Knockdown of LOX-1 ameliorates bone quality and generation of type H blood vessels in diabetic mice.

Our previous studies have shown that lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) is expressed in liver sinusoidal endothelial cells, and oxidized low-density lipoprotein induces liver sinusoidal dysfunction and defenestration through the LOX-1/ROS/NF-kB pathway, revealing that LOX-1 can mediate liver sinusoidal barrier function, involved in the regulation of non-alcoholic fatty liver disease. Here, we investigated whether, in the context of bone metabolic diseases, LOX-1 could affect bone quality and type H blood vessels in diabetic mice. We used db/db mice as model and found that LOX-1 knockdown can ameliorate bone quality and type H blood vessel generation in db/db mice. This further verifies our hypothesis that LOX-1 is involved in the regulation of bone quality and type H blood vessel homeostasis, thus inhibiting osteoporosis progression in db/db mice.

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.

Frequency-Specific Alterations of Fractional Amplitude of Low-Frequency Fluctuations in Adult-Onset Hypothyroidism.

BACKGROUND: The neuropathophysiological mechanisms of brain damage underlying hypothyroidism remain unclear. Fractional amplitude of low-frequency fluctuations (fALFF) has been established as a reliable indicator for investigation of abnormal spontaneous brain activity that occurs at specific frequencies in different types of mental disorder. However, the changes of fALFF in specific frequency bands in hypothyroidism have not yet been investigated. METHODS: Fifty-three hypothyroid patients and 39 healthy controls (HCs) underwent thyroid-related hormone levels tests, neuropsychological assessment, and magnetic resonance imaging (MRI) scans. The fALFF in the standard band (0.01-0.1 Hz), slow-4 (0.027-0.073 Hz), and slow-5 bands (0.01-0.027 Hz) were analyzed. An analysis of Pearson correlation was conducted between fALFF, thyroid-related hormone levels, and neuropsychological scores in hypothyroid patients. RESULTS: Compared to HCs, within the routine band, hypothyroidism group showed significantly decreased fALFF in left lingual gyrus, middle temporal gyrus (MTG), precentral gyrus, calcarine cortex, and right inferior occipital gyrus; within the slow-5 band, the hypothyroidism group exhibited decreased fALFF in left lingual gyrus, MTG, superior temporal gyrus, postcentral gyrus, and paracentral lobule, and increased fALFF in supplementary motor area (SMA) and right middle frontal gyrus; additionally, fALFF in the left lingual gyrus within the routine and slow-5 bands were negatively correlated with the level of thyroid stimulating hormone. CONCLUSIONS: In this study, the slow-5 frequency band exhibits better sensitivity than the standard band in detecting fALFF values. A decrease of fALFF values in the lingual gyrus and MTG was observed in both the standard and slow-5 bands and might present potential neuroimaging biomarkers for hypothyroidism. CLINICAL TRIAL REGISTRATION: No: ChiCTR2000028966. Registered 9 January, 2020, https://www.chictr.org.cn.

Oncolytic Newcastle disease virus expressing the co-stimulator OX40L as immunopotentiator for colorectal cancer therapy.

NDV as an attractive candidate for oncolytic immunotherapy selectively lyses tumor cells but shows limited anti-tumor immunity. Immune co-stimulator OX40 ligand (OX40L) boosts anti-tumor immunity response by delivering a potent costimulatory signal to CD4+ and CD8+ T cells. To improve the anti-tumor immunity of NDV, the recombinant NDV expressing the murine OX40L (rNDV-mOX40L) was engineered. The viral growth kinetics was examined in CT26 cell lines. The ability of rNDV-mOX40L to express mOX40L was detected in the infected tumor cells and tumor tissues. The anti-tumor activity of rNDV-mOX40L was studied in the CT26 animal model. Tumor-specific CD4+, CD8+ and OX40+ T cells were examined by immunohistochemistry staining. The virus growth curve showed that the insertion of the mOX40L gene did not affect the growth kinetics of NDV. rNDV-mOX40L expresses mOX40L and effectively inhibits the growth of CT26 colorectal cancer in vivo. The tumor inhibition rate of the rNDV-mOX40L-treated group was increased by 15.8% compared to that of  NDV-treated group in the CT26 model. Furthermore, immunohistochemistry staining of tumor tissues removed from the CT26 model revealed that intense infiltration of tumor-specific CD4+, CD8+ T cells, especially OX40+ T cells were found in the rNDV-mOX40L-treated group. FACS showed that rNDV-mOX40L significantly enhanced the number of CD4+ and CD8+ T cells in spleen. Moreover, compared to the NDV-treated group, the level of mouse IFN-γ protein in the tumor site increased significantly in the rNDV-mOX40L-treated group. Taken together, rNDV-mOX40L exhibited superior anti-tumor immunity by stimulating tumor-specific T cells and may be a promising agent for cancer immunotherapy.

Segmental Abnormalities of White Matter Microstructure in Primary Hypothyroidism Identified by Automated Fiber Quantification.

INTRODUCTION: Hypothyroidism leads to impaired white matter (WM) integrity, associated with cognitive/neuropsychiatric dysfunction. However, the specific segmental abnormalities of the fibers remain unexplored. Therefore, this study aimed to investigate whether the damage of the WM is limited to a specific segment or the entire bundle via diffusion metrics using automated fiber quantification. METHODS: A cross-sectional study was conducted on 31 hypothyroid patients and 28 healthy controls. Thyroid-related hormone levels, cognitive/neuropsychiatric function, and diffusion tensor image data were collected and analyzed. Correlation and random forest analyses were also performed. RESULTS: The mean fractional anisotropy (FA) values were reduced at the fiber tract level. The mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values were increased in several fiber tracts, i.e., cingulum cingulate (CC), anterior forceps of corpus callosum (CCF_A). Significant correlations were found between cognitive function and diffusion indicators such as the FA value of the left corticospinal tract and arcuate fasciculus (AF), the MD value of left CC, the RD value of left AF, the AD value of left CC, and CCF_A. The widespread microstructure disruption was spread on multiple specific segments of different tracts at the point-wise level. The random forest revealed that the accuracy of recognizing hypothyroid patients was 82.5%, with the anterior component of CCF_A having the most significant contribution. CONCLUSION: WM microstructural integrity impairments were found in multi-segments of the multiple fiber bundles in hypothyroidism, which might be a potential mechanism of the underlying neurocognitive decline and cerebral impairment. The CCF_A might serve as a neuro biomarker for early warning of cerebral impairment in hypothyroidism.

The Effectiveness of Thyroid Hormone Replacement Therapy on Heart Failure and Low-Triiodothyronine Syndrome: An Updated Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: The purpose of this study was to conduct a systematic review and meta-analysis evaluating the role of thyroid hormone therapy in patients with heart failure and low-triiodothyronine syndrome. METHODS: The electronic databases PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and China Biology Medicine disc were systematically searched to identify eligible studies published before November 27, 2021. The mean difference was pooled for randomized controlled trials using a random-effects model. RESULTS: The meta-analysis showed that thyroid hormone treatment improved the left ventricular ejection fraction (weighted mean difference [WMD] 5.61, 95% confidence interval [CI]: 4.38 to 6.85, I2 = 63.12%, P < 0.01). The cardiac output improved with thyroid hormone therapy (WMD 0.65, 95% CI: 0.42 to 0.89, I2 = 84.28%, P < 0.01). The early-to-late diastolic transmitral flow velocity in the thyroid hormone group was also improved compared to the control group (WMD 0.29, 95% CI: 0.15 to 0.42, I2 = 95.08%, P < 0.01). The left ventricular diastolic dysfunction was decreased with thyroid hormone treatment (WMD -5.17, 95% CI: -7.47 to -2.88, I2 = 90.18%, P < 0.01). The brain natriuretic peptide decreased with thyroid hormone treatment (standardized mean difference -1.49, 95% CI: -2.15 to -0.84, I2 = 90.18%, P < 0.01). Noradrenaline decreased with thyroid hormone therapy (WMD -349.86, 95% CI: -401.05 to -298.67, I2 = 0%, P < 0.01). Free triiodothyronine increased with thyroid hormone treatment (standardized mean difference 2.18, 95% CI: 0.75 to 2.60, I2 = 98.20%, P < 0.01). CONCLUSION: This meta-analysis showed that thyroid hormone replacement therapy was effective in patients with heart failure and low-triiodothyronine syndrome.

Oxidized low-density lipoprotein activates extracellular signal-regulated kinase signaling to downregulate sortilin expression in liver sinusoidal endothelial cells.

BACKGROUND AND AIM: Both type 2 diabetes mellitus and non-alcoholic fatty liver disease are closely associated with elevated levels of low-density lipoprotein cholesterol and its oxidized form (ox-LDL). This study aimed to investigate the regulation of sortilin in liver tissue and its potential implications for lipid metabolism. METHODS: Sixty male Wistar rats were randomly divided into four groups: control group (n = 15), ox-LDL group (n = 15), PD98059 group (n = 15), and ox-LDL + PD98059 group (n = 15). Liver sinusoidal endothelial cells were extracted from liver tissue of the control group and were identified using an anti-CD31 antibody. Lipid droplet accumulation was observed by Oil red O and hematoxylin-eosin staining. The protein expression levels were detected by immunohistochemical staining, real-time reverse transcription-polymerase chain reaction, and western blot. Histopathologic examinations were performed by Gomori methenamine silver staining. RESULTS: The ox-LDL group exhibited increased lipid droplet accumulation. Further, ox-LDL activated the extracellular signal-regulated kinase (ERK)-mediated downregulation of sortilin expression, whereas blocking of ERK signaling by PD98059 increased sortilin protein expression. Consistently, hematoxylin-eosin staining showed that the structure of the hepatocytes was loose and disordered in arrangement, with lipid droplets present in the cytoplasm of the ox-LDL group. However, PD98059 significantly improved the integration of the scaffold structure. Gomori methenamine silver staining showed that the ox-LDL group had darker and more obvious fragmented silver nitrate deposits in the basement membrane and sinus space. CONCLUSIONS: Sortilin can protect liver sinusoidal endothelial cells from injury and maintain integration of the liver scaffold structure in ox-LDL-induced lipid-injured liver.

Impact on decision making framework for medicine purchasing in Chinese public hospital decision-making: determining the value of five dipeptidyl peptidase 4 (DPP-4) inhibitors.

BACKGROUND: Medicine purchasing in Chinese public hospitals is decided by the hospital Pharmacy Management Committee (PMC), that is complex, subjective and requires efficient approaches to ensure transparency and consistency for the factors being considered. This study aimed to use the Evidence and Value: Impact on Decision Making (EVIDEM) framework to assess medicine in these hospitals. In this study anti-diabetic drugs DPP-4 inhibitors, which work by inhibiting the activation of the Dipeptidyl Peptidase 4 (DPP-4) inhibitors, were appraised. METHODS: Following EVIDEM methodology (EVIDEM-10th), we convened an appraisal group and asked each individual to express their perspectives by assigning weights to each criterion. A systematic literature search for information of each criterion of five DPP-4 inhibitors was completed. Then the appraisal group scored for each criterion of the five DPP-4 inhibitors. The estimated value of the five DPP-4 inhibitors was obtained by Multi-Criteria Decision Analysis (MCDA) which combined individual weighting of each criterion with individual scoring for each intervention in each criterion. RESULTS: By assigning weights, the most important criterion was the quality of evidence (4.01±0.52), and that the comparative cost consequences-non-medical cost was the least important criterion (2.87±1.03). Criteria included disease severity, size of the affected population, comparative effectiveness, type of therapeutic/preventive benefit and cost of intervention, all of which were assigned the same weight of 3.58. After MCDA, the overall value orders for each DPP-4 inhibitor included Sitagliptin (0.45), Linagliptin (0.44), Vildagliptin (0.43), Alogliptin (0.42) and Saxagliptin (0.40). CONCLUSIONS: Based on EVIDEM framework and MCDA, we found that overall value of five DPP-4 inhibitors was similar. It is feasible to use the EVIDEM framework and MCDA in purchasing medicine for Chinese public hospitals.

High glucose/ox-LDL induced hepatic sinusoidal capillarization via αvß5/FAK/ERK signaling pathway.

OBJECTIVE: The main purpose of this study is to explore the role of integrin αvß5 in hepatic sinusoidal capillarization under high glucose/ox-LDL conditions. METHODS: Establish rat model of diabetic fatty liver disease. LSECs were extracted from tissue obtained from rats of control group, cultured and treated with media containing glucose (25 mM, 24 h)/ox-LDL (100 µg/ml, 24 h) in different inhibitors. The expression of integrin αvß5, FAK, ERK, VN in LSECs were detected by RT-PCR and Western blot. Hematoxylin-eosin staining and gomori methenaminutese silver stain was used to observe the basement membrane histopathological features of the liver tissue. Immunohistochemical to detected the protein expression of integrin αvß5 and VN in liver tissue. Using scanning electron microscopy to visualise the fenestration frequency and fenestration diameter. Protein expression of VN was also testified by immunofluorescence assay. RESULTS: CONCLUSIONS: Integrin αvß5 which induces LSECs dysfunction, promoting hepatic sinusoidal capillarization regulates VN expression via ERK/FAK pathway under high glucose/ox-LDL, may be a potential target for prevention and treatment of T2DM with fatty liver disease.

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.

Retraction Note To: The relationship between subclinical thyroid dysfunction and the risk of fracture or low bone mineral density: a systematic review and meta-analysis of cohort studies.

The editors have retracted this article [1] because it shows significant overlap with a publication by Blum et al. [2] Limin Tian does not agree to this retraction. All the other authors have not responded to any correspondence from the editor about this retraction.

Methodological Quality Assessment of Meta-Analyses of Hyperthyroidism Treatment.

Hyperthyroidism is a common condition that is associated with increased morbidity and mortality. A number of meta-analyses (MAs) have assessed the therapeutic measures for hyperthyroidism, including antithyroid drugs, surgery, and radioiodine, however, the methodological quality has not been evaluated. This study evaluated the methodological quality and summarized the evidence obtained from MAs of hyperthyroidism treatments for radioiodine, antithyroid drugs, and surgery. We searched the PubMed, EMBASE, Cochrane Library, Web of Science, and Chinese Biomedical Literature Database databases. Two investigators independently assessed the meta-analyses titles and abstracts for inclusion. Methodological quality was assessed using the validated AMSTAR (Assessing the Methodological Quality of Systematic Reviews) tool. A total of 26 MAs fulfilled the inclusion criteria. Based on the AMSTAR scores, the average methodological quality was 8.31, with large variability ranging from 4 to 11. The methodological quality of English meta-analyses was better than that of Chinese meta-analyses. Cochrane reviews had better methodological quality than non-Cochrane reviews due to better study selection and data extraction, the inclusion of unpublished studies, and better reporting of study characteristics. The authors did not report conflicts of interest in 53.8% meta-analyses, and 19.2% did not report the harmful effects of treatment. Publication bias was not assessed in 38.5% of meta-analyses, and 19.2% did not report the follow-up time. Large-scale assessment of methodological quality of meta-analyses of hyperthyroidism treatment highlighted methodological strengths and weaknesses. Consideration of scientific quality when formulating conclusions should be made explicit. Future meta-analyses should improve on reporting conflict of interest.

The relationship between subclinical thyroid dysfunction and the risk of fracture or low bone mineral density: a systematic review and meta-analysis of cohort studies.

Our aim was to assess the risk of fractures or low bone mineral density (BMD) associated with subclinical thyroid dysfunction among cohorts. We systematically searched Medline (via PubMed), EMBASE, Cochrane Library, Web of Science, CENTRAL and SinoMed up to 31 July 2016 to identify cohort studies which have analyzed associations between subclinical thyroid dysfunction and fracture or BMD. A total of 19 population-based cohorts including 79,368 participants with relationships between subclinical thyroid dysfunction and fractures or BMD were identified as eligible for this meta-analysis. Subclinical hypothyroidism was associated with relative risks (RRs) of 1.34 (95% confidence interval [CI] 1.14, 1.58; I 2 = 32%) for hip fracture, 1.27 (95% CI 1.02, 1.58; I 2 = 51.9%) for any location of fracture, and 1.25 (95% CI 1.04, 1.50) for forearm fracture. Subclinical hyperthyroidism was associated with RRs of 1.71 (95% CI 1.06, 2.76; I 2 = 0.0%) for spine fracture, 1.20 (95% CI 1.03, 1.39; I 2 = 0.0%) for non-spine fracture, 1.44 (95% CI 1.21, 1.71; I 2 = 0.0%) for hip fracture, and 1.38 (95% CI 1.21, 1.58; I 2 = 0.0%) for any location of fracture. Subgroup analysis was conducted according to whether thyroid/anti-thyroid drug users were excluded or not and the results were similar. The change in BMD at the hip (weighted mean difference [WMD] = -0.060, 95% CI -0.116, -0.004; I 2 = 0.0%) and femoral neck (WMD = -0.046, 95% CI -0.077, -0.015; I 2 = 0.0%) was significantly decreased in the subclinical hyperthyroidism group compared with the euthyroidism groups in females. We failed to find any associations between the change in BMD and subclinical hypothyroidism. The overall quality of evidence was low in all outcomes. Subclinical hyperthyroidism and subclinical hypothyroidism were associated with an increased risk of fractures. Although subclinical hyperthyroidism was related to reduced BMD, no evidence could prove a definite association between subclinical hypothyroidism and the risk of low BMD.

Impaired Sensitivity to Thyroid Hormones is Associated with the Risk of Diabetic Nephropathy in Euthyroid Patients with Type 1 Diabetes Mellitus.

Purpose: This study aims to investigate the relationship between thyroid and type 1 diabetic nephropathy (T1DN) in euthyroid populations, focusing on thyroid hormone sensitivity. Methods: A cross-sectional study was conducted between January 2016 and December 2021, including 357 euthyroid patients with type 1 diabetes mellitus (T1DM). Parameters representing thyroid hormone sensitivity were assessed, including the thyroid feedback quantile-based index (TFQI), parameter thyroid feedback quantile index (PTFQI), thyroid stimulating hormone index (TSHI), thyrotropin thyroxine resistance index (TT4RI), and free triiodothyronine/free thyroxine (FT3/FT4). Logistic regression and restricted cubic spline regression were performed to detect the association between thyroid hormone sensitivity and the risk of T1DN. Results: The study found a negative correlation between the risk of T1DN and FT3/FT4 in euthyroid T1DM patients (OR 0.71, 95% CI 0.51-0.97, P <0.01). PTFQI (P<0.05), TSHI (P<0.05), and TT4RI (P<0.01) showed an M-shaped nonlinear relationship with the risk of T1DN. Elevated risk of T1DN was associated with PTFQI, TSHI, and TT4RI values outside the range of zero, 2.3-3.88, and 27.56-32.19, respectively. Conclusion: This study confirms the relationship between impaired thyroid hormone sensitivity and the risk of T1DN in euthyroid patients. It emphasizes the importance of evaluating thyroid hormone sensitivity in T1DM patients, even when their thyroid function appears normal, to promptly prevent the occurrence of T1DN.

Effect of glycemic control on cognitive function in patients with type 1 diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: It is controversial whether the level of glycemic control in patients with type 1 diabetes mellitus (T1DM) correlates with reduced cognitive function. This study explored the influence of glycemic management quality on cognitive function in T1DM patients by examining the association between glycemic control level and impaired cognitive function. METHODS: The electronic databases PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, China Science and Technology Journal database, Wanfang database, and China Biology Medicine disc database were systematically searched to identify eligible studies published before January 2023. Search, selection, and data extraction were performed by two independent reviewers. RevMan 5.4 software was used for meta-analysis, and standardized mean difference (SMD) between groups was calculated. RESULTS: Six studies involving 351 patients with T1DM were included in this study. Compared with T1DM subjects with good glycemic control, those with poor glycemic control performed worse in full-scale intellectual quotient (P = 0.01, SMD = -0.79, 95%CI = -1.42 to -0.17), but no significant differences were observed in verbal intellectual quotient (P = 0.08, SMD = -1.03, 95%CI = -2.20 to 0.13), memory (P = 0.05, SMD = -0.41, 95%CI = -0.82 to 0.00), and attention (P = 0.23, SMD = -0.26, 95%CI = -0.69 to 0.16). CONCLUSIONS: T1DM patients with suboptimal glycemic control may have a worse cognitive function, mainly focusing on the full-scale intellectual quotient. The current study highlights the significance of maintaining satisfactory glycemic control in T1DM patients to improve their health status and quality of life. Standardized tests should be employed in clinical neuropsychological practice to provide early and complete cognitive assessment of individuals with poor glycemic control. SYSTEMATIC REVIEW REGISTRATION: The study protocol has been registered in the PROSPERO database (CRD42023390456).

FNDC5/irisin ameliorates bone loss of type 1 diabetes by suppressing endoplasmic reticulum stress­mediated ferroptosis.

BACKGROUND: Ferroptosis is known to play a crucial role in diabetic osteopathy. However, key genes and molecular mechanisms remain largely unclear. This study aimed to identify a crucial ferroptosis-related differentially expressed gene (FR-DEG) in diabetic osteopathy and investigate its potential mechanism. METHODS: We identified fibronectin type III domain-containing protein 5 (FNDC5)/irisin as an essential FR-DEG in diabetic osteopathy using the Ferroptosis Database (FerrDb) and GSE189112 dataset. Initially, a diabetic mouse model was induced by intraperitoneal injection of streptozotocin (STZ), followed by intraperitoneal injection of irisin. MC3T3-E1 cells treated with high glucose (HG) were used as an in vitro model. FNDC5 overexpression plasmid was used to explore underlying mechanisms in vitro experiments. Femurs were collected for micro-CT scan, histomorphometry, and immunohistochemical analysis. Peripheral serum was collected for ELISA analysis. Cell viability was assessed using a CCK-8 kit. The levels of glutathione (GSH), malondialdehyde (MDA), iron, reactive oxygen species (ROS), and lipid ROS were detected by the corresponding kits. Mitochondria ultrastructure was observed through transmission electron microscopy (TEM). Finally, mRNA and protein expressions were examined by quantitative real-time PCR (qRT-PCR) and western blot analysis. RESULTS: The expression of FNDC5 was found to be significantly decreased in both in vivo and in vitro models. Treatment with irisin significantly suppressed ferroptosis and improved bone loss. This was demonstrated by reduced lipid peroxidation and iron overload, increased antioxidant capability, as well as the inhibition of the ferroptosis pathway in bone tissues. Furthermore, in vitro studies demonstrated that FNDC5 overexpression significantly improved HG-induced ferroptosis and promoted osteogenesis. Mechanistic investigations revealed that FNDC5 overexpression mitigated ferroptosis in osteoblasts by inhibiting the eukaryotic initiation factor 2 alpha (eIF2α)/activated transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) pathway. CONCLUSIONS: Collectively, our study uncovered the important role of FNDC5/irisin in regulating ferroptosis of diabetic osteopathy, which might be a potential therapeutic target.

Naringenin ameliorates atopic dermatitis by inhibiting inflammation and enhancing immunity through the JAK2/STAT3 pathway.

OBJECTIVE: Atopic dermatitis (AD) is an inflammatory skin disease. Naringenin (Nar) possesses an anti-inflammatory property. This paper attempts to discuss the functional mechanism of Nar in AD mice through the Janus kinase 2 (JAK2)/signal transducer and activation of transcription 3 (STAT3) pathway. METHODS: Mouse models of DNFB-induced AD were established and treated with Nar, followed by intraperitoneal injection with the JAK2/STAT3 pathway activator Coumermycin A1. Dermatitis severity was scored and the thickness of right ear was measured. The pathological changes in dorsal skin tissues were observed by HE staining. The number of infiltrated mast cells and eosinophilic granulocytes was counted by TB staining. The serum IgE level and levels of TNF-α, IL-6, IFN-γ, IL-12, and IL-5 in dorsal skin tissues were measured by ELISA. The levels of p-JAK2, JAK2, p-STAT3, and STAT3 were determined by Western blot. RESULTS: Nar decreased dermatitis scores and right ear thickness, alleviated skin lesions, and reduced the number of infiltrated mast cells and eosinophilic granulocytes in AD mice. The serum IgE level and levels of TNF-α, IL-6, IFN-γ, IL-12, and IL-5 in dorsal skin tissues of AD mice were diminished after Nar treatment in a dose-dependent manner. Nar inhibited the activation of the JAK2/STAT3 pathway. The activation of the JAK2/STAT3 pathway partially nullified the therapeutic function of Nar on AD mice. CONCLUSION: Nar protects mice from AD by inhibiting inflammation and promoting immune responses through the inhibition of the JAK2/STAT3 pathway.

[MOR106 alleviates inflammation in mice with atopic dermatitis by blocking the JAK2/STAT3 signaling pathway and inhibiting IL-17C-mediated Tfh cell differentiation].

Objective To explore the significance of interleukin-17C(IL-17C)-mediated follicular helper T cell (Tfh) differentiation in atopic dermatitis (AD) model. Methods BALB/c mice were divided into control group, AD model group, low-dose MOR106 (anti-IL-17C huIgG1)(MDR106-L)treatment group and high-dose MOR106 (MOR106-H) treatment group, 8 mice in each group. Except for the control group, all the other groups were treated with 2, 4- dinitrochlorobenzene (DNCB) to establish AD models. The low-dose and high-dose MOR106 groups were treated with 5 mg/kg or 10 mg/kg MOR106 respectively. The differentiation of Tfh cell subsets in peripheral blood of mice was analyzed by flow cytometry, and the expression of Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3) signal pathway protein in skin tissue was detected by Western blot analysis. Results Compared with the control group, the dermatitis severity score, mass difference between two ears, spleen mass and spleen index of DNCB group increased significantly, while those of MOR106-L group and MOR106-H group decreased significantly. Compared with the control group, the Tfh subgroup of AD mice showed deregulated differentiation, resulting in a significant increase in the percentage of CD4+CXCR5+IFN-γ+Tfh1 cells, CD4+CXCR5+IL-17A+Tfh17 and CD4+CXCR5+IL-21+Tfh21 cells, and a significant decrease in the percentage of CD4+CXCR5+IL-10+Tfh10 cells and CD4+CXCR5+FOXP3+Tfr cells in peripheral blood. The protein levels of phosphorylated JAK2(p-JAK2) and p-STAT3 were significantly increased. MOR106 effectively reversed these changes of Tfh1, Tfh10, Tfh17, Tfh21 and Tfr cells in peripheral blood of AD mice. Compared with AD group, the levels of p-JAK2 and p-STAT3 protein in low-dose and high-dose MOR106 treatment groups decreased significantly. Conclusion MOR106 can reduce the inflammatory response of AD mice by blocking JAK2/STAT3 signaling pathway and inhibiting the differentiation of Tfh cells mediated by IL-17C.

Hepatic Sinusoid Capillarizate via IGTAV/FAK Pathway Under High Glucose.

The incidence of diabetic patients with non-alcoholic fatty liver disease (NAFLD) is continuously increasing worldwide. However, the specific mechanisms of NAFLD patients with diabetes are still not clear. Recent studies have indicated that integrins play an important role in NAFLD. In this study, we considered the relationship between integrin αv (IGTAV)/FAK pathway and sinusoidal capillarization. We investigated the difference between the expression of IGTAV, laminin (LN), focal adhesion kinase (FAK), and phosphor-FAK protein in human liver sinusoidal endothelial cells (HLSECs) to explore the specific mechanisms of the diseases of NAFLD with diabetes under high glucose. We cultured and identified the HLSECs and constructed the recombinant lentivirus vector with IGTAV shRNA by quantitative real-time PCR (qRT-PCR) to silence the IGTAV gene. Cells were divided into groups of 25 mmol/L glucose and 25 mmol/L mannitol. We measured the protein levels of IGTAV, LN, FAK, and phosphor-FAK by western blot at 2 h, 6 h, and 12 h before and after IGTAV gene silencing. The lentivirus vector was successfully constructed with IGTAV shRNA. The HLSECs under high glucose were observed by scanning electron microscope. SPSS19.0 was used for statistical analysis. High glucose significantly increased the expression of IGTAV, LN, and phosphor-FAK protein in HLSECs; the shRNA IGTAV could effectively inhibit the expression of phosphor-FAK and LN at 2 h and 6 h. Inhibition of the phosphor-FAK could effectively decrease the expression of LN in HLSECs at 2 h and 6 h under high glucose. Inhibition of IGTAV gene of HLSECs under high glucose could improve hepatic sinus capillarization. Inhibition of IGTAV and phosphor-FAK decreased the expression of LN. High glucose led to hepatic sinus capillarization via IGTAV/ FAK pathway.

Inhibiting sEH suppresses NF-κB p65 signaling and reduces CXCL10 expression as a potential therapeutic target in HT.

BACKGROUND: Although Hashimoto's thyroiditis (HT) is one of most common autoimmune thyroid diseases, its treatment remains focused on symptom relief. The soluble epoxide hydrolase (sEH) shows potential functions as drug target in alleviating some autoimmune diseases, however, we seldom know its role in HT. METHODS: The protein expression of sEH and related downstream molecules were evaluated by immunohistochemistry, western blotting, enzyme linked immunosorbent assay or immunofluorescence staining. RNA sequencing of tissue samples was performed to analyze differential genes and dysregulated pathways in HT and controls. The thyroid follicular epithelial cells (TFECs) and rat HT model were used to verify the biological function of sEH and the inhibition role of adamantyl-ureido-dodecanoic acid (AUDA) in HT. RESULTS: The sEH was significantly up-regulated in HT patients compared with healthy individuals. Transcriptome sequencing showed cytokine-related pathways and chemokine expression, especially chemokine CXCL10 and its receptor CXCR3 were aberrant in HT patients. In TFECs and rat HT model, blocking sEH by AUDA inhibitor could effectively inhibit the autoantibody, pro-inflammatory NF-κB signaling, chemokine CXCL10/CXCR3 expression and type-1 helper CD4+ T cells. CONCLUSIONS: Our findings suggest that sEH/NF-κB p65/CXCL10-CXCR3 might be promising therapeutic targets for HT.