Propylthiouracil Research Articles

Melissa officinalis extract suppresses endoplasmic reticulum stress-induced apoptosis in the brain of hypothyroidism-induced rats exposed to γ-radiation

The purpose of this study was to demonstrate the neuroprotective effect of Melissa officinalis extract (MEE) against brain damage associated with hypothyroidism induced by propylthiouracil (PTU) and/or γ-radiation (IR) in rats. Hypothyroidism induction and/or exposure to IR resulted in a significant decrease in the serum levels of T3 and T4 associated with increased levels of lipid peroxidation end product, malondialdehyde (MDA), and nitrites (NO) in the brain tissue homogenate. Also, hypothyroidism and /or exposure to IR markedly enhance the endoplasmic reticulum stress by upregulating the gene expressions of the protein kinase RNA-like endoplasmic reticulum kinase (PERK), activated transcription factor 6 (ATF6), endoplasmic reticulum-associated degradation (ERAD), and CCAAT/enhancer-binding protein homologous protein (CHOP) in the brain tissue homogenate associated with a proapoptotic state which indicated by the overexpression of Bax, BCl2, and caspase-12 that culminates in brain damage. Meanwhile, the PTU and /or IR-exposed rats treated with MEE reduced oxidative stress and ERAD through ATF6. Also, the MEE treatment prevented the Bax and caspase-12 gene expression from increasing. This treatment in hypothyroid animals was associated with neuronal protection as indicated by the downregulation in the gene expressions of the microtubule-associated protein tau (MAPT) and amyloid precursor protein (APP) in the brain tissue. Furthermore, the administration of MEE ameliorates the histological structure of brain tissue. In conclusion, MEE might prevent hypothyroidism-induced brain damage associated with oxidative stress and endoplasmic reticulum stress.

Safety of Antithyroid Drugs in Avoiding Hyperglycemia or Hypoglycemia in Patients With Graves' Disease and Type 2 Diabetes Mellitus: A Literature Review.

Graves' disease (GD) may increase the difficulty of glucose control in patients with type 2 diabetes mellitus (T2DM). Therefore, selecting a drug with limited blood glucose side effects is an important issue in patients with T2DM and GD. Antithyroid drugs (ATDs)including propylthiouracil (PTU), methimazole, and carbimazoleare commonly prescribed for the treatment of GD. Here, we review and summarize the literature from the last 10 years and discuss the effects of current ATDs used for GD for blood glucose control in patients with T2DM. A search of the literature published between January 1, 2012 and December 1, 2022 was conducted using three major medical databases: Google Scholar, Ovid Medline, and Scopus. An initial search was conducted on PubMed using the MeSH terms "propylthiouracil," "methimazole," "carbimazole," and "hyperglycemia" or "hypoglycemia" in academic databases. All articles included "Graves' disease" and "type 2 diabetes mellitus" in the title. Based on the results of previous studies, the hyperglycemic andhypoglycemic side effects of ATDs can be explained by several possible mechanisms. The most widely accepted hypothesis is that sulfhydryl group drugs (e.g., methimazole and carbimazole) cleave the disulfide bond of insulin and enhance its immunogenicity, resulting in hypoglycemia. Moreover, some reports have indicated that methimazole is associated with hypoglycemia; therefore, if the patient has a history of autoimmune diseases, it is necessary to consider whether to change drugs or actively track the production of autoimmune antibodies. Innon-diabetic and diabetic patients with GD, the hyperglycemic and hypoglycemic side effects of PTU (on glycemic variation) were less than that of thiamazole. However, as relatively few reports have investigated the side effects of blood sugar changes, further research is necessary to confirm these effects. In addition to autoimmune diseases, drug side effects may need to be considered. These findings provide considerations for clinicians to select more appropriate ATDs for patients with GD and T2DM, and implement improved care guidelines.

Phytochemical screening and evaluation of glucose-6-phosphate dehydrogenase activity of fermented honey-garlic in hypothyroidism rats

Introduction: Hypercholesterolemia is an indicator of atherosclerosis in blood vessels and is currently a top priority in overcoming health problems, especially non-communicable diseases in developed and developing countries. Thyroid hormones regulate various metabolic processes in the body including synthesis, mobilization, and lipid degradation. A lack of thyroid hormone in the body or called hypothyroidism will decrease the number of LDL receptors in the liver. This causes an increase in plasma LDL levels which also increases total cholesterol levels. Despite the lack of study, Fermented Honey-Garlic (FHG) is now widely developed for its high antioxidant activity. This study aims to determine the content of bioactive compounds in FHG by qualitative secondary metabolite testing and GC-MS analysis and to evaluate the activity of the enzyme glucose-6-phosphate dehydrogenase (G6PD) in rats with hypothyroidism. Method: Rats were grouped into 6 groups: positive control group induced by propylthiouracil (PTU) with a dose of 20 mg/day, negative control treated with distilled water, treatment group with a dose of FHG 0.2 g/kg BW (P1), treatment group with a dose of FHG 0.5 g/kg BW (P2), treatment group with a dose of FHG 1 g/kg BW (P3) and standard drug Simvastatin group with the dose 0,18 mg/day/200 g BW. Results: Results showed that FHG contained flavonoid compounds, alkaloids, tannins, and saponins, and statistical results showed that the significance value for G6PD activity was 0.014 (P<0.05). Conclusion: Therefore, it can be concluded that FHG administration yields a significant effect on G6PD levels.

Exploring the effect and mechanism of Haizao Yuhu decoction containing three variants of glycyrrhiza on goiter using an integrated strategy of network pharmacology and RNA sequencing

Ethnopharmacological relevanceHaizao Yuhu decoction (HYD) is a classic Chinese herbal formula described in the surgical monographs of the Ming Dynasty “Waikezhengzong.” It has been widely used to treat goiter for approximately 500 years and found to be particularly effective. HYD contains glycyrrhiza and sargassum. This pair of herbs belongs to “18 incompatible medicaments” of traditional Chinese medicine theory. Although these two herbs are opposite, our preliminary study proved that they have superior effect when added into HYD at 2 times the dose of Chinese Pharmacopoeia. However, the species of glycyrrhiza in HYD that are the most effective have not been recorded in ancient Chinese medical texts. According to the Chinese Pharmacopoeia, glycyrrhiza is divided into the following three species: Glycyrrhiza uralensis Fish., G. glabra L., and G. inflata Bat. The effect of HYD containing different species of glycyrrhiza and their mechanisms remain to be further explored. Aim of the studyTo investigate the effect of HYD containing three species of glycyrrhiza on goiter, and to elucidate the molecular mechanism using network pharmacology combined with RNA sequencing (RNA-seq). Materials and methodsA rat model of goiter was established by 14 days of intragastric gavage of propylthiouracil (PTU), and the rats were treated for 4 weeks with HYD containing three different species of glycyrrhiza. The body weight and rectal temperature of rats were tested weekly. At the end of the experiment, the serum and thyroid tissues of rats were collected. The effect of the three HYDs was assessed based on general observations (including body weight, rectal temperature, and living status of rats), absolute/relative thyroid weight, thyroid function (including triiodothyronine, thyroxine, free triiodothyronine, free thyroxine, and thyroid-stimulating hormone levels), and thyroid tissue pathology. Next, we explored their pharmacological mechanisms using network pharmacology combined with RNA-seq and validated key targets using real-time quantitative reverse-transcription polymerase chain reaction (RT-qPCR), western blotting (WB), and immunofluorescence (IF) assays. ResultsThe three HYDs reduced the absolute/relative weights of thyroid tissues and improved the pathological structure, thyroid function, and general findings of rats with goiter. Overall, the effect of HYD-G. uralensis Fish. (HYD-U) was better. Results from network pharmacology and RNA-seq jointly suggested that both the pathogenesis of goiter and the mechanism of action of HYD for goiter were related to the phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) pathway. We validated the key targets in the pathway, namely, vascular endothelial growth factor (VEGF) A, VEGF receptor 2, phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) and its encoded protein PI3K (p85), AKT serine/threonine kinase 1 (AKT1), phospho-AKT and cyclin D1 using RT-qPCR, WB, and IF assays. The PI3K-Akt pathway was hyperactivated in rats with PTU-induced goiter, whereas the three HYDs could inhibit the pathway. ConclusionThis study confirmed the definite effect of the three HYDs in the treatment of goiter, and HYD-U was found to be more effective. The three HYDs inhibited angiogenesis and cell proliferation in goiter tissue by inhibiting the PI3K-Akt signaling pathway.

Methimazole and propylthiouracil design as a drug for anti-graves' disease: Structural studies, Hirshfeld surface analysis, DFT calculations, molecular docking, molecular dynamics simulations, and design as a drug for anti-graves' disease

Methimazole (MMI) and propylthiouracil (PTU), two commonly used anti-Graves' disease drugs, were studied using density functional theory (DFT) with the B3LYP approach and 6–311G(d,p) as the basis set. Molecular electrostatic potential (MEP), Hirshfeld investigations, and interactions energy analysis (IEA) were used to study the surface of the compounds to identify the various reactive surfaces which are essential for determining a variety of biological activities. Using an in-silico designing technique, fifteen new compounds with enhanced activity and docking scores were developed on the basis of information acquired from the standard drugs (MMI and PTU). These novel compounds featured improved activity and docking score results. Furthermore, molecular dynamics simulations were carried out on the standard drugs as well as the compound D10 with the highest binding affinity using protein 5hpw. In addition to this, the NBOs, FT-IR, and FT-Raman spectra of D10, as well as some of its thermochemistry, were reported and examined. These findings may provide useful information for future development.

HYPERTHYROIDISM SECONDARY TO GESTATIONAL TROPHOBLASTIC DISEASE : A LITERATURE REVIEW

Gestational trophoblastic disease (GTD) is a rare form of pregnancy-related cancer that is effectively treatable. GTD is accompanied by the potentially fatal complication of hyperthyroidism. We created a review consisting of five case reports. This case report was conducted on women who became pregnant when they were >35 years old. They showed consistent laboratory results, in which there was an increase in hCG levels. TSH and thyroid stimulating antibodies cannot account for the hyperthyroidism associated with GTD. The source of the thyroid stimulating agent is trophoblastic tissue. The thyrotropic effects of ?-hCG mediate GTD hyperthyroidism. Other research examined the prevalence of hyperthyroidism in women with normal pregnancy, hydatidiform mole, and choriocarcinoma who had ?-hCG serum levels below 100,000 IU/ml. Early prenatal screening may significantly reduce hyperthyroidism rates. Thyroid hormone synthesis inhibitors treat hyperthyroidism in pregnancy. Thioamides, propylthiouracil (PTU), and methimazole (MMI) are the most prevalent U.S. antithyroid medications (ATD). Plasmaphoresis may be an option for people who are resistant to therapy or need emergency surgery. GTD can cause fatal hyperthyroidism. Anti-thyroid medicines can handle most GTD hyperthyroidism. Surgery may be a possibility for patients refractory to medical treatment.

Sonographic Assessment of Submandibular Salivary Glands in Hypothyroid Rat’s Pups Before and After Ashwagandha Root Extract Treatment

Background: One of the most common chronic diseases globally is hypothyroidism. Thyroid hormones serve a significant role in maintaining the proper function and shape of the salivary gland. The aim of the study: Investigate the function of Ashwagandha roots extract in providing a protection role for salivary glands in hypothyroid rats following postnatal exposure to Propylthiouracil. Materials and Methods: Ten pregnant albino rats were obtained. Until the rat pups were detected, each pregnant rat was kept individually in clean rodent plastic. At postnatal day 3 (PND3), forty male rats were randomly assigned to one of two groups: group A, which served as a control group, and group B, which received orally (1mg/kg) Propylthiouracil (PTU) for three weeks. At PND22, group B was divided up into three subgroups: B1, the hypothyroid group that got no therapy; B2, the hypothyroid group that received an aqueous extract of Ashwagandha roots (200 mg/kg) for 21 days; and B3, the hypothyroid group that received Levothyroxine (4g/100g/day) for 21 days. At the end of the trial, the submandibular gland was assessed using sonographic instruments in all groups. Results: the sonographic assessment of hypothyroid group’s submandibular gland showed an increase in the overall size of the gland, a heterogeneous gland with a honeycomb appearance and hypoechoic regions in group remains without treatment, while the results in hypothyroid pups fed with Ashwagandha roots extract indicated a small improvement in gland size and echotexture when compared to pups who received levothyroxine, owing to its antioxidant properties.

Comparison of the safety between propylthiouracil and methimazole with hyperthyroidism in pregnancy: A systematic review and meta-analysis.

The purpose of this meta-analysis was to assess the safety of the anti-thyroid drugs (ATDs) propylthiouracil (PTU) and methimazole (MMI) in the treatment of hyperthyroidism during pregnancy. From inception until June 2, 2022, all available studies were searched in PubMed, Web of Science, Cochrane, EBSCO, Embase, Scopus, and CNKI. Thirteen articles satisfying the inclusion criteria were examined. Our meta-analysis indicated that pregnant women treated with MMI had a higher risk of congenital anomalies than those treated with PTU (OR 0.80, 95%CI 0.69-0.92, P = 0.002, I2 = 41.9%). Shifting between MMI and PTU during pregnancy did not reduce the risk of birth defects compared to PTU alone (OR 1.18, CI 1.00 to 1.40, P = 0.061, I2 = 0.0%). There were no statistically significant differences in hepatotoxicity (OR 1.54, 95%CI 0.77-3.09, P = 0.221, I2 = 0.0%) or miscarriage (OR 0.89, 95%CI 0.72-1.11, P = 0.310, I2 = 0.0%) between PTU and MMI exposure. The study confirmed propylthiouracil is a safer alternative to methimazole for treating hyperthyroidism in pregnant women, and it is appropriate to treat maternal thyroid disease with PTU during the first trimester of pregnancy. However, it is not clear whether switching between propylthiouracil and methimazole is a better option than treating PTU alone during pregnancy. Further studies on this matter may be needed to develop new evidence-based guidelines for the treatment of pregnant women with hyperthyroidism.

A disproportionality analysis of the adverse effect profiles of methimazole and propylthiouracil in patients with hyperthyroidism using the Japanese Adverse Drug Event Report Database.

Antithyroid drugs (ATDs) are frequently used to achieve euthyroidism in patients with hyperthyroidism. ATDs cause characteristic common and rare adverse events; however, comprehensive comparisons between methimazole (MMI) and propylthiouracil (PTU) in terms of adverse events are limited. In this study, we thoroughly explored adverse events in association with MMI and PTU use with a disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database and evaluated the prevalence of MMI and PTU prescriptions using the National Database of Health Insurance Claims and Specific Health Checkups (NDB) Open Data Japan. We analyzed 3271 cases of MMI use and 1029 cases of PTU use with respect to 9789 preferred terms (PTs) for adverse events registered in the JADER database by calculating and comparing reporting odds ratios (RORs). We found that 8 PTs, including agranulocytosis (p < 0.0001, 4.01-fold), aplasia cutis congenita (p < 0.0001, 123.22-fold), and exomphalos (p = 0.0002, 22.17-fold), demonstrated significantly higher RORs (more than 4-fold) for MMI use than for PTU use. Nineteen PTs, including anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (p < 0.0001, 29.84), rapidly progressive glomerulonephritis (p < 0.0001, 6.44), and pulmonary alveolar hemorrhage (p < 0.0001, 7.77), had RORs for PTU use more than four times those for MMI use. NDB Open Data Japan showed more frequent PTU prescriptions than MMI prescriptions for women of reproductive age. This large-scale study confirmed that a variety of congenital malformations were identified as having significantly high RORs for MMI use, while diseases related to ANCA-associated vasculitis were specific to PTU.

Drug-Induced Liver Injury (DILI) related to Propylthiouracil (PTU) in hyperthyroidism with liver cirrhosis

Link of Video Abstract: https://youtu.be/_dm9Vyddxvg Background: Hyperthyroidism is an excessive concentration of thyroid hormone in tissues caused by increased thyroid hormone synthesis, excessive thyroid hormone release, or an endogenous or exogenous extrathyroid source. There are 3 types of hyperthyroid therapy: antithyroid drugs (PTU, thiamazole, and carbimazole), radioactive ablation, and surgery. However, PTU is one of the drugs included in the list of medications that cause Drug-induced Liver Injury (DILI). Case Presentation: A-36-years old male came to the IRD Dr. Sutomo General Hospital with a chief complaint of weakness for 1 month. The patient also complained of yellowing of the skin on the body, especially in the eyes, for 1 month, and the stomach was getting bigger and bloated before admission to the hospital. The patient has had a history of hyperthyroidism since 6 months ago and has taken PTU for 5 months. Exophthalmos eyes, icteric eyes, ascites, and splenomegaly were found on physical examination. The laboratory results showed hyperbilirubinemia, an increase in transaminase enzymes, and hypoalbumin. In the hospital, the patient was given an infusion of albumin, tyrosol, UDCA, spironolactone, and propranolol. Conclusion: It has been reported that a man, 36 years old, has an underlying disease of liver cirrhosis. The patient has habitual risk factors for consuming alcohol. The patient had received PTU therapy for 1 month and came to the hospital suspected of DILI. Based on these cases, it is necessary to be vigilant about administering medications to patients with underlying diseases.

Nano-selenium relieved hepatic and renal oxidative damage in hypothyroid rats.

Hypothyroidism can induce oxidative stress. Nano-selenium (Nano Sel) has antioxidant effects. The current research explored Nano Sel effects on hepatic and renal oxidative damage induced by hypothyroidism in rats. Animals were grouped into (1) Control; (2) Propylthiouracil (PTU) group which received water mixed with 0.05% of PTU; (3) PTU-Nano Sel 50; (4) PTU-Nano Sel 100; and (5) PTU-Nano Sel 150. Besides PTU, the PTU-Nano Sel groups were treated with 50, 100, or 150 μg/kg of Nano Sel intraperitoneally. Treatments were done for 6 weeks. The serum level of T4, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), albumin, total protein, creatinine, and blood urea nitrogen (BUN) was evaluated. Malondialdehyde (MDA) and total thiol concentration and the activity of catalase (CAT) and superoxide dismutase (SOD) in hepatic and renal tissues also were checked. Hypothyroidism induced by PTU significantly increased AST, ALT, ALP, creatinine, BUN, and MDA concentration and noticeably reduced albumin, total protein, total thiol level, and SOD and CAT activity. Administration of Nano Sel ameliorated the adverse effects of hypothyroidism on liver and kidney function. Nano Sel applied protective effects against hepatic and renal damage resulting from hypothyroidism via ameliorating the oxidative stress status. More cellular and molecular experiments need to be done to understand the exact mechanisms.

Abstract #1409027: Paraneoplastic Hyperthyroidism

Non-seminomatous germ cell tumors producing human chorionic gonadotropin (HCG) were first described in 1964. HCG is capable of inducing hyperthyroidism by stimulating the TSH receptor, due to its identical alpha subunit. We report a case of HCG-mediated hyperthyroidism in the setting of a choriocarcinoma. A 28-year-old man presented with a 3-week history of unintentional weight loss, cough, hemoptysis, palpitations, shortness of breath, nausea and vomiting. Chest x-ray showed a large pleural effusion and multifocal nodular opacities on lungs measuring up to 4 cm. CT abdomen/pelvis showed a 1.4 cm left renal mass concerning for metastasis, and hepatomegaly. CT chest demonstrated a 16 cm heterogeneous enhancing mass in the mediastinum, a large pericardial effusion, moderate left pleural effusion and metastatic pulmonary nodules. Laboratory results showed elevated HCG of 947,825 mIU/mL, AFP 25 ng/ml, LDH 1,394 U/L, TSH 0.011 mcIU/mL, FT4 2.0 ng/dL, Ferritin 2680 ng/mL, CRP 118 mg/L. Testicular ultrasound was unremarkable. Biopsy of mediastinal mass was consistent with choriocarcinoma. Endocrinology was consulted for evaluation of abnormal thyroid function. He was tachycardic, without other overt symptoms of hyperthyroidism and no clinical findings of Graves’ Disease. TRAB, TSI, TPO antibodies were negative. Propylthiouracil (PTU) 100mg every 8 hours and low dose propranolol were started. Chemotherapy with Etoposide, Ifosfamide, and Cisplatin was initiated. Thyroid function improved 5 days after initiation of therapy. After 3 cycles of chemotherapy, his TSH and Free T4 levels normalized and the HCG level decreased to 1,521 mIU/mL. His most recent thyroid function tests were TSH 5.8 mcIU/ml and Free T4 level 1.1 ng/dL and the decision was made to stop PTU. HCG is a heterodimer with an alpha subunit identical to that of TSH, LH and FSH. High HCG levels can stimulate the TSH receptor and cause hyperthyroidism. Hyperthyroidism has been reported in trophoblastic tumors when HCG levels are >200,000 mIU/mL. Initiation of chemotherapy produces rapid decline in HCG levels and improvement of Free T4 levels. Diagnosis of paraneoplastic hyperthyroidism is challenging, as symptoms of hyperthyroidism may overlap with those of metastatic disease. Symptomatic patients should be started on thianomide and beta blocker which improve well-being and tolerance to chemotherapy. We illustrated the challenge of diagnosing hyperthyroidism in HCG-secreting choriocarcinoma and the importance of initiating chemotherapy and anti-thyroidal medication in symptomatic patients to improve outcomes.

Abstract #1413864: Perioperative Management of Hyperthyroidism in Molar Pregnancy: A Case Report

Hyperthyroidism is a rare complication of molar pregnancy. Perioperative management in hyperthyroidism treatment needs a comprehensive approach. A 23-year-old woman with molar pregnancy at 11 weeks of gestation was consulted for perioperative consultation for an emergency dilatation and curettage by the obstetrics and gynecology department. She had a chief complaint of intermittent light bleeding from the vagina two weeks ago. Due to the bleeding, she changed her pads twice a day. She also complained of a decreased body weight for one month, with a loss of about 4 kg, tremors, and irregular menstruation. She has had general weakness since last month. On physical examination, she was tachycardic (119 bpm). She showed a resting tremor on both hands. Significant laboratory findings included a hemoglobin concentration was 6.7 g/dL, increased transaminase (AST 109 unit/L and ALT 81 unit/L), increased fT4 (7.77 ng/dL), and decreased TSH (0.01 micro IU/mL). Propylthiouracil (PTU) 200 mg every 4 hours and dexamethasone 5 mg every 12 hours were administered before the surgery as a treatment for hyperthyroidism while receiving a transfusion to correct her hemoglobin concentration. She was curetted without any complications. She has a molar pregnancy which causes increased human chorionic gonadotropin. Its alpha subunit has a similar structure to TSH that can bond to TSH receptors on thyroid cells, leading to increased circulation of fT4. Pregnancy termination is indicated if patients present with significant thyrotoxicosis and bleeding. However, hyperthyroidism carries an increased risk for thyroid storm in surgery. PTU administration aims to inhibit the thyroid peroxidase enzyme that converts iodide to an iodine molecule and incorporates the iodine molecule into the amino acid tyrosine, decreasing T4 production. She was given a steroid (dexamethasone) to inhibit peripheral conversion from T4 to T3.

Ameliorating Effect of Ashwagandha (Withania Somnifera) Extract on Hippocampus and Growth Plate Changes Associated With Propylthiouracil Induced Hypothyroidism in Juvenile Rats

Background: Hypothyroidism is a decrease in the production of the thyroid hormones and leads to gland dysfunction. Ashwagandha extract was used as an ayurvedic treatment and supposed to be as antihypothyroidism agent. Objectives: to investigate the impact of ashwagandha (Ash) extract on propylthiouracil (PTU)-induced hypothyroidism in rats. Subjects and Methods: The rats were divided into three groups, control group, PTU (hypothyroid) group (6mg/kg/day by oral route), PTU (6mg/kg/day by oral route) +Ash (50mg/kg/day by oral route) treated group. All treatment continued for 30 days. At the end of experiment, measurement of serum T3, T4 and TSH was performed. Thyroid gland, right sided tibia and dentate gyrus region of hippocampus were examined using histological, histochemical and immunohistochemical studies. All measurements were statistically analyzed. Results: Decrease in serum T3 and T4 and congestion of the blood capillaries, follicular distortion, and vacuolar degeneration of some follicular cells were exhibited in thyroid gland of hypothyroid group. Histological changes in growth plate cartilage in the form of decrease of matrix deposition and plate thickness were detected. Dentate gyrus showed distorted granule cell layer. Immunohistochemically, low expression of the GFAP was expressed in astrocytes. PTU+Ash treated group showed improvement of the previous changes. Conclusion: Administration of ashwagandha with PTU displayed protective effect on the thyroid gland and its associated histological changes in growth plate cartilage and dentate gyrus. Higher doses of ashwagandha should be used for extrapolation if it may give better results than the used dose.

Combined levothyroxine and testosterone treatment for restoring erectile dysfunction in propylthiouracil-induced hypothyroid rats.

Sexual dysfunction may indicate severe endocrine diseases. Recent research has suggested a link between hypothyroidism, low testosterone (T) levels, and erectile dysfunction (ED); however, the exact cause is unknown. We sought to investigate possible beneficial effects of levothyroxine and T alone or in combination on ED in propylthiouracil (PTU)-induced hypothyroid rats. Adult Wistar rats (n = 35) were divided into 5 groups: control, PTU-induced hypothyroidism, PTU + levothyroxine, PTU + Sustanon (a mixture of 4 types of T: propionate, phenylpropionate, isocaproate, and decanoate) and PTU + levothyroxine + Sustanon. PTU was given in drinking water for 6 weeks. Four weeks after PTU administration, levothyroxine (20μg microgram kg/day, oral) and Sustanon (10mg/kg/week, intramuscular) were given for 2weeks. Serum levels of total T, triiodothyronine (T3), and thyroxine (T4) were determined. In vivo erectile response and in vitro relaxant responses were measured. Localization of neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS), and phosphodiesterase type 5 (PDE5) were determined using immunohistochemical analysis. The relative area of smooth muscle to collagen was measured using Masson trichrome staining. Outcome variables included in vivo erectile function, in vitro relaxant and contractile responses of corpus cavernosum (CC) strips; protein localization of eNOS, nNOS, and PDE5; and smooth muscle content in penile tissue. The rat model of hypothyroidism showed a significant decline in serum levels of total T, T3, and T4. Levothyroxine increased T3 and T4 levels, whereas Sustanon normalized only total T levels. Combined treatment enhanced all hormone levels. Rats with hypothyroidism displayed the lowest erectile response (P < 0.001 vs controls). Combined treatment returned reduced responses, while partial amelioration was observed after levothyroxine and Sustanon treatment alone. Acetylcholine (P < 0.01 vs controls), electrical field stimulation (P < 0.001 vs controls), and sildenafil-induced relaxant responses (P < 0.05 vs controls) were decreased in the CC strips from hypothyroid rats. The combined treatment increased the reduction in relaxation responses. Levothyroxine and Sustanon restored decreases in eNOS and nNOS expression in the hypothyroid group. There was no significant difference in PDE5 expression among groups. Monotreatment partially enhanced reduced smooth muscle mass, while combined therapy completely recovered. The combination of thyroid hormones and T is likely to be a therapeutic approach for treatment of hypothyroidism-induced ED in men. Beneficial effects of levothyroxine and Sustanon treatment were shown in vitro and in vivo in PTU-induced hypothyroid rats. The main limitation of the study was the lack of measurement of androgen-sensitive organ weights and luteinizing hormone, follicle-stimulating hormone, and prolactin levels. These findings demonstrate that neurogenic and endothelium-dependent relaxation responses are reduced by hypothyroidism, which is detrimental to T levels and erectile responses. Levothyroxine and Sustanon combination medication was able to counteract this effect.

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

Ethnopharmacological relevanceThe 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 studyThis 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 methodsAdult 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. ResultsLC-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 (TRβ1) and TSH receptor (TSHR). ConclusionFor 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.

Gustatory dysfunction is related to Parkinson's disease: A systematic review and meta-analysis.

Olfactory dysfunction has been reported to be involved in Parkinson's disease (PD) pathogenesis. However, gustatory dysfunction in PD has not been evaluated as in-depth as olfactory dysfunction. We reviewed the previously published studies regarding gustatory function in PD patients and suggested the possibility that gustatory dysfunction may also be associated with PD. MEDLINE, Cochrane Library, Embase, and PubMed databases were searched for studies evaluating gustatory function in PD patients. We used the standardized mean difference and a 95% confidence interval (CI) as the effect analysis index regarding the taste strip test. The relative risk and 95% CI were used as the effect analysis index for the questionnaires and propylthiouracil (PTU)/phenylthiocarbamide (PTC) perception test. Statistical heterogeneity was assessed using forest plots, Cochran's Q, and the I2 statistic; heterogeneity was considered high when I2 was over 75%. Publication bias was assessed by funnel plots and the Egger bias test. We identified 19 articles that reported the results of gustatory function tests in PD patients and healthy controls. Most of these studies used various gustatory tests, including taste strips, questionnaires, taste solutions, PTU/PTC perception tests, and electrogustometry, and reported significantly lower gustatory function in PD patients than in the controls. However, several articles reported contradictory results. Based on these studies, gustatory dysfunction is closely related to PD. However, the number of studies and enrolled subjects was small, and a unified gustatory function test was lacking. Therefore, further studies with larger populations and normalized gustatory function tests are needed.

Jagged/Notch proteins promote endothelial-mesenchymal transition-mediated pulmonary arterial hypertension via upregulation of the expression of GATAs.

This study tested the hypothesis that Jagged2/Notches promoted the endothelial-mesenchymal transition (endMT)-mediated pulmonary arterial hypertension (PAH) (i.e. induction by monocrotaline [MCT]/63 mg/kg/subcutaneous injection) through increasing the expression of GATA-binding factors which were inhibited by propylthiouracil (PTU) (i.e. 0.1% in water for daily drinking since Day 5 after PAH induction) in rodent. As compared with the control (i.e. HUVECs), the protein expressions of GATAs (3/4/6) and endMT markers (Snail/Zeb1/N-cadherin/vimentin/fibronectin/α-SMA/p-Smad2) were significantly reduced, whereas the endothelial-phenotype markers (CD31/E-cadherin) were significantly increased in silenced JAG2 gene or in silenced GATA3 gene of HUVECs (all p < 0.001). As compared with the control, the protein expressions of intercellular signallings (GATAs [3/4/6], Jagged1/2, notch1/2 and Snail/Zeb1/N-cadherin/vimentin/fibronectin/α-SMA/p-Smad2) were significantly upregulated in TGF-ß/monocrotaline-treated HUVECs that were significantly reversed by PTU treatment (all p < 0.001). By Day 42, the results of animal study demonstrated that the right-ventricular systolic-blood-pressure (RVSBP), RV weight (RVW) and lung injury/fibrotic scores were significantly increased in MCT group than sham-control (SC) that were reversed in MCT + PTU groups, whereas arterial oxygen saturation (%) and vasorelaxation/nitric oxide production of PA exhibited an opposite pattern of RVW among the groups (all p < 0.0001). The protein expressions of hypertrophic (ß-MHC)/pressure-overload (BNP)/oxidative-stress (NOX-1/NOX-2) biomarkers in RV and the protein expressions of intercellular signalling (GATAs3/4/6, Jagged1/2, notch1/2) and endMT markers (Snail/Zeb1/N-cadherin/vimentin/fibronectin/TGF-ß/α-SMA/p-Smad2) in lung parenchyma displayed an identical pattern of RVW among the groups (all p < 0.0001). Jagged-Notch-GATAs signalling, endMT markers and RVSBP that were increased in PAH were suppressed by PTU.

Melanogenesis of quality markers in Vernonia anthelmintica Injection based on UPLC-Q-TOF-MS combined network pharmacology

This study aimed to evaluate the biological effect and mechanism of Vernonia anthelmintica Injection(VAI) on melanin accumulation. The in vivo depigmentation model was induced by propylthiouracil(PTU) in zebrafish, and the effect of VAI on melanin accumulation was evaluated based on the in vitro B16F10 cell model. The chemical composition of VAI was identified according to the high-performance liquid chromatography quadrupole-time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS). Network pharmaco-logy was applied to predict potential targets and pathways of VAI. A &quot;VAI component-target-pathway&quot; network was established, and the pharmacodynamic molecules were screened out based on the topological characteristics of the network. The binding of active molecules to key targets was verified by molecular docking. The results showed that VAI promoted tyrosinase activity and melanin production in B16F10 cells in a dose-and time-dependent manner and could restore the melanin in the body of the zebrafish model. Fifty-six compounds were identified from VAI, including flavonoids(15/56), terpenoids(10/56), phenolic acids(9/56), fatty acids(9/56), steroids(6/56), and others(7/56). Network pharmacological analysis screened four potential quality markers, including apigenin, chrysoeriol, syringaresinol, and butein, involving 61 targets and 65 pathways, and molecular docking verified their binding to TYR, NFE2L2, CASP3, MAPK1, MAPK8, and MAPK14. It was found that the mRNA expression of MITF, TYR, TYRP1, and DCT in B16F10 cells was promoted. By UPLC-Q-TOF-MS and network pharmacology, this study determined the material basis of VAI against vitiligo, screened apigenin, chrysoeriol, syringaresinol, and butein as the quality markers of VAI, and verified the efficacy and internal mechanism of melanogenesis, providing a basis for quality control and further clinical research.

THE INHIBITION EFFECT OF MORINGA (Moringa oleifera L.) LEAVES AND RED GINGER RHIZOME (Zingiber officinale Rosc.) PT. "P" ETHANOL EXTRACT ON ENHANCEMENT SERUM CREATININE LEVELS OF MALE WISTAR RATS DYSLIPIDEMIA MODEL

The elevation of serum creatinine levels can be used as a biomarker of decreased kidney function. Dyslipidaemia is one of the causes of decreased kidney function. Long-term consuming statins has been shown to lower cholesterol levels but can increase serum creatinine levels. Moringa leaves (Moringa oleifera L.) and red ginger rhizomes (Zingiber officinale Rosc.) have antioxidant effects. The aim of this study was to determine the inhibitory effect on increasing serum creatinine levels of the concoction Moringa Leaves and Red Ginger Rhizome extract (CML-RGRE). This True Laboratory Experimental Study with Completely Randomized Design was conducted on 30 male Wistar rat dyslipidemia models, induced by high-fat feeding (HFF) and Propylthiouracil (PTU) 0.01% for 21 days. The subjects were divided into 6 groups (n=5), during treatment all subjects were still given HFD and PTU. Groups I, II, III were treated with CML-RGRE dose 135, 202.5, 270 mg/kg BW, IV as dyslipidemia control no added any treatment, comparison control groups V treated with 1.8 mg/kg BW and VI with fenofibrate 5.4 mg/kg BW. Serum creatinine levels (mg/dL) of all subjects were measured after 7 days acclimatization, after creating dyslipidemia models, and after 21 days treatment by using a spectrophotometer with colorimetric kinetic methods. Data of decreased serum creatinine levels were analyzed using ANOVA test, followed by Fischer's LSD, ? = 0.05. All doses of CML-RGRE were very effectively inhibited the increase of serum creatinine levels (p &lt; 0.01). The concoction Moringa leaves, and Red Ginger Rhizome ethanol extract has effectively inhibited the increase of serum creatinine levels of animal dyslipidemia models.