Effect of Thyroid-Stimulating Hormone Suppression Therapy on Cardiac Structure and Function in Patients With Differentiated Thyroid Cancer After Thyroidectomy: A Systematic Review and Meta-Analysis.

OBJECTIVE: We aimed to evaluate the effects of thyroid-stimulating hormone (TSH) suppression therapy on cardiac structure and function in patients with differentiated thyroid cancer (DTC) following thyroidectomy. METHODS: Two investigators independently searched the PubMed, Embase, Cochrane Library, and Web of Science databases for relevant studies published from inception to January 6, 2023, without any restrictions on language. Standard mean differences and 95% confidence intervals were calculated using fixed or random effects models. Thirteen clinical outcomes were analyzed, mainly evaluating cardiac morphology, systolic function, and diastolic function. RESULTS: Thirteen studies were included in the quantitative analysis. Compared to healthy controls, left ventricular mass index, left ventricular posterior wall thickness, interventricular septal thickness, and isovolumic relaxation time values increased; the ratio of E-wave velocity to A-wave velocity and E-wave velocity values decreased. The left ventricular ejection fraction and cardiac output did not change in patients with DTC who underwent long-term TSH suppression therapy. Interventricular septal thickness values were significantly correlated with the duration of TSH suppression therapy. CONCLUSION: Long-term TSH suppression therapy leads to cardiac hypertrophy and impaired cardiac diastolic function in patients with DTC. These changes may be related to the duration of TSH suppression therapy. Large prospective studies with long follow-up periods are needed to validate these findings.

Potential economic indicators and environmental quality in African economies: new insight from cross-sectional autoregressive distributed lag approach.

Growing economic development and substantial demographic shifts may have a momentous consequence on environmental quality in a number of African countries. Consequently, this recent study offers the opportunity to explore the nexus among unobserved influential economic indicators and environmental quality (measured through CO2 emissions) in a panel of 26 African economies spanning from 1990 to 2018. The aggregated panel is sub-classified into net exporters (NEC) and net importers (NIC) of embodied carbon. Considering existence of cross-section reliance and heterogeneity issues, all observed series are preliminarily confirmed stationary and cointegrated. Further, key outcomes from the common correlated effect Pooled Mean Group (CCEPMG) estimator through cross-sectional autoregressive distributed lag (CSARDL) approach showed that (i) economic growth and fossil fuel energy use stimulate environmental degradation among all panels, (ii) urbanization and trade openness enhance environmental quality in NEC panel while environmental damage is increased in NIC and aggregated panels, (iii) financial development also enhanced environmental quality in the totaled and NEC panel of African countries, but rather maturated climate deterioration in NIC panel, (iv) industrialization had a substantial adverse effect on environmental quality through surge in emission of CO2 concerning the aggregated panel and NEC African states, and (v) overall the environmental Kuznets curve (EKC) conjuncture is validated among all panels. The findings were also affirmed by Augmented Mean Group (AMG) technique. Finally, Dumitrescu-Hurlin Granger causality checks showed strong causal affiliations heterogeneously across all panels. From the policy perspective, the analytical outcomes from this study summarily encourage the introduction of profitable policies that can facilitate green energy and economic structural change to diminish the degree of environmental degradation from emission of CO2. Steps to strengthen a low-carbon and sustainable green environment should therefore collectively address these factors during policy growth.

Investigation on key contributors of energy consumption in dynamic heterogeneous panel data (DHPD) model for African countries: fresh evidence from dynamic common correlated effect (DCCE) approach.

The main aim of this current study is to empirically scrutinize the determinants of energy consumption for 24 African countries sub-grouped into three panels based on income levels: low-, lower-middle-, and upper-middle-income countries, from 1990 to 2015. Due to the presence of heterogeneity and cross-sectional reliance among country groups, recently developed econometric approaches, which include cross-sectional Im, Pesaran, and Shin together with cross-sectional Augmented Dickey-Fuller stationarity tests, Pedroni and Westerlund-Edgerton cointegration assessment, dynamic common correlated effect estimation approach and Dumitrescu-Hurlin Granger causality test are employed. Empirically, our findings depict analyzed variables are stationary and characterized by long-term stability affiliations for all panels. Economic growth, urbanization, population growth, and oil price with labor and capital stock as intermittent variables had palpable significant positive sway on energy consumption for all panels though their respective weight of contribution differed from one country group to another. The granger test of causation unveiled that (i) among all panels, urbanization and energy consumption are connected bidirectionally, whereas population growth causes energy consumption; (ii) a one-way causal link from economic growth to energy use is evidenced in low-income African countries, whereas a two-sided connection is confirmed in both lower-middle- and upper-middle-income economies; (iii) a bilateral causal association in low-income African nations is observed amid oil price and energy use, while a uni-lateral relationship extends from oil price to energy consumption in both lower-middle- and upper-middle-income nations in Africa. Such new methodologies and findings reveal that the long-term estimated effects as well as causal affiliations amid variables are skewed by different income levels of African countries in an attempt to conserve energy. Policy recommendations are further propose.

Endothelial Function in Patients with Subclinical Hypothyroidism: A Meta-Analysis.

The purpose of this meta-analysis was to determine whether patients with subclinical hypothyroidism (SCH) have impaired endothelial function, which is assessed by carotid intima-media thickness (C-IMT) and flow-mediated dilatation (FMD) of brachial artery. PubMed, Embase and Cochrane Library databases and the key studies references were searched in our study, prior to July 2017 for all language articles about FMD or C-IMT in SCH and euthyroid subjects. Two authors screened documents and extracted data by pre-established standard independently. The pooled estimate for continuous data was calculated using random-effects models. Statistical heterogeneity was evaluated using I2 statistics. Subgroup analyses were conducted to assess the robustness of the meta-analysis. Publication bias was examined with funnel plot analysis and Egger's test. In this meta-analysis, 10 studies with 760 subjects are related to FMD with SCH and 23 studies with 1521 subjects are related to C-IMT with SCH. The pooled estimate of the weighted mean difference (WMD) has revealed that SCH correlated with increased C-IMT [WMD 0.069 mm; 95% CI (0.042, 0.095); p<0.001] and decreased FMD [WMD -1.848%; 95% CI (-2.298, -1.399); p<0.001] with high heterogeneity.: Compared with EU controls, SCH was also associated with an increased diastolic blood pressure (DBP), systolic blood pressure (SBP), triglyceride (TG), total cholesterol (TC) levels, and low density lipoprotein cholesterol (LDL-C). This meta-analysis demonstrates that SCH is associated with endothelial dysfunction, which may relate with increased thyroid-stimulating hormone (TSH). Hypertension and dyslipidemia may play a crucial part in the development of endothelial dysfunction.

Hypothyroidism and related diseases: a methodological quality assessment of meta-analysis.

OBJECTIVES: There is an increasing prevalence of hypothyroidism and there is a growing body of meta-analyses (MAs) on the association between hypothyroidism and other diseases. However, the methodological quality of the MAs significantly varies. Thus, this study aimed to evaluate and summarise data on the methodological quality of MAs on the associations between hypothyroidism and other diseases using the Assessment of Multiple Systematic Reviews (AMSTAR) scale, providing suggestions for clinical decision-making processes. DESIGN: To assess the methodological quality of MAs using the AMSTAR scale. DATA SOURCES: A systematic literature search was performed in PubMed, EMBASE, the Cochrane Library, web of science and Chinese Biomedicine Literature Database. ELIGIBILITY CRITERIA: We included MAs that had assessed the association between hypothyroidism and other diseases in humans and that had full texts regardless of the publication status. No restriction applied on language or date. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened the titles and abstracts of all searched literature to acquire potentially eligible publications. The full texts of possible eligible publications were downloaded and assessed. Inconsistent comments were resolved through discussions with a third reviewer. RESULTS: 52 studies were included. The average AMSTAR score of the included articles was 8.6 (range: 5-10), and those of English and Chinese MAs were 8.8 and 7.0, respectively. A total of 52 MAs were evaluated, and 19 (36.5%) and 33 (63.5%) of these MAs were of moderate and high quality, respectively. None of the MAs were of low quality. Only two MAs had an a priori design. Items 3, 5 and 9 had the highest compliance (50/52, 96.2%), and aside from item 1, items 7 and 8 had the lowest compliance (33/52,63.5%). According to the results of these MAs, hypothyroidism was significantly associated with cardiovascular diseases, metabolic diseases, neuropsychiatric disorders, breast cancer and pregnancy outcome. CONCLUSIONS: The methodological quality of the included MAs on the association between hypothyroidism and other diseases was moderate to high. MAs with high qualities confirmed that hypothyroidism was significantly associated with cardiovascular diseases, metabolic syndrome, preterm birth and neonatal outcomes. Consideration of scientific quality when formulating conclusions should be made explicit and more attention should be paid to improving the methodological quality of MAs, and increasing their applicability for clinical decision-making.

Isoforms S and L of MRPL33 from alternative splicing have isoform­specific roles in the chemoresponse to epirubicin in gastric cancer cells via the PI3K/AKT signaling pathway.

Drug resistance is a major cause of cancer­associated mortality. Epirubicin­based chemotherapy initially benefits patients with metastatic or advanced gastric cancer; however, tumor recurrence can occur following several courses of treatment. Mitochondrial ribosomal protein L33 (MRPL33)­long (L) and MRPL33­short (S), isoforms of MRPL33 that arise from AS, have been reported to regulate cell growth and apoptosis in cancer; however, few studies have evaluated the roles of MRPL33­L and MRPL33­S in gastric cancer. In the present study, MRPL33­L was demonstrated to be significantly more abundant in gastric tumor tissues than the MRPL33­S isoform. MRPL33­S promoted chemosensitivity to epirubicin in gastric cancer as demonstrated by a chemoresponse assay; chemosensitivity was suppressed in response to MRPL33­L. Gene microarray analysis was performed to investigate the underlying mechanisms. Bioinformatic analysis revealed that overexpression of MRPL33­L and MRPL33­S served critical roles in transcription, signal transduction and apoptosis. In particular, the phosphoinositide 3­kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway was markedly regulated. A total of 36 target genes, including PIK3 regulatory subunit α, AKT2, cAMP response element­binding protein (CREB) 1, forkhead box 3, glycogen synthase kinase 3ß and mammalian target of rapamycin, which are involved in the PI3K/AKT signaling pathway, were selected for further investigation via protein­protein interaction network and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Furthermore, western blot analysis indicated that MRPL33­S promoted the chemoresponse to epirubicin by deactivating PI3K/AKT/CREB signaling and inducing apoptosis, while MRPL33­L had the opposite effects. In conclusion, the results of the present study revealed that isoforms S and L of MRPL33, which arise from alternative splicing, exhibited opposing roles in the chemoresponse to epirubicin in gastric cancer via the PI3K/AKT signaling pathway. These findings may contribute to the development of potential therapeutic strategies for the resensitization of patients with gastric cancer to epirubicin treatment.

Evolution of China's water footprint and virtual water trade: A global trade assessment.

Water embodied in traded commodities is important for water sustainability management. This study provides insight into China's water footprint and virtual water trade using three specific water named Green, Blue and Grey. A multi-region input-output analysis at national and sectoral analysis levels from the years 1995 to 2009 is conducted. The evolution and position of China's virtual water trade across a global supply chain are explored through cluster analysis. The results show that China represented 11.2% of the global water footprint in 1995 and 13.6% in 2009. The green virtual water is the largest of China's exports and imports. In general, China is a net exporter of virtual water during this time period. China mainly imports virtual water from the USA, India and Brazil, and mainly exports virtual water to the USA, Japan and Germany. The agriculture sector and the food sector represent the sectors with both the largest import and export virtual water quantities. China's global virtual water trade network has been relatively stable from 1995 to 2009. China has especially close relationships with the USA, Indonesia, India, Canada, Mexico, Brazil and Australia. Trade relations, resource endowment and supply-demand relationships may play key roles in China's global virtual water footprint network rather than geographical location. Finally, policy implications are proposed for China's long term sustainable water management and for global supply chain management in general.

The Change of Left Ventricular Function in Rats with Subclinical Hypothyroid and the Effects of Thyroxine Replacement.

OBJECTIVE: The main purpose of this study was to explore the relationships between serca2a, Ryr2, adipokines, and the left ventricular function in the subclinical hypothyroidism with different TSH levels and to determine the impact of L-T4 treatment on these indexes. METHODS: Sixty-five male Wistar rats were randomly divided into five groups: control group; sHT A, B, and C group; and sHT + T4 group. The sHT rats were induced by methimazole (MMI), and the sHT + T4 rats were administered with L-T4 treatment after 8 weeks of MMI administration. Serum TT4, TSH, APN, chemerin, and TNF-α were detected by radioimmunoassay kits and ELISA kits; left ventricular function was measured by PowerLab system via subclavian artery catheter. The expression of Serca2a, Ryr2, APN, chemerin, and TNF-α were detected by RT-PCR, Western blot, and immunohistochemistry. RESULTS: The sHT groups had significantly higher TSH, chemerin, and TNF-α and lower Serca2a, Ryr2, and APN. The left ventricular pressure and heart rate in sHT groups were significantly lower in control and sHT + T4 group. Histopathological examination revealed the pathological changes in the sHT rats' heart. L-T4 administration reduced TSH level and improved left ventricular function. CONCLUSIONS: TSH can impair left ventricular function by regulating several factors, and L-T4 treatment ameliorates it in sHT rats.

Adipokine expression and endothelial function in subclinical hypothyroidism rats.

The purpose of our study was to observe adipokine expression and endothelial function in subclinical hypothyroidism (sHT) rats and to determine whether levothyroxine (LT4) treatment affects these changes. Sixty-five male Wistar rats were randomly divided into five groups: the control group; sHT A, B and C groups and the sHT + T4 group. The sHT rats were induced by methimazole (MMI) and the sHT + T4 rats were administered LT4 treatment after 8 weeks of MMI administration. Thyroid function and lipid levels were measured using radioimmunoassays and enzymatic colorimetric methods, respectively. Serum adiponectin (APN), chemerin, TNF-α, endothelin (ET-1) and nitric oxide (NO) levels were measured using ELISA kits and a nitric-reductive assay. The expression of APN, chemerin and TNF-α in visceral adipose tissue (VAT) was measured in experimental rats using RT-PCR and Western blotting. Hematoxylin-eosin (HE) staining was used to observe changes in adipose tissue. The sHT rats had significantly higher levels of thyroid-stimulating hormone (TSH), TNF-α, chemerin, ET-1, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and lower levels of APN and NO than those in control and sHT + T4 rats. Based on Pearson correlation analysis, the levels of chemerin, TNF-α, ET-1, LDL-C, TC and triglyceride (TG) were positively correlated with TSH, but APN and NO levels were negatively correlated with TSH. These findings demonstrated that high TSH levels contribute to the changes of adipokines and endothelial dysfunction in sHT, but LT4 treatment ameliorates those changes.

Effect of subclinical hypothyroidism on the skeletal system and improvement with short-term thyroxine therapy.

The purpose of the study was to observe changes in the skeletal system of rats with subclinical hypothyroidism (SCH) and to determine whether L-thyroxine (L-T4) administration suppresses those changes. Sixty male Wistar rats were randomly divided into control, SCH, and SCH+T4 groups. SCH was induced in rats by administration of methimazole (MMI), and rats in the SCH+T4 group were treated with L-T4 after 45 days of MMI administration. The SCH group had higher thyroid-stimulating hormone (TSH) level than the control and SCH+T4 groups. There were no differences in serum thyroid hormone (FT4 and FT3) levels among the three groups. Bone mineral density; serum levels of BALP and TRACP-5b, two bone metabolic markers; and the biomechanical properties of the femurs were lower in the SCH group than in the control group. After L-T4 treatment, serum BALP and TRACP-5b levels and the femur biomechanical properties were higher in the SCH+T4 than the SCH group. Histopathological examination revealed damage to the structure of the femur trabecular bone network in rats with SCH, and L-T4 treatment improved this condition to some extent. These findings demonstrate that L-T4 treatment ameliorates the destructive effects of SCH on the skeletal system in rats.

TEOA, a triterpenoid from Actinidia eriantha, induces autophagy in SW620 cells via endoplasmic reticulum stress and ROS-dependent mitophagy.

2α,3α,24-Thrihydroxyurs-12-en-28-oicacid (TEOA), a pentacyclic triterpenoid, isolated from the roots of Actinidia eriantha, exhibits significant cytotoxicity against SW620, BGC-823, HepG-2, A549 and PC-3 cancer cells. In this study, we investigated the underlying molecular mechanism of the anticancer activity of TEOA in SW620 cells. We demonstrated that TEOA induced apoptosis through cleavage of caspase-9 and PARP in SW620 cells. In addition, evidence of TEOA-mediated autophagy included the induction of autophagolysosomes and activation of autophagic markers LC-3B and p62. Further analysis illustrated that TEOA promoted the phosphorylation of PERK and elF2α, followed by up-regulation of the downstream protein CHOP, suggesting the involvement of PERK/eIF2α/CHOP pathway and ER stress in TEOA-induced autophagy in SW620 cells. Meanwhile, TEOA-mediated PINK1, Parkin, ubiquitin and p62 activation revealed that TEOA induced specific autophagy-mitophagy in SW620 cells. Additionally, an antioxidant NAC attenuated the TEOA-induced mitophagy, indicating that TEOA triggers mitophagy via a ROS-dependent pathway. Collectively, our findings revealed a novel cellular mechanism of TEOA in the colon cancer cell line SW620, thus providing a molecular basis for developing TEOA into an anti-tumor candidate.

Enhanced metabolic process to indole alkaloids in Clematis terniflora DC. after exposure to high level of UV-B irradiation followed by the dark.

BACKGROUND: Indole alkaloids, which characteristically contain an indole nucleus, have pharmaceutical potential in a diverse range of applications. UV-B can elicit the accumulation of indole alkaloids. The indole alkaloid (6-hydroxyl-1H-indol-3-yl) carboxylic acid methyl ester with cytotoxic activity was found to accumulate in Clematis terniflora DC. leaves after exposure to high level of UV-B irradiation and the dark. However, a more in-depth analysis of the process behind this response has not yet been performed. Therefore, an integrated approach involving metabolomic, proteomic, and transcriptomic analyses is essential to detail the biosynthetic mechanisms of the regulation of indole alkaloid under binary stress. RESULTS: Indole alkaloid (6-hydroxyl-1H-indol-3-yl) carboxylic acid methyl ester was found to increase 7-fold in C. terniflora leaves post-treatment with high level of UV-B irradiation followed by an incubation in the dark compared with pre-treatment. Analysis by proteomics and metabolomics indicates a decrease in photosynthesis and carbohydrate metabolism, respectively. By contrast, amino acid metabolism was activated by this binary stress, and, specifically, the genes involved in the metabolic pathway converting shikimate to L-tryptophan were concurrently upregulated. Metabolites involved in indole biosynthesis (shikimate metabolic) pathway were anthranilate, indole, and L-tryptophan, which increased 2-, 441-, and 1-fold, respectively. In addition, there was an increase of 2- and 9-fold in L-serine deaminase (L-SD) and L-tryptophan synthase activity in C. terniflora leaves after exposure to high level of UV-B irradiation and the dark. CONCLUSIONS: (6-hydroxyl-1H-indol-3-yl) carboxylic acid methyl ester was found to increase in response to high level of UV-B irradiation followed by an incubation in the dark, implying that indole alkaloid biosynthesis was activated in C. terniflora leaves. Analysis of perturbations in metabolism in these leaves demonstrated that amino acid metabolism was specifically activated by this binary stress. In addition, an enhancement in serine level and L-SD activity was noted, which likely leads to an accumulation of pyruvate that, in turn, supplies shikimate metabolic pathway. The genes, metabolites, and L-tryptophan synthase activity that are involved in the metabolic pathway leading from shikimate to L-tryptophan all increased under the experimental binary stress, resulting in an enhancement of indole biosynthesis (shikimate metabolic) pathway. Therefore, the metabolic process to indole alkaloids in C. terniflora was enhanced after exposure to high level of UV-B irradiation followed by the dark.

Proteomic and Metabolomic Analyses of Leaf from Clematis terniflora DC. Exposed to High-Level Ultraviolet-B Irradiation with Dark Treatment.

Clematis terniflora DC. has potential pharmaceutical value; on the contrary, high-level UV-B irradiation with dark treatment led to the accumulation of secondary metabolites. Metabolomic and proteomic analyses of leaf of C. terniflora were performed to investigate the systematic response mechanisms to high-level UV-B irradiation with dark treatment. Metabolites related to carbohydrates, fatty acids, and amino acids and/or proteins related to stress, cell wall, and amino acid metabolism were gradually increased in response to high-level UV-B irradiation with dark treatment. On the basis of cluster analysis and mapping of proteins related to amino acid metabolism, the abundances of S-adenosylmethionine synthetase and cysteine synthase as well as 1,1-diphenyl-2-picrylhydrazyl scavenging activity were gradually increased in response to high-level UV-B irradiation with dark treatment. Furthermore, the abundance of dihydrolipoyl dehydrogenase/glutamate dehydrogenase and the content of γ-aminobutyric acid were also increased following high-level UV-B irradiation with dark treatment. Taken together, these results suggest that high-level UV-B irradiation with dark treatment induces the activation of reactive oxygen species scavenging system and γ-aminobutyric acid shunt pathway in leaf of C. terniflora.

TSH inhibits SERCA2a and the PKA/PLN pathway in rat cardiomyocytes.

Elevated thyroid-stimulating hormone (TSH) levels often accompany impaired LV diastolic function and subtle systolic dysfunction in subclinical hypothyroidism (sHT). These cardiac dysfunctions are characterized by increases in mean aortic acceleration and pre-ejection/ejection time ratios. To explore the mechanism underlying these pathologies, we investigated the effects of TSH on sarcoplasmic reticulum calcium ATPase (SERCA2a) activity and expression in neonatal rat cardiomyocytes. TSH inhibited SERCA2a activity and expression by binding to TSH receptors in cardiomyocyte membranes and inhibiting the protein kinase A/phoshpolamban (PKA/PLN) signaling pathway. These results suggest that increases in serum TSH levels contribute to the development of cardiac diastolic and systolic dysfunction.

Factors associated with diet barriers in patients with poorly controlled type 2 diabetes.

BACKGROUND: The study was conducted to investigate the diet barriers perceived by patients with poorly controlled type 2 diabetes and examine the associations between diet barriers and sociodemographic characteristics, medical condition, and patient-centered variables. METHODS: Secondary subgroup analyses were conducted based on the responses of 246 adults with poorly controlled type 2 diabetes from a multicenter, cross-sectional study. Diet barriers were captured by the Diet Barriers subscale of the Personal Diabetes Questionnaire. Participants also completed validated measures of diet knowledge, empowerment level, and appraisal of diabetes. Multiple regression techniques were used for model building, with a hierarchical block design to determine the separate contribution of sociodemographic characteristics, medical condition, and patient-centered variables to diet barriers. RESULTS: Diet barriers were moderately evident (2.23±0.86) among Chinese patients with poorly controlled type 2 diabetes. The feeling of deprivation as a result of complying with a diet was the most recognized diet barrier (3.24±1.98), followed by "eating away from home" (2.79±1.82). Significantly higher levels of diet barriers were observed among those with lower levels of diet knowledge (ß=-0.282, P<0.001) and empowerment (ß=-0.190, P=0.015), and more negative appraisal (ß=0.225, P=0.003). CONCLUSION: Culturally tailored, patient-centered intervention programs that acknowledge individuals' preferences and allow for flexibility in diet management should be launched. Interventions programs that could enhance diet knowledge, promote positive appraisal, and improve empowerment level might effectively address diet barriers perceived by patients with poorly controlled type 2 diabetes.

The complete chloroplast genome sequence of Fatsia japonica (Apiales: Araliaceae) and the phylogenetic analysis.

In this study, we have sequenced the complete chloroplast genome of Fatsia japonica, a well-known ornamental and potential medicinal plant. The complete chloroplast genome of F. japonica is 155 613 bp in length with 62.09% AT content, has a typical quadripartite structure with large (LSC 86 487 bp) and small (SSC 17 866 bp) single-copy regions separated by a pair of inverted repeats (IRs 25 929 bp) and contains 114 unique genes with 18 genes duplicated in the IR making a total of 132 genes. The phylogenetic analysis indicated the position of F. japonica in Apiales and has the potential to facilitate a better understanding of the intergeneric relationships in the family.

Endothelial Functioning and Hemodynamic Parameters in Rats with Subclinical Hypothyroid and the Effects of Thyroxine Replacement.

OBJECTIVE: Subclinical hypothyroidism (SCH) and its associations with atherosclerosis (AS) and cardiovascular disease remain controversial. The purpose of our study was to observe changes in endothelial functioning and hemodynamics in rats with SCH and to determine whether L-thyroxine (L-T4) administration affects these changes. METHODS: In total, sixty male Wistar rats were randomly divided into the following three groups with 20 rats each: control euthyroid rats, SCH rats and SCH rats that had been treated with thyroxine (SCH+T4). The SCH rats were induced by administration of 10 mg x kg(-1) x d(-1) methimazole (MMI) once daily by gavage for 3 months. The SCH+T4 rats were administered the same dose of MMI for three months in addition to 2 µg x kg(-1) x d(-1) L-T4 once daily by gavage after 45 days of MMI administration. The control rats received physiological saline via gavage. RESULTS: The SCH group had significantly higher thyroid-stimulating hormone (TSH), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and endothelin (ET) levels and a lower nitric oxide (NO) level than the control and SCH+T4 groups. The tail and carotid artery blood pressures, left ventricular systolic pressure, heart rate and aorta ventralis blood flow were significantly lower in the SCH group than in the control and SCH+T4 groups. ACH treatment caused concentration-dependent relaxation, which was reduced in the SCH arteries compared with the control and SCH+T4 arteries. Histopathological examination revealed the absence of pathological changes in the SCH rat arteries. CONCLUSIONS: These findings demonstrate that L-T4 treatment ameliorates endothelial dysfunction and hemodynamic changes in SCH rats.

Combination delivery of Adjudin and Doxorubicin via integrating drug conjugation and nanocarrier approaches for the treatment of drug-resistant cancer cells.

Combination therapy has been regarded as a potent strategy to overcome multidrug resistance (MDR). In this study, we adopt Adjudin (ADD), a mitochondria inhibitor, and Doxorubicin (DOX), a common chemo-drug, to treat drug-resistant cancer cells (MCF-7/ADR) in combination. Given the different physico-chemical properties of ADD and DOX, we develop a novel drug formulation (ADD-DOX (M)) by integrating drug conjugation and nanocarrier approaches to realize the co-delivery of the two drugs. We demonstrate the conjugation of ADD and DOX via formation of an acid-sensitive hydrazone bond, and then the encapsulation of ADD-DOX conjugates by DSPE-PEG2000 micelles with high drug encapsulation efficiency and well-controllable drug loading efficiency. The obtained ADD-DOX (M) micelles are found to be stable under physiological conditions, but can rapidly release drugs within acidic environments. Following cellular experiments confirm that ADD-DOX (M) vehicles can be internalized by MCF-7/ADR cancer cells through an endocytic pathway and exist within the moderate acidic endolysosomes, thus accelerating the hydrolysis of ADD-DOX and the release of free ADD and DOX. As a result, the ADD-DOX (M) formulation exhibits an excellent anti-MDR effect. In summary, we for the first time report the combinational use of ADD and DOX with an effective co-delivery strategy for the treatment of MDR cancer cells.

Effects of TSH on the function of human umbilical vein endothelial cells.

Recent studies have reported that subclinical hypothyroidism (SCH) is associated with atherosclerosis (AS). Thyroid hormone is maintained at normal levels in patients with SCH, whereas TSH is increased. However, the pathogenesis of AS in association with SCH is only partially understood. In addition, endothelial dysfunction plays an important role in the development of AS. The purpose of the present research was to study the direct effect of TSH on human umbilical vein endothelial cells (HUVECs). The expression of some genes associated with endothelial dysfunction after treatment with TSH was evaluated by real-time PCR and western blotting respectively. At first, we showed that the TSH receptor (TSHR) is expressed in HUVECs. We also provide evidence indicating that TSH treatment promotes tumor necrosis factor α-induced endothelial cells interactions by upregulating the expression of the adhesion molecules intercellular adhesion molecule-1. Furthermore, the expression of endothelial nitric oxide synthase (eNOS) and prostacyclin (PGI2) was significantly attenuated following treatment with TSH in dose- and time-dependent manner. Conversely, the results indicated that TSH upregulated endothelin-1 (ET1) mRNA and protein expression in HUVECs, similar effects were observed for plasminogen activator inhibitor-1 (PAI1) after treatment with various concentrations of TSH. Taken together, these results demonstrate that elevated TSH can promote endothelial dysfunction by altering gene expression in HUVECs.