the levels of total thiol groups and superoxide dismutase while decreasing the levels of malondialdehyde and AChE.Our results suggest that thiamine supplementation could effectively improve memory loss in a rat model of hypothyroidism. The positive effects of thiamin on the learning and memory of hypothyroid rats may be due to amelioration of redox hemostasis and cholinergic disturbance.

Folic acid supplementation improved cognitive deficits associated with lithium administration during pregnancy in rat offspring.

INTRODUCTION: The present study aimed to analyse both neurobehavioural and biochemical results of neonates born of mothers exposed to different doses of lithium along with the groups that received lithium at the highest dose with folic acid as a preventive treatment. MATERIALS AND METHODS: Male and female rats were mated in separate cages, and pregnant rats were divided into eight first group as (1) vehicle; (2) propylthiouracil (PTU)-induced hypothyroidism; (3-4) received two different doses of lithium carbonate (15 and 30 mg/kg); (5-7) the highest doses of lithium (30 mg/kg) plus three different doses of folic acid (5, 10 and 15 mg/kg); and (8) received just folic acid (15 mg/kg). All treatments were dissolved in drinking water and continued until delivery, followed by returning to a regular diet without treatment. RESULTS: Lithium (30 mg/kg) disrupts both behavioural and biochemical markers, including TSH, T3 and T4 as measuring indicators to assess thyroid function, IL-10 and TNF-α as anti-inflammatory and inflammatory agents, respectively, malondialdehyde as an oxidative stress marker, alongside SOD, and catalase activity as antioxidant indicators. Besides, folic acid, almost at the highest dose (15 mg/kg), attenuated memory impairement and anxiety-like behaviour caused by lithium. Moreover, the groups treated with folic acid alone in comparison with vehicles demonstrated higher levels of antioxidant and anti-inflammatory indicators. CONCLUSION: According to the results, prenatal exposure to a high dose of lithium (30 mg/kg) leads to foetal neurodevelopmental disorder and growth restriction through various mechanisms more likely attributed to hypothyroidism, which means it should be either prohibited or prescribed cautiously during pregnancy.

Demographic, Healthcare Access, and Dietary Factors Associated With Thyroid Hormone Treatments for Hypothyroidism.

CONTEXT: Clinical guidelines have recommended a trial of liothyronine (LT3) with levothyroxine (LT4) in select patients with hypothyroidism. However, little is known about the real-world use of LT3 and desiccated thyroid extract (DTE) and the characteristics of patients treated with LT3 and DTE. OBJECTIVES: (1) Determine national trends of new LT4, LT3, and DTE prescriptions in the United States; (2) determine whether sociodemographic, healthcare access, and dietary factors are associated with different thyroid hormone (TH) therapies. METHODS: Parallel cross-sectional studies were conducted using 2 datasets: (1) a national patient claims dataset (2010-2020) and (2) the National Health and Nutrition Examination Study (NHANES) dataset (1999-2016). Included participants had a diagnosis of primary or subclinical hypothyroidism. Study outcomes included the impact of demographics and healthcare access on differences in the proportion of TH therapies consisting of LT4, LT3, and DTE (patient claims) and differences in dietary behaviors between DTE-treated participants and LT4-treated matched controls (NHANES). RESULTS: On an average annual basis, 47 711 adults received at least 1 new TH prescription, with 88.3% receiving LT4 monotherapy, 2.0% receiving LT3 therapy, and 9.4% receiving DTE therapy. The proportion receiving DTE therapy increased from 5.4% in 2010 to 10.2% in 2020. In the analysis between states, high primary care and endocrinology physician densities were associated with increased use of LT4 monotherapy (odds ratio 2.51, P < .001 and odds ratio 2.71, P < .001). DTE-treated NHANES participants (n = 73) consumed more dietary supplements compared to LT4-treated participants (n = 146) (4.7 vs 2.1, P < .001). CONCLUSIONS: The proportion of new TH therapies containing DTE for hypothyroidism doubled since 2010 while LT3 therapies remained stable. DTE treatment was associated with decreased physician density and increased dietary supplement use.

Phytochemical profiling of polyphenols and thyroid stimulatory activity of Ficus religiosa leaf extract in 6-propyl-thiouracil-induced hypothyroid rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The plant, Ficus religiosa (L.) from the family Moraceae, has been extensively used in Ayurveda and Unani. Traditionally this plant is known for the treatment of constipation, liver diseases and neurological disorders that are related to hypothyroidism. AIM OF THE STUDY: This study was primarily designed to evaluate the effect of Ficus religiosa leaf (FL) extract in ameliorating hypothyroidism in rats and to identify the major bioactive compounds in the test extract that might be responsible for the thyroid-altering activity. In addition, the probable mechanism underlying the thyroid regulation of the main FL constituents were analyzed by molecular docking. MATERIALS AND METHODS: Adult female Wistar rats were used. LC-ESI-MS/MS was performed to identify the compounds present in the extract. HPLC analysis of FL extract was also performed. A pilot study was made using 3 doses of FL extract. Out of 50, 100, and 200 mg/kg, 100 mg/kg appeared to be the most effective one as it could increase thyroid hormones and decreased TSH levels. In the final experiment, propyl-thiouracil (PTU)-induced hypothyroid rats were orally treated with FL extract (100 mg/kg) or L-thyroxine (100 µg/kg, i.p.) daily for 28 consecutive days. On 29th day, all rats were sacrificed and the serum levels of triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and hepatic 5' deiodinase-1(5'D1) were estimated by ELISA. Liver marker enzymes (alanine aminotransferase, ALT and aspartate aminotransferase, AST); total cholesterol (TC) and triglycerides (TG); hepatic lipid peroxidation (LPO) and the activities of antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) content were estimated in liver tissues. RESULTS: LC-MS-MS analyses of the leaf extract identified 11 compounds including the three major compounds, betulinic acid (BA), chlorogenic acid (CGA), and quinic acid (QA). While the PTU treatment decreased the levels of thyroid hormones and 5'D1 activity, it increased the TSH, ALT, AST, TNF-α, IL-6, TC, and TG levels. Furthermore, hepatic LPO significantly increased with a decrease in reduced GSH, SOD, CAT, and GPx. However, FL treatment in PTU-induced animals nearly reversed these adverse effects and improved liver function by decreasing ALT, AST, hepatic LPO and increasing the levels of antioxidants. FL not only improved the liver histology, but also suppressed the inflammatory cytokines, TNF-α and IL-6 in PTU-induced animals. A molecular docking study towards the understanding of the thyroid stimulatory mechanism of action revealed that BA, CGA, and QA might have augmented thyroid hormones by interacting with the thyroid hormone receptor (TRß1) and TSH receptor (TSHR). CONCLUSION: For the first time, we report the pro-thyroidal potential of Ficus religiosa leaf extract. We postulate that its main bioactive compounds, BA, CGA, and QA involved in this action may serve as novel thyroid agonists in ameliorating hypothyroidism.

Cardiovascular protective effect of nano selenium in hypothyroid rats: protection against oxidative stress and cardiac fibrosis.

BACKGROUND: Nano selenium (Nano Sel) has many therapeutic properties including antioxidant, anticancer, and anti-inflammatory actions. OBJECTIVE: Impacts of Nano Sel administration against cardiac fibrosis and heart and aorta tissue oxidative damage observed in hypothyroid rats were explored. METHODS: The animals were randomly grouped and treated as: 1) Control; 2) Propylthiouracil (PTU) in which PTU was added to the drinking water (0.05%) to induce hypothyroidism; 3-5) PTU-Nano Sel 50, PTU-Nano Sel 100, and PTU-Nano Sel 150 groups, which received daily PTU plus 50,100 or 150 µg/kg of Nano Sel for 6 weeks intraperitoneally. The heart and aorta tissues were removed under deep anesthesia and then biochemical parameters including malondialdehyde (MDA), total thiol groups, catalase (CAT), and superoxide dismutase (SOD), as well as cardiac fibrosis were assessed. RESULTS: Hypothyroidism induced by PTU was remarkably associated with myocardial hypertrophy and perivascular fibrosis in Masson's trichrome staining. Moreover, hypothyroidism increased MDA level, while it subtracted total thiol group content and activity of SOD and CAT. Treatment with Nano Sel recovered hypothyroidism-induced cardiac fibrosis in the histological assessment. Nano Sel also promoted CAT and SOD activity and thiol content, whereas alleviated MDA levels in the heart and aorta tissues. CONCLUSION: Results propose that administration of Nano Sel exerts a protective role in the cardio vascular system via preventing cardiac fibrosis and inhibiting oxidative stress.

Effect of sodium selenite on synaptic plasticity and neurogenesis impaired by hypothyroidism.

AIM OF THE STUDY: We investigated protective effect of sodium selenite (Se) on hypothyroidism-induced impairments in, Morris water maze (MWM), long-term potentiation (LTP) and hippocampal neurogenesis male Wistar rats aged of 2 months. MATERIALS AND METHODS: Hypothyroidism was induced by administration of propylthiouracil (Ptu, 1 mg/kg/d) solution to the rats from postnatal day 60 for 81 days with or without Se (0.5mg/kg/d). Neurogenesis was examined by Ki-67 immunohistochemical staining. Se values on plasma and hippocampus were measured with inductively coupled plasma-mass spectrometry (ICP-MS). RESULTS: Measurement of fT3 and fT4 levels confirmed that the fT3 levels, but not fT4, in Ptu-treated rats (5435.44±816.05 fg/ml, p < 0.05) has returned to control values (8721.66±2567.68 fg/ml) by Se treatment (8661.65±711.43 fg/ml). Analysis of learning performance in water escape learning task showed that Se supplementation disappeared memory deficit in Ptu-treated rats as shown by significantly decreased time spent in the target quadrant (33.7±0.24% in control group; 26.1±0.48% in Ptu-group, p < 0.05; 33.9±0.44 in Ptu+Se group), although there was no significant difference among groups in any measurement of learning performance on the last day. Considering LTP, Se supplementation improved the deficit in synaptic plasticity in Ptu-treated rats, as shown by significant increase in the excitatory postsynaptic potential slope (% 243±31 in control group; 172±49 in Ptu-group, p < 0.05; 222±65 in Ptu+Se group) without affecting of the impairment in somatic plasticity. Se supplementation did not improve the decrease in the number of progenitor cells in the subgranular layer (SGL) of dentate gyrus (DG) of Ptu treated rats. CONCLUSIONS: These findings suggest that selenium supplementation in hypothyroid patients may improve learning and memory disorders with different physiological mechanisms.HighlightsSe increased serum fT3 levels and hippocampus Se levels in hypothyroid rats.Se attenuated impairment of population spike-LTP in hypothyroid ratsHypothyroidism disrupts neurogenesis process in the dentate gyrus of hippocampus.Se supplementation could not increase new born cells in hypothyroid rats.

AMIODARONE AND THYROID DYSFUNCTION.

Thyroid gland has a key role in maintaining the body homeostasis. Thyroxine is the main hormone secreted from the thyroid gland, its effect being predominantly achieved after the intracellular conversion of thyroxine to triiodothyronine, which exhibits a higher affinity for the receptor complex, thus modifying gene expression of the target cells. Amiodarone is one of the most commonly used antiarrhythmics in the treatment of a broad spectrum of arrhythmias, usually tachyarrhythmias. Amiodarone contains a large proportion of iodine, which is, in addition to the intrinsic effect of the medication, the basis of the impact on thyroid function. It is believed that 15%-20% of patients treated with amiodarone develop some form of thyroid dysfunction. Amiodarone may cause amiodarone-induced hypothyroidism (AIH) or amiodarone-induced thyrotoxicosis (AIT). AIT is usually developed in the areas with too low uptake of iodine, while AIH is developed in the areas where there is a sufficient iodine uptake. Type 1 AIT is more common among patients with an underlying thyroid pathology, such as nodular goiter or Graves' (Basedow's) disease, while type 2 mostly develops in a previously healthy thyroid. AIH is more common in patients with previously diagnosed Hashimoto's thyroiditis. Combined types of the diseases have also been described. Patients treated with amiodarone should be monitored regularly, including laboratory testing and clinical examinations, to early detect any deviations in the functioning of the thyroid gland. Supplementary levothyroxine therapy is the basis of AIH treatment. In such cases, amiodarone therapy quite often need not be discontinued. Type 1 AIT is treated with thyrostatic agents, like any other type of thyrotoxicosis. If possible, the underlying amiodarone therapy should be discontinued. In contrast to type 1 AIT, the basic pathophysiological substrate of which is the increased synthesis and release of thyroid hormones, the basis of type 2 AIT is destructive thyroiditis caused by amiodarone, desethylamiodarone as its main metabolite, and an increased iodine uptake. Glucocorticoid therapy is the basis of treatment for this type of disease.

Green tea extract modulates lithium-induced thyroid follicular cell damage in rats.

BACKGROUND: The aim of the current work was to clarify the modulation role of green tea extract (GTE) over structural and functional affection of the thyroid gland after long term use of lithium carbonate (LC). The suggested underlying mechanisms participating in thyroid affection were researched. MATERIALS AND METHODS: Twenty-four Sprague-Dawley adult albino rats were included in the work. They were divided into three groups (control, LC, and concomitant LC + GTE). The work was sustained for 8 weeks. Biochemical assays were performed (thyroid hormone profile, interleukin 6 [Il-6]). Histological, histochemical (Periodic Acid Schiff [PAS]) and immunohistochemical (caspase-3, tumour necrosis factor alpha [TNF-α], proliferating cell nuclear antigen [PCNA]) evaluations were done. Oxidative/antioxidative markers (malondialdehyde [MDA]/gluthathione [GSH], superoxide dismutase [SOD]) and Western blot evaluation of the Bcl2 family were done. RESULTS: Lithium carbonate induced hypothyroidism (decreased T3, T4/increased thyroid-stimulating hormone [TSH]). The follicles were distended, others were involuted. Some follicles were disorganised, others showed detached follicular cells. Apoptotic follicular cells were shown (BAX and caspase-3 increased, Bcl2 decreased, BAX/Bcl2 ratio increased). The collagen fibres' content and proinflammatory markers (TNF-α and IL-6) increased. The proliferative nuclear activity was supported by increased expression of PCNA. Oxidative stress was established (increased MDA/decreased GSH, SOD). With the use of GTE, the thyroid hormone levels increased, while the TSH level decreased. Apoptosis was improved as BAX decreased, Bcl2 increased, and BAX/Bcl2 ratio was normal. The collagen fibres' content and proinflammatory markers (TNF-α and IL-6) decreased. The expression of PCNA and caspase-3 were comparable to the control group. The oxidative markers were improved (decreased MDA/increased GSH, SOD). CONCLUSIONS: In conclusion, prolonged use of LC results in hypothyroidism, which is accompanied by structural thyroid damage. LC induced thyroid damage through oxidative stress that prompted sterile inflammation and apoptosis. With the use of GTE, the thyroid gland regained its structure and function. The protecting role of GTE is through antioxidant, antifibrotic, anti-inflammatory, and antiproliferative effects.

Hypothyroidism: morphological and metabolic changes in the testis of adult albino rat and the amelioration by alpha-lipoic acid.

BACKGROUND: The objective of this study is to evaluate the influence of carbimazole- induced hypothyroidism on the testes of adult albino rats and the probable protective effect of alpha-lipoic acid (ALA). MATERIALS AND METHODS: The rats were divided into four groups; control group, ALA group, carbimazole, and carbimazole + ALA groups. Rats were exposed to ALA (60 mg/kg body weight) or carbimazole (1.35 mg/kg body weight), or both, administered via gavages for 30 days. RESULTS: Morphometric analysis revealed a significant decrease in tubular diameter, germinal epithelium thickness, and interstitial space as compared to the controls. Also, rats exposed to carbimazole showed a significant decline in testicular weight, sperm motility, and count. Additionally, deterioration of the testicular architecture was observed. ALA supplementation resulted in a significant improvement in the tubular diameter and germinal epithelium thickness, but no significant improvement regarding interstitial space was observed. Another observation was the significant decline in serum testosterone and follicle-stimulating hormone (FSH) in the carbimazole group, indicating reduced steroidogenesis. A significant reduction in reduced glutathione content was detected in the testes of the carbimazole group compared with the controls, while malonaldehyde concentration significantly increased. Conversely, ALA supplementation ameliorated the toxicity induced by hypothyroidism as illustrated by enhanced reproductive organ weights, testosterone, luteinizing hormone, and FSH levels, testicular steroidogenesis, and oxidative stress parameters. CONCLUSIONS: Hypothyroidism altered testicular antioxidant balance and negatively affected spermatogenesis. On the other hand, ALA through its antioxidant properties alleviated testicular toxicity in carbimazole-exposed rats.

Effect of myrtle (Myrtus communis L.) essential oil on oxidant-antioxidant balance in rats with propylthiouracil-induced hypothyroidism.

Among today's health problems, metabolic diseases are at the forefront. Hypothyroidism (HT) is a disease characterized by increased TSH, decreased T3&T4 concentrations in serum, with overall metabolic slowdown. Although there are many studies in the literature about oxidative status in HT, statements in these studies are contradictory. In our study, the effect of essential oils obtained from the leaves, flowers, and roots of Myrtus communis L. on oxidative metabolism in an HT model induced by propylthiouracil (PTU) in rats was investigated. A total of 36 Wistar albino rats were randomly divided into six groups as follows: (1) Control, (2) PTU, (3) M. communis L. oil 200 (MO 200), (4) M. communis L. oil 400 (MO 400), (5) PTU + MO 200, and (6) PTU + MO 400. In our study, while oxidative status deteriorates in groups given PTU, antioxidant activity increases in groups given M. communis L. oil. PRACTICAL APPLICATIONS: Essential oils are aromatic oily liquids derived from different parts of plants. M. communis L. is one of the best-known herbs in the class of aromatic and medicinal plants. This paper emphasizes the effect of M. communis L. oil on the negative oxidative state that occurs in HT conditions. The present study provides a positive effect of essential oils obtained from the M. communis L. on the oxidative state seen in HT. In light of this information, it may be beneficial to use M. communis L. oil due to its antioxidative effect in HT conditions.

Thymoquinone Upregulates Catalase Gene Expression and Preserves the Structure of the Renal Cortex of Propylthiouracil-Induced Hypothyroid Rats.

BACKGROUND: The association between hypothyroidism and renal diseases has been described in many studies. Nigella Sativa was among the recently reported natural product that has the potential to prevent renal tissue damage and fibrosis. The aim of this study was to evaluate the possible protective effect of thymoquinone on the structure of the renal cortex of hypothyroid rats and explore the mechanism behind it. METHODS: An experimental model of hypothyroidism was induced in adult male Wistar rats by administration of propylthiouracil (6 mg/kg/body weight). One hypothyroid group was treated with thymoquinone at the dose of 50 mg/kg/body weight and compared to the untreated group. Thyroid function and oxidant/antioxidant status were assessed in the serum. Catalase gene expression was assessed using the real-time polymerase chain reaction. The kidney was assessed both histologically and immunohistochemically. RESULTS: Administration of propylthiouracil resulted in a significant decrease in the serum levels of nitric oxide, reduced glutathione, and superoxide dismutase activity while the level of malondialdehyde significantly (p < 0.001) increased. Administration of thymoquinone alleviated this effect on the thyroid hormones and significantly increased the serum levels of antioxidants. Thymoquinone significantly (p < 0.001) upregulated catalase transcription by about 24-fold and could block the hypothyroidism-induced glomerular and tubular injury. CONCLUSION: Thymoquinone may have a potential protective effect against hypothyroidism-induced renal injury acting through the attenuation of the oxidative stress and upregulation of renal catalase gene expression.

The effects of the combination of Cyperus rotundus, Crocus sativus, Piper nigrum, and Boswellia serrata on learning and memory deficit and oxidative damage in brain tissue of hypothyroid rats.

In the present study, the impact of a combination of four memory-enhancer herbs on cognitive impairment and brain tissue oxidative damage due to hypothyroidism was evaluated. Propylthiouracil (PTU; 0.05%) was administrated in drinking water. Rats were treated with a combination of four herbal products (Cyperus rotundus, Crocus sativus, Piper nigrum, and Boswellia serrata) mixed with honey at two doses (640 and 1,280 mg/kg) or donepezil (0.5 mg/kg), for 6 weeks. Memory performance on the Morris water maze (MWM) and avoidance behavior in passive avoidance was impaired by hypothyroidism, and brain tissue oxidative damage occurred. Herbal combination and donepezil significantly improved memory impairment, reduced malondialdehyde concentration, and nitric oxide metabolites while increased the thiol contents and catalase and superoxide dismutase enzymes activity in the brain. Our findings suggest that the mixture of herbal products improves learning and memory deficits caused by hypothyroidism, probably by reducing the brain tissue oxidative damage. PRACTICAL APPLICATIONS: Learning and memory impairment is a common feature of thyroid hormones deficiency. Several studies are showing that hypothyroidism in juvenile and mature rats induces significant cognitive impairment. Likewise, in humans, a close relationship between thyroid hormone deficiency and cognitive impairment has been reported. We used a mixture of herbal products, including Cyperus rotundus, Crocus sativus, Piper nigrum, and Boswellia serrata, to treat hypothyroidism-induced memory impairment. All these herbs are widely used as a food additive across the world. In Iranian traditional medicine, this herbal combination traditionally used to treat cognitive impairments. Numerous studies have indicated that these herbs show neuroprotective and memory-enhancing properties. Our finding indicated that a traditionally used herbal combination could potentially use as a treatment of cognitive impairment induced by thyroid hormone deficiency.

Rosmarinic acid alleviates di-2-ethylhexyl phthalate (DEHP) -induced thyroid dysfunction via multiple inflammasomes activation.

DEHP (di-2-ethylhexyl phthalate), an environmental endocrine disruptor, is widely used in industrial products, particularly as plasticizers and softeners which could disrupt the function of the hypothalamic-pituitary-thyroid (HPT) axis. Rosmarinic acid (RA) possesses potential antioxidant and anti-inflammatory capacities in disease models. Nevertheless, evidence on the association between DEHP-induced thyroid dysfunction and inflammation, as well as the molecular mechanism underlying the protective effects of RA-mitigated DEHP-induced thyroid injury remains inconclusive. Male Sprague Dawley (SD) rats were intragastrically administered DEHP (150 mg/kg, 300 mg/kg, 600 mg/kg) once a day for 90 consecutive days. Also, FRTL-5 cells were treated with a wide range of DEHP concentrations (10-8, 10-7, 10-6, 10-5, 10-4, 10-3, 10-2 M) for 24 hr. Subsequently, RA (50 µM) was administered for 24 hr before 10-4 M DEHP challenge. We found that DEHP induced thyroid damage and inflammatory infiltration in vivo. In addition, we showed that DEHP triggered inflammatory cell death, which is mediated by multiple inflammasomes. Moreover, RA, pyroptosis inhibitor (Ac-YVAD-cmk) and antioxidant inhibitor (NAC) treatment significantly alleviated DEHP-induced thyrocyte death, suppressing pro-inflammatory cytokine production, inhibiting multiple inflammasomes activation and attenuating thyrocyte death, respectively. Collectively, our results reveal that a critical role of inflammasomes activation in DEHP-induced thyroid injury, and suggest that RA confers protection against DEHP-induced thyroid inflammation, and facilitating control of the effects of DEHP after given pyroptosis inhibitor or antioxidant inhibitor. These results indicate that it should be possible to provide novel insights into toxicologically and pharmacologically targeting this molecule to DEHP-induced inflammation.

Integrative analysis of key candidate genes and signaling pathways in autoimmune thyroid dysfunction related to anti-CTLA-4 therapy by bioinformatics.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), the first immune checkpoint to be targeted clinically, has provided an effective treatment option for various malignancies. However, the clinical advantages associated with CTLA-4 inhibitors can be offset by the potentially severe immune-related adverse events (IRAEs), including autoimmune thyroid dysfunction. To investigate the candidate genes and signaling pathways involving in autoimmune thyroid dysfunction related to anti-CTLA-4 therapy, integrated differentially expressed genes (DEGs) were extracted from the intersection of genes from Gene Expression Omnibus (GEO) datasets and text mining. The functional enrichment was performed by gene ontology (GO) annotation and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. Protein-protein interaction (PPI) network, module enrichment, and hub gene identification were constructed and visualized by the online Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software. A total of 22 and 17 integrated human DEGs in hypothyroidism and hyperthyroidism group related to anti-CTLA-4 therapy were identified, respectively. Functional enrichment analysis revealed 24 GO terms and 1 KEGG pathways in the hypothyroid group and 21 GO terms and 2 KEGG pathways in the hyperthyroid group. After PPI network construction, the top five hub genes associated with hypothyroidism were extracted, including ALB, MAPK1, SPP1, PPARG, and MIF, whereas those associated with hyperthyroidism were ALB, FCGR2B, CD44, LCN2, and CD74. The identification of the candidate key genes and enriched signaling pathways provides potential biomarkers for autoimmune thyroid dysfunction related to anti-CTLA-4 therapy and might contribute to the future diagnosis and management of IRAEs for cancer patients.

New and Worsening Long-term Immune-Related Adverse Events with PD-1/PD-L1 Pathway Agents in Patients with Cancer.

STUDY OBJECTIVES: Immune checkpoint inhibitors have produced durable responses across a variety of cancers. Although programmed cell death protein 1 (PD-1) and its ligand (PD-L1) inhibitors activate T cells against tumor cells, they may also cause autoimmune-like toxicities termed immune-related adverse events (irAEs). Although much is known regarding irAEs that occur early during treatment, data on the long-term toxicity profile of these agents are more limited. Our primary objective was to evaluate the frequency of patients receiving anti-PD-1/PD-L1 therapy for at least 6 continuous months who experienced new or worsening irAEs requiring clinical interventions. Secondary objectives included assessment of other factors associated with clinically significant irAEs after at least 6 months of therapy. DESIGN: Retrospective chart review. SETTING: Large university-affiliated National Cancer Institute-designated comprehensive cancer center. PATIENTS: A total of 159 adults diagnosed with any malignancy who received a PD-1/PD-L1 inhibitor-nivolumab, pembrolizumab, or atezolizumab-as monotherapy or with concurrent cytotoxic agents, for at least 6 months, between January 1, 2014, and September 1, 2017. MEASUREMENTS AND MAIN RESULTS: We collected information on the incidence and timing of irAEs, along with patient demographics and other treatment outcomes. Thirty-eight patients (24%) experienced clinically significant, new, or worsening irAEs after 6 months of treatment with anti-PD-1/PD-L1 therapy. Hypothyroidism was the most common irAE experienced (20 patients [12.6%]), followed by pneumonitis (5 patients [3%]); 2 patients died due to pneumonitis. Four patients (2.5%) had a deepened disease response beyond 6 months of treatment. CONCLUSION: Our results revealed that a significant proportion of patients continue to experience irAEs with long-term use of PD-1/PD-L1 inhibitors. These results further contribute to the risk-benefit understanding of chronic PD-1/PD-L1 antagonism and support discontinuation of these agents following deepest response.

Administration of Nigella sativa during neonatal and juvenile growth period improved liver function of propylthiouracil-induced hypothyroid rats.

Aim: Propylthiouracil (PTU) is frequently used as an antithyroid medication. It is also commonly used to induce hypothyroidism in rodents. PTU administration and hypothyroidism have been shown to affect the liver function. Nigella sativa (NS) has been suggested to have antioxidant and hepatoprotective effects. The objective of this study was to investigate the effects of NS extract administration during neonatal and juvenile growth period on liver function of PTU-induced hypothyroid rats.Methods: The pregnant rats were kept in separate cages. After delivery, the mothers and their offspring were randomly divided into five groups and were treated with the following programs: (1) control; (2) PTU, 0.005% in their drinking water (3-5); PTU-plus 100, 200, or 400 mg/kg NS extract. After lactation period, the offspring continued to receive the same experimental treatment for the first 8 weeks of their life. Ten offspring of each group were randomly selected and weighted at days 10, 30, and 60 after delivery. Their blood samples were collected and the liver tissues were removed.Results: Malondialdehyde (MDA) concentration was increased while, thiol concentration and superoxide dismutase (SOD) and catalase (CAT) activity were decreased in the liver tissues of PTU-treated rats. Serum aspartate amino transferase (AST), alkaline phosphatase (ALK-P), and alanine aminotransferase (ALT) levels in the PTU group were higher than the control group. Treatment with 200 and 400 mg/kg decreased MDA while increasing thiol concentration in the liver tissues compared to the PTU group. Treatment with all doses of the extract decreased serum ALK-P concentration compared with the PTU group. Treatment with 400 mg/kg NS increased CAT and SOD concentrations in the liver tissues and decreased serum AST and ALT concentrations compared to the PTU group. PTU decreased body weight gain of offspring and while, the extract increased the body weight gain of offspring rats.Conclusion: The results of this study demonstrated that administration of NS hydroalcoholic extract in the neonatal and juvenile growth period has an improving effect on the liver function of PTU- induced hypothyroid rats.

Protective effects of a mixed plant extracts derived from Astragalus membranaceus and Laminaria japonica on PTU-induced hypothyroidism and liver damages.

Protective effects of a mixed hot water extracts of Astragalus membranaceus (AWE) and Laminaria japonica (LWE), AWE: LWE 85:15 (g/g; AL mix), were investigated against propylthiouracil (PTU)-induced hypothyroidism in rats. Rats were challenged with PTU, resulting in, increased thyroid gland weight, decreased liver weight and antioxidant activities, reduced serum tri-iodothyronine and thyroxine levels with increased thyroid stimulating hormone levels, and elevated serum aspartate aminotransferase level. However, orally administered AL mix with 100, 200, and 400 mg kg-1  day-1 , significantly inhibited such abnormalities, dose-dependently. Moreover, PTU-induced abnormal histological architecture of the rat thyroid gland and liver were also significantly ameliorated by an AL mix. The results suggested that, therapeutic use of AL mix for treating hypothyroidism can be characterized by its diversified active ingredients particularly iodine and ferulic acid as confirmed by phytochemical analyses. PRACTICAL APPLICATIONS: The AL mix has synergistic effects in modulating thyroid hormone synthesis and preventing liver damages in PTU-induced hypothyroid rats. These effects of AL mix are mainly related to its richness specifically in iodine and ferulic acid. The growing interests of iodine and ferulic acid in AL mix are principally due to their beneficial effects in releasing sufficient thyroid hormones in hypothyroid conditions and promoting liver-protective functions through its antioxidant and anti-inflammatory potentials, respectively. Moreover, the results of AL mix are well-matched with the effects of standard drug levothyroxine in the present study. Therefore, appropriate dosage of AL mix will be promising as new medicinal food for preventing thyroid dysfunctions and its related liver damages.