Effect of thyroid hormone replacement treatment on cardiac diastolic function in adult patients with subclinical hypothyroidism: a meta-analysis.

Background: Although subclinical hypothyroidism (SCH) is related to abnormalities in left ventricular diastolic function, the use of levothyroxine as a regular treatment remains debatable. This meta-analysis aimed to determine whether thyroid hormone replacement therapy affects cardiac diastolic function in patients with SCH as measured by echocardiography. Methods: This meta-analysis included a search of the EMBASE, PubMed, Web of Science, and Cochrane Library databases from their inception to May 18, 2023, for studies analyzing cardiac morphology and functional changes in patients with SCH before and after thyroid hormone replacement. The outcome measures were cardiac morphology and diastolic and overall cardiac function, as assessed using ultrasound parameters (including ventricular wall thickness, chamber size, mitral wave flow, tissue Doppler, and speckle tracking). The quality of the studies was assessed using the Newcastle-Ottawa Scale. The standard mean differences (MDs) and 95% confidence intervals (CI) were calculated using fixed- or random-effects models. Results: Seventeen studies met the inclusion criteria. A total of 568 patients participated and completed the follow-up. All studies specifically stated that serum thyrotropin levels returned to normal by the end of the study period. Compared with baseline levels, no significant morphological changes were observed in the heart. In terms of diastolic function, we discovered that the ratios of E-velocity to A-velocity (E/A) had greatly improved after thyroid hormone replacement therapy, whereas the ratios of the mitral inflow E wave to the tissue Doppler e' wave (E/e') had not. Global longitudinal strain (GLS) increased significantly after treatment with levothyroxine. Conclusion: In adult patients with SCH, thyroid hormone supplementation can partially but not completely improve parameters of diastolic function during the observation period. This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement, an updated guideline for reporting systematic reviews (11) and was registered with INPLASY (INPLASY202320083). Systematic review registration: https://inplasy.com/inplasy-2023-2-0083.

NQO1 regulates expression and alternative splicing of apoptotic genes associated with Alzheimer's disease in PC12 cells.

PURPOSE: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive dysfunction. Quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme that plays an important role in controlling cellular redox state, whose expression is altered in the brain tissues of AD patients. In addition to its traditional antioxidant effects, NQO1 also acts as a multifunctional RNA-binding protein involved in posttranscriptional regulation. Whether the RNA-binding activity of NQO1 influences AD pathology has not been investigated yet. METHODS: The RNA-binding functions of NQO1 in rat pheochromocytoma (PC12) cells were investigated using siRNA knockdown followed by total RNA sequencing. Reverse transcription quantitative polymerase chain reaction was performed to explore the impact of NQO1 on the transcription and alternative splicing of apoptotic genes. RESULTS: NQO1 knockdown led to a significant increase in cellular apoptosis. Genes involved in certain apoptosis pathways, such as positive regulation of apoptotic processes and mitogen-activated protein kinase signaling, were under global transcriptional and alternative splicing regulation. NQO1 regulated the transcription of apoptotic genes Cryab, Lgmn, Ngf, Apoe, Brd7, and Stat3, as well as the alternative splicing of apoptotic genes BIN1, Picalm, and Fyn. CONCLUSION: Our findings suggest that NQO1 participates in the pathology of AD by regulating the expression and alternative splicing of the genes involved in apoptosis. These results extend our understanding of NQO1 in apoptotic pathways at the posttranscriptional level in AD.

Thiostrepton confers protection against reactive oxygen species-related apoptosis by restraining FOXM1-triggerred development of gastric cancer.

Gastric cancer is a leading cause of tumor-associated death worldwide. Metastasis and chemoresistance are crucial barriers for gastric cancer treatment. The Forkhead Box M1 (FOXM1) transcription factor has been reported as a promising treatment target for various types of tumors, but its effects on gastric cancer progression are not fully understood. In the present study, we found that FOXM1 expression levels were significantly up-regulated in human gastric cancer cell lines and tissues, and its expression was much higher in patients with metastasis. We then found that suppressing FOXM1 with its inhibitor thiostrepton (THIO) significantly reduced the proliferation of gastric cancer cells, while induced G0/G1 and apoptosis. Moreover, reactive oxygen species (ROS) production, mitochondrial impair and autophagy were remarkably provoked in gastric cancer cells treated with THIO, which were required for the regulation of apoptotic cell death. Furthermore, THIO exposure considerably suppressed the migration, invasion and angiogenesis in gastric cancer cells. The inhibitory effects of THIO on tumor growth and metastasis were confirmed in an established gastric cancer xenograft mouse model without detectable toxicity. Intriguingly, our in vitro studies showed that the anti-cancer effects of THIO on gastric cancer were almost abolished upon FOXM1 over-expression, indicating the necessity of FOXM1 suppression in THIO-inhibited tumor growth. In addition, higher FOXM1 expression was detected in gastric cancer cells with chemoresistance. Both in vitro and in vivo studies illustrated that THIO strongly promoted the drug-resistant gastric cancer cells to chemotherapies, proved by the considerably decreased cell proliferation and epithelial-mesenchymal transition (EMT) process. Together, these findings revealed that FOXM1 was a promising therapeutic target for gastric cancer treatment, and THIO exerted potential as an therapeutic agent for the disease.

Smad Anchor for Receptor Activation and Phospho-Smad3 Were Upregulated in Patients with Temporal Lobe Epilepsy.

Smad anchor for receptor activation (SARA) is an important regulator of transforming growth factor ß (TGF-ß) signaling by recruiting Smad2/3 to TGF-ß receptors. We recently demonstrated that the expressions of SARA and level of downstream phospho-Smad3 (p-Smad3) were upregulated in the brain in the epileptic rat model, but were never examined in patients with temporal lobe epilepsy (TLE). In this study, we examined the expressions of SARA and level of p-Smad3 in brain tissues of TLE patients using immunohistochemistry and western blot to demonstrate that SARA activation in neurons is sufficient to facilitate TGF- ß pathway in patients to regulate epilepsy. We found that the expressions of SARA and level of p-Smad3 were significantly upregulated in neurons of the temporal cortex of TLE patients compared to controls. Moreover, SARA and p-Smad3 were strongly stained in the cytoplasm in the temporal cortex of TLE patients. Our results indicate that upregulation of SARA and p-Smad3 in cortex neurons might be involved in the development of intractable temporal lobe epilepsy.

Smad anchor for receptor activation contributes to seizures in temporal lobe epilepsy.

PURPOSE: Smad anchor for receptor activation (SARA) is an important regulator of transforming growth factor ß (TGF-ß) signaling by recruiting Smad2/3 to TGF-ß receptors. Although TGF-ß signaling is critically involved in epileptogenesis, whether SARA activation is sufficient to facilitate TGF-ß pathway to regulate epilepsy remains unknown. METHODS: The expression of SARA and downstream Phospho-Smad3 (p-Smad3) was examined in rats with pilocarpine induced epilepsy. Additionally, knockdown of SARA was performed via recombinant lentiviral vector in the pilocarpine-induced rats. RESULTS: Here we show that expressions of SARA and p-Smad3 are increased in the hippocampus as rats subjected to pilocarpine-induced status epilepticus (SE). Both SARA and p-Smad3 are also upregulated in the temporal cortex of epileptic rats. Furthermore, SARA mRNA levels reach peak as early as 6 hr following SE onset and remain elevated in the chronic phase. Transfection of recombinant lentiviral shRNA targeting SARA knocks down SARA expression, attenuates TGF-ß/p-Smad3 signaling in the hippocampus, and postpones the SE onset. CONCLUSION: Our results demonstrate that SARA/Smad3 pathway contributes to mechanism of seizure and SARA in TGF-ß signaling may be a potential therapeutic target for epilepsy.

Altered cerebrospinal fluid concentrations of TGFß1 in patients with drug-resistant epilepsy.

Transforming growth factor beta (TGFß) signaling participates in pathogenesis of epilepsy. TGFß1, as a transmitter of TGFß signaling, might be a useful marker for predicting the prognosis of patients with epilepsy. The present study aimed to measure TGFß1 level in the cerebrospinal fluid (CSF) of patients with drug-resistant epilepsy and non-resistant epilepsy. A total of 43 patients with epilepsy were recruited, 28 were non-resistant epilepsy subgroup, 15 drug-resistant epilepsy subgroup. 11 patients with intracranial infection and 11 individuals with primary headache were used as controls. The concentration of CSF and serum TGFß1 was measured by enzyme-linked immunosorbent assay. The concentration of CSF-TGFß1 was 209.26 ± 81.07 pg/ml in the drug-resistant epilepsy subgroup, 121.80 ± 40.32 pg/ml in the non-resistant epilepsy subgroup, 552.17 ± 456.20 pg/ml in intracranial infection control, 133.80 ± 68.55 pg/ml in headache control, respectively. TGFß1 level was significantly increased in the drug-resistant epilepsy subgroup compared to the non-resistant epilepsy subgroup. TGFß1 level in intracranial infection control was higher than that in the non-resistant epilepsy subgroup. There was no statistically difference of CSF-TGFß1 between the non-resistant epilepsy subgroup and headache controls, between the resistant epilepsy subgroup and intracranial infection controls. TGFß levels are increased in the CSF of patients with drug-resistant epilepsy. High CSF-TGFß1 levels may be a potential screening biomarker of antiepileptic drug resistance in patients with epilepsy.

Synchronous alteration pattern between serine-threonine kinase receptor-associated protein and Smad7 in pilocarpine-induced rats of epilepsy.

PURPOSE: Recent studies have shown that transforming growth factor ß (TGFß) signaling participates in the epileptogenesis. Serine-threonine kinase receptor-associated protein (STRAP) and Smad7 synergize in the inhibition of the TGFß signaling. The aim of the present study was to determine the expression pattern of STRAP and Smad7 in the hippocampus and temporal lobe cortex of pilocarpine-induced rats models of epilepsy. METHODS: Lithium chloride-pilocarpine-induced rats with status epilepticus (SE) were established. Total of 60 male Sprague-Dawley rats was used as control (n = 10), 24 h (n = 10), 72 h (n = 10), 1 week (n = 10), 1 month (n = 10), and 2 months (n = 10) after pilocarpine-induced SE, respectively. We detected the expression levels of STRAP and Smad7 in the hippocampus and temporal lobe cortex of rats at the aforementioned time points using western blotting and immunohistochemistry. RESULTS: STRAP level was significantly decreased in 24 h, 72 h (acute stage), 1 week (latent stage), 1 month, 2 months (chronic stage), respectively, in the rat models compared with the control rats by using both western blotting and immunohistochemistry. Smad7 had similar reduced pattern as STRAP. CONCLUSIONS: Our results indicate that STRAP and Smad7 proteins might be involved in the development of temporal lobe epilepsy.

Hypoxia-up-regulated mitochondrial movement regulator does not contribute to the APP/PS1 double transgenic mouse model of Alzheimer's disease.

BACKGROUND/AIMS: It has been demonstrated that mitochondrial dysfunction is associated with Alzheimer's disease (AD); meanwhile, hypoxia-up-regulated mitochondrial movement regulator (HUMMR) plays an important role in regulating mitochondrial function. The present study aimed to confirm the association between HUMMR and mitochondrial function in AD. METHODS: We detected the expression of HUMMR at transcriptional and translational levels in APP/PS1 double transgenic mice using real-time quantitative RT-PCR and Western blotting. Age- and gender-matched wild-type (WT) littermates were used as controls. Mitochondrial morphology was observed in the hippocampus and cortex of APP/PS1 double transgenic mice using transmission electron microscopy. RESULTS: Damage to mitochondrial morphology in the hippocampus and cortex of APP/PS1 double transgenic mice was found, including swelling and cavitations. Our analysis showed no statistical differences in the expression of HUMMR between APP/PS1 double transgenic mice and WT littermates (p > 0.05). These results showed that there was no association between HUMMR and mitochondrial dysfunction in APP/PS1 transgenic mice. CONCLUSION: These results indicate that HUMMR does not play a key role in mitochondrial dysfunction in the APP/PS1 double transgenic AD mouse.

Expression pattern of sorting Nexin 25 in temporal lobe epilepsy: a study on patients and pilocarpine-induced rats.

PURPOSE: The transforming growth factor ß (TGF-ß) signaling pathway is involved in the epileptogenesis. Sorting Nexin 25 (SNX25) has been recently proposed to modulate TGF-ß signaling through endosomal sorting of TGF-ß receptors for lysosomal degradation. The aim of the present study was to determine the expression pattern of SNX25 in brains of epilepsy patients and in animal model of epilepsy. METHODS: We investigated the expression of SNX25 in the brain tissues of patients with temporal lobe epilepsy (TLE) and in the pilocarpine-induced rat model of epilepsy using western blotting, real-time quantitative RT-PCR, and double-label immunofluorescence. RESULTS: The expression of SNX25 was significantly increased in TLE patients in comparison to controls (0.21±0.07 vs. 0.11±0.03, P<0.05). In the lithium-pilocarpine induced epileptic rats, significant elevation of SNX25 levels was detected in the chronic phase, while no SNX25 alteration occurred in the acute and latent phases. Moreover, SNX25 localized to astrocytes and neurons, in both human samples and animal models. CONCLUSION: Our results indicate that upregulation of SNX25 might be involved in the development of temporal lobe epilepsy.