Thyroid hormone deprival and TSH/TSHR signaling deficiency lead to central hypothyroidism-associated intestinal dysplasia.

BACKGROUND: Central hypothyroidism (CH) is characterized by low T4 levels and reduced levels or bioactivity of circulating TSH. However, there is a lack of studies on CH-related intestinal maldevelopment. In particular, the roles of TH and TSH/TSHR signaling in CH-related intestinal maldevelopment are poorly understood. Herein, we utilized Tshr-/- mice as a congenital hypothyroidism model with TH deprival and absence of TSHR signaling. METHODS: The morphological characteristics of intestines were determined by HE staining, periodic acid-shiff staining, and immunohistochemical staining. T4 was administrated into the offspring of homozygous mice from the fourth postnatal day through weaning or administrated after weaning. RT-PCR was used to evaluate the expression of markers of goblet cells and intestinal digestive enzymes. Single-cell RNA-sequencing analysis was used to explore the cell types and gene profiles of metabolic alternations in early-T4-injected Tshr-/- mice. KEY FINDINGS: Tshr deletion caused significant growth retardation and intestinal maldevelopment, manifested as smaller and more slender small intestines due to reduced numbers of stem cells and differentiated epithelial cells. Thyroxin supplementation from the fourth postnatal day, but not from weaning, significantly rescued the abnormal intestinal structure and restored the decreased number of proliferating intestinal cells in crypts of Tshr-/- mice. Tshr-/- mice with early-life T4 injections had more early goblet cells and impaired metabolism compared to Tshr+/+ mice. SIGNIFICANCE: TH deprival leads to major defects of CH-associated intestinal dysplasia while TSH/TSHR signaling deficiency promotes the differentiation of goblet cells and impairs nutrition metabolism.

TSHR signaling promotes hippocampal dependent memory formation through modulating Wnt5a/ß-catenin mediated neurogenesis.

Subclinical hyperthyroidism is defined biochemically as a low or undetectable thyroid-stimulating hormone (TSH) with normal thyroid hormone levels. Low TSHR signaling is considered to associate with cognitive impairment. However, the underlying molecular mechanism by which TSHR signaling modulates memory is poorly understood. In this study, we found that Tshr-deficient in the hippocampal neurons impairs the learning and memory abilities of mice, accompanying by a decline in the number of newborn neurons. Notably, Tshr ablation in the hippocampus decreases the expression of Wnt5a, thereby inactivating the ß-catenin signaling pathway to reduce the neurogenesis. Conversely, activating of the Wnt/ß-catenin pathway by the agonist SKL2001 results in an increase in hippocampal neurogenesis, resulting in the amelioration in the deficits of memory caused by Tshr deletion. Understanding how TSHR signaling in the hippocampus regulates memory provides insights into subclinical hyperthyroidism affecting cognitive function and will suggest ways to rationally design interventions for neurocognitive disorders.

Superior predictive value of estimated pulse wave velocity for all-cause and cardiovascular disease mortality risk in U.S. general adults.

BACKGROUND: Estimated pulse wave velocity (ePWV) has been proposed as a potential approach to estimate carotid-femoral pulse wave velocity. However, the potential of ePWV in predicting all-cause mortality (ACM) and cardiovascular disease mortality (CVM) in the general population is unclear. METHODS: We conducted a prospective cohort study using the data of 33,930 adults (age ≥ 20 years) from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2014 until the end of December 2019. The study outcomes included ACM and CVM. Survey-weighted Cox proportional hazards models were used to assess hazard ratios (HRs) and 95% confidence intervals (CIs) to determine the association between ePWV and ACM and CVM. To further investigate whether ePWV was superior to traditional risk factors in predicting ACM and CVM, comparisons between ePWV and the Framingham Risk Score (FRS) and Pooled Cohort Equations (PCE) models were performed. Integrated Discriminant Improvement (IDI) and Net Reclassification Improvement (NRI) were employed to analyze differences in predictive ability between models. RESULTS: The weighted mean age of the 33,930 adults included was 45.2 years, and 50.28% of all participants were men. In the fully adjusted Cox regression model, each 1 m/s increase in ePWV was associated with 50% and 49% increases in the risk of ACM (HR 1.50; 95% CI, 1.45-1.54) and CVM (HR 1.49; 95% CI, 1.41-1.57), respectively. After adjusting for FRS, each 1 m/s increase in ePWV was still associated with 29% (HR 1.29; 95% CI, 1.24-1.34) and 34% (HR 1.34; 95% CI, 1.23-1.45) increases in the risk of ACM and CVM, respectively. The area under the curve (AUC) predicted by ePWV for 10-year ACM and CVM were 0.822 and 0.835, respectively. Compared with the FRS model, the ePWV model improved the predictive value of ACM and CVM by 5.1% and 3.8%, respectively, with no further improvement in event classification. In comparison with the PCE model, the ePWV model's ability to predict 10-year ACM and CVM was improved by 5.1% and 3.5%, and event classification improvement was improved by 34.5% and 37.4%. CONCLUSIONS: In the U.S. adults, ePWV is an independent risk factor for ACM and CVM and is independent of traditional risk factors. In the general population aged 20 to 85 years, ePWV has a robust predictive value for the risk of ACM and CVM, superior to the FRS and PCE models. The predictive power of ePWV likely originates from the traditional risk factors incorporated into its calculation, rather than from an indirect association with measured pulse wave velocity.

Predictive value of estimated pulse wave velocity with all-cause and cause-specific mortality in the hypertensive population: the National Health and Nutrition Examination Surveys 1999-2014.

BACKGROUND: Estimated pulse wave velocity (ePWV) has been proposed as a potential approach to assess carotid-femoral pulse wave velocity (cfPWV). However, the potential ability of ePWV to predict all-cause and cause-specific mortality in the population group with hypertension remains unresolved. METHODS: We conducted a prospective cohort study using the data of 14 044 adults (age ≥18 years) from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2014, and followed this cohort until the end of December 2019. ePWV was calculated by using a regression equation for age and mean blood pressure (MBP), derived by the Arterial Stiffness Collaborative Group. RESULTS: The weighted mean age of the 14 044 adults included was 54.79 years; 49.42% of all participants were men. During the median follow-up period of 11 years, 3795 deaths were recorded. In the fully adjusted cox regression model, each 1 m/s increase in ePWV was associated with an increased risk of 56% [hazard ratio 1.61; 95% confidence interval (CI) 1.49-1.64] risk for all-cause mortality. Every 1 m/s increase in ePWV resulted in an increased risk of mortality from cardiovascular disease, cerebrovascular disease, respiratory disease, Alzheimer's disease, accidents, cancer, influenza and pneumonia by 60, 70, 47, 118, 73, 41 and 103%, respectively. ePWV has a robust predictive value for 5- and 10-year all-cause mortality in the hypertensive population with AUCs of 0.749 and 0.741, respectively. CONCLUSION: Elevated ePWV is positively correlated with all-cause mortality and most cause-specific mortalities, independent of traditional risk factors. Moreover, ePWV demonstrates high accuracy in predicting 5-year and 10-year all-cause mortality, outperforming Framingham Risk Score.

Impact of glucagon-like peptide 1 analogs on cognitive function among patients with type 2 diabetes mellitus: A systematic review and meta-analysis.

Background: Diabetes is an independent risk factor for cognitive impairment. However, little is known about the neuroprotective effects of glucagon-like peptide 1 (GLP-1) analogs on type 2 diabetes mellitus (T2DM). Herein, we assessed the impact of GLP-1 analogs on the general cognitive functioning among patients with T2DM. Methods: Relevant studies were retrieved from PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases from their inception till June 30, 2022, without any language restrictions. For continuous variables, the mean and standard deviation (SD) were extracted. Considering the heterogeneity in general cognitive functioning assessments among the pooled studies, the standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs), were calculated. Results: Five studies including 7,732 individuals with T2DM were selected for the meta-analysis. The use of GLP-1 analogs exerted no significant effects on the general cognitive functioning in self-controlled studies (SMD 0.33, 95% CI -0.03 to 0.69). Subgroup analyses among the self-controlled studies based on age and history of cardio-cerebrovascular disease showed that GLP-1 analogs significantly improved the general cognitive functioning in T2DM patients younger than 65 years (SMD 0.69, 95% CI 0.31 to 1.08) or those without cardio-cerebrovascular diseases (SMD 0.69, 95% CI 0.31 to 1.08). Similarly, differences in the general cognitive functioning for GLP-1 analogs between treated and non-treated patients with T2DM were significant in subgroups with patients younger than 65 years (SMD 1.04, 95% CI 0.61 to 1.47) or those with no history of cardio-cerebrovascular diseases (SMD 1.04, 95% CI 0.61 to 1.47). Conclusion: Limited evidence suggests that the use of GLP-1 analogs exerts no significant effects on general cognitive functioning but may be beneficial for patients with T2DM younger than 65 years or those without a history of cardio-cerebrovascular diseases. Further prospective clinical studies with large sample sizes are needed to validate these findings. Systematic Review Registration: www.inplasy.com, identifier 202260015.

Thyrotropin receptor signaling deficiency impairs spatial learning and memory in mice.

Subclinical hyperthyroidism, a condition characterized by decreased thyroid-stimulating hormone (TSH) and normal concentration of thyroid hormone, is associated with an elevated risk for cognitive impairment. TSH is the major endogenous ligand of the TSH receptor (TSHR) and its role is dependent on signal transduction of TSHR. It has not, however, been established whether TSHR signaling is involved in the regulation of cognition. Here, we utilized Tshr knockout mice and found that Tshr deletion led to significantly compromised performance in learning and memory tests. Reduced dendritic spine density and excitatory synaptic density as well as altered synaptic structure in CA1 subfield of the hippocampus were also noted. Furthermore, the synapse-related gene expression was altered in the hippocampus of Tshr -/- mice. These findings suggest that TSHR signaling deficiency impairs spatial learning and memory, which discloses a novel role of TSHR signaling in brain function.

FSHR ablation induces depression-like behaviors.

Alteration in reproductive hormones profile is associated with the increasing risk of menopausal depression in women. Serum follicle-stimulating hormone (FSH) level is changed during the menopause transition, while the effect of FSH on menopausal depression has remained undefined. In this study we investigated whether or how FSH affected menopausal depression in postmenopausal (ovariectomized) FSHR knockout mice (Fshr-/-). We found that Fshr-/- mice displayed aggravated depression-like behaviors, accompanied by severe oxidative stress in the whole brain, resulted from significantly reduced glutamate cysteine ligase modifier subunit (GCLm) in glutathione synthesis and glucose-6-phosphate dehydrogenase (G6PD) in NADP/NADPH transition. Importantly, administration of ROS scavenger N-acetyl cysteine (NAC, 150 mg · kg-1 · d-1, i.p. for 12 weeks) attenuated the depression-like behaviors of Fshr-/- mice. Consistent with these in vivo experiment results, we found that pretreatment with FSH (50, 100 ng/mL) dose-dependently increased protein levels of GCLm and G6PD, and decreased the ROS production in N2a mouse neuroblastoma cells. These findings demonstrate that FSH signaling is involved in pathogenesis of menopausal depression, and likely to maintain the redox-optimized ROS balance in neurons.

FSH signaling is involved in affective disorders.

Affective disorders are a set of mental disorders and particularly disrupt the mental health of susceptible women during puberty, pregnancy, parturition and menopause transition, which are characterized by dramatic changes in reproductive hormone profiles. The serum FSH level changes significantly during these periods; yet, the role of FSH in mood regulation is poorly understood. In the current study, FSHR knockout (Fshr-/-) mice displayed enhanced affective disorder behaviors in an open field test and a forced swim test, accompanied by altered gene expression profiles. The differentially expressed genes between Fshr-/- mice and Fshr+/+ mice were enriched in multiple neuroendocrine metabolic pathways. FSHR deletion significantly increased/decreased the mRNA and/or protein expression levels of AOX1, RDH12, HTR3a and HTR4 in mood-mediating brain regions, including the hippocampus and prefrontal cortex. These results reveal that FSH signaling is involved in the development of affective disorders.

Methods used for evaluation of volume retention rate in autologous fat grafting for breast augmentation: a systematic review.

BACKGROUND: Autologous fat grafting has gained popularity in breast augmentation. Various methods can be used to estimate the volume retention rate. This systematic review aimed to establish whether the type of method used for measuring breast volume is a factor that influences the reported volume retention rate. METHODS: Studies were identified using the electronic databases PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science from inception of the database up to February 2019. Articles describing autologous fat grafting for breast augmentation were selected based on pre-determined inclusion and exclusion criteria. The characteristics of the included studies were summarized, and the reported volume retention rate from the studies was compared. A quality assessment of all included articles was performed using the methodological index for non-randomized studies criteria. RESULTS: A total of 618 articles were identified, of which 12 studies, with a total of 1337 cases, were eligible. The retention rate of injected adipose tissue varied when the method of fat grafting and volume analysis used were both the same, as well as when the method of fat grafting was the same but the method of volumetric evaluation used was different. CONCLUSIONS: Currently, the tools available for estimating the volume retention rate come with limitations. In order to objectively evaluate the percentage of graft retention, a standard protocol that applies to the different methods should be established in the future.

Effectiveness and Safety of Hyaluronic Acid Gel with Lidocaine for the Treatment of Nasolabial Folds: A Systematic Review and Meta-analysis.

BACKGROUND: Hyaluronic acid (HA) gel is a widely used dermal filler for the correction facial volume loss. The incorporation of lidocaine with HA provides a pain-relieving alternative for individuals considering facial rejuvenation. The aim of this systematic review and meta-analysis is to compare the effectiveness and safety of HA with lidocaine (HAL) with that of HA without lidocaine for the treatment of nasolabial folds (NLFs). METHODS: Studies were identified using the electronic databases PubMed, Embase, Cochrane Central Register of Controlled Trials and Web of Science from inception up to January 2018. Randomized controlled trials (RCTs) were selected based on the inclusion criteria. Outcomes included 100-mm Visual Analogue Scale (VAS) score, Wrinkle Severity Rating Scale score and adverse events. RESULTS: A total of 908 patients from 12 RCTs were included in the meta-analysis. VAS score within 30 min after injection in the HAL group was much lower than that with just HA group (MD = - 28.83, 95% CI - 36.38 to - 21.28). There was no significant difference in effectiveness between the two products 24 months post-injection (MD = 0.13, 95% CI - 0.15 to 0.41). The main adverse events, such as swelling, erythema, bruising, itching and induration, also showed no significant difference. CONCLUSIONS: HAL is more effective for pain relief than HA alone, but both display similar effectiveness and safety for the correction of NLFs. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Quantitative proteomics study of protective effects of grape seed procyanidin B2 on diabetic cardiomyopathy in db/db mice.

Diabetic cardiomyopathy is one of the major complications of diabetes mellitus. Oxidative stress appears to play a substantial role in cardiomyopathy. Grape seed procyanidin B2 (GSPB2) has been known as an anti-oxidant in treating diabetes mellitus; however, little is known about its effects and underlying mechanisms on diabetic cardiomyopathy. The present study is to explore the molecular targets of GSPB2 responsible for the anti-oxidative effects in db/db mice by quantitative proteomics. GSPB2 (30 mg/kg body weight/day) were intragastric administrated to db/db mice for 10 weeks. Proteomics of the heart tissue extracts by isobaric tags for relative and absolute quantification analysis was obtained from db/db mice. Our study provides important evidence that GSPB2 protect against cardiomyopathy in diabetes mellitus, which are believed to result from regulating the expression of key proteins involving cardiac fibrosis and proliferation. GSPB2 could be expected to become novel clinical application in fighting against diabetic cardiomyopathy.