The risk of concurrent malignancies in patients with multiple endocrine neoplasia type 1: insights into clinical characteristics of those with multiple endocrine neoplasia type 1.

OBJECTIVE: Summarize and analyze the characteristics of patients with Multiple Endocrine Neoplasia type 1 (MEN-1) who were diagnosed with malignant tumors that do not belong to MEN-1 components. METHODS: Clinical data from patients with MEN-1 who visited Peking Union Medical College Hospital between April 2012 and April 2022 were collected. We compared the clinical characteristics of patients with malignant tumors outside of their MEN-1 components to those without additional tumors. MEN-1 gene testing was performed on most of these patients using Sanger sequencing, whole-exome sequencing, or MLPA. RESULTS: A total of 221 MEN-1 patients were diagnosed, of which 23 (10.40%) were found to have malignant tumors that did not belong to MEN-1 components, including papillary thyroid carcinoma (PTC) (4.52%), breast cancer (1.81%), urologic neoplasms (1.35%), primary hepatic carcinoma (PCC) (0.09%), meningeal sarcoma (0.05%), glioblastoma (0.05%), cervical cancer (0.05%), and lung carcinoma (0.05%). MEN-1 gene mutations were identified in 11 patients, including missense mutations, frameshift mutations, and splice mutations. The prevalence of each endocrine neoplasm, particularly gastroenteropancreatic neuroendocrine tumor, was higher in MEN-1 patients with other malignant tumors compared to MEN-1 patients without malignant tumors. CONCLUSION: Our retrospective study revealed a higher incidence of non-MEN-1 component malignant tumors in MEN-1 patients, especially breast cancer, PTC, and urologic neoplasms. These patients also exhibit more severe clinical phenotypes of MEN-1.

The Whole-transcriptome Landscape of Diabetes-related Sarcopenia Reveals the Specific Function of Novel lncRNA Gm20743.

While the exact mechanism remains unclear, type 2 diabetes mellitus increases the risk of sarcopenia which is characterized by decreased muscle mass, strength, and function. Whole-transcriptome RNA sequencing and informatics were performed on the diabetes-induced sarcopenia model of db/db mice. To determine the specific function of lncRNA Gm20743, the detection of Mito-Sox, reactive oxygen species, Ethynyl-2'-deoxyuridine, and myosin heavy chain was performed in overexpressed and knockdown-Gm20743 C2C12 cells. RNA-seq data and informatics revealed the key lncRNA-mRNA interactions and indicated a potential regulatory role of lncRNAs. We characterized three core candidate lncRNAs Gm20743, Gm35438, 1700047G03Rik, and their potential function. Furthermore, the results suggested lncRNA Gm20743 may be involved in regulating mitochondrial function, oxidative stress, cell proliferation, and myotube differentiation in skeletal muscle cells. These findings significantly improve our understanding of lncRNAs that may mediate muscle mass, strength, and function in diabetes and represent potential therapeutic targets for diabetes-induced sarcopenia.

Appendiceal Neuroendocrine Tumor Is a Rare Cause of Ectopic Adrenocorticotropic Hormone Syndrome With Cyclic Hypercortisolism: A Case Report and Literature Review.

OBJECTIVE: Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a condition of hypercortisolism caused by non-pituitary tumors secreting ACTH. Appendiceal neuroendocrine tumor as a rare cause of ectopic ACTH syndrome was reported scarcely. We aimed to report a patient diagnosed with EAS caused by an appendiceal neuroendocrine tumor and summarized characteristics of these similar cases reported before. CASE REPORT AND LITERATURE REVIEW: We reported a case with Cushing's syndrome who was misdiagnosed as pituitary ACTH adenoma at first and accepted sella exploration. Serum and urinary cortisol decreased, and symptoms were relieved in the following 4 months after surgery but recurred 6 months after surgery. The abnormal rhythm of plasma cortisol and ACTH presented periodic secretion and seemingly rose significantly after food intake. EAS was diagnosed according to inferior petrosal sinus sampling (IPSS). Appendiceal mass was identified by 68Ga-DOTA-Tyr3-octreotate (DOTATATE)-PET-CT and removed. The pathological result was consistent with appendiceal neuroendocrine tumor with ACTH (+). The literature review demonstrated 7 cases diagnosed with EAS caused by appendiceal neuroendocrine tumor with similarities and differences. CONCLUSION: The diagnosis of an ectopic ACTH-producing tumor caused by the appendiceal neuroendocrine tumor can be a challenging procedure. Periodic ACTH and cortisol secretion may lead to missed diagnosis and misdiagnosis. IPSS is crucial in the diagnosis of EAS and 68Ga-DOTATATE-PET-CT plays an important role in the identification of lesions.

Fibrinogen, fibrin degradation products and risk of sarcopenia.

BACKGROUND & AIMS: Increasing data suggests that chronic low-grade inflammation plays an important role on development of sarcopenia. The present study was designed to identify the association between fibrinogen, fibrin degradation products (FDP) and sarcopenia risk in hospitalized old patients. METHODS: A total of 437 patients were enrolled in this cross-sectional study (148 with sarcopenia and 289 without sarcopenia). Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Body composition, grip strength and gait speed were performed to participants. Fibrinogen, FDP levels were measured. Logistic regression analyses were carried out to assess the association between fibrinogen and sarcopenia, between FDP and sarcopenia, respectively. RESULTS: Compared to non-sarcopenic patients, fibrinogen and FDP levels were found to be higher in the sarcopenic group (3.07 g/L vs 2.79 g/L, 1.75 µg/mL vs 1.00 µg/mL, respectively, p < 0.05). Multiple linear regression analysis showed a significant negative association between fibrinogen and gait speed (ß: -0.164, p = 0.008), and muscle strength (ß: -0.231, p < 0.001). Multivariable logistic regression analysis showed that fibrinogen and FDP were independently associated with sarcopenia (odds ratio 1.32 [95% confidence interval 1.03, 1.70], p = 0.009; odds ratio 1.07 [95% confidence interval 1.01, 1.19], p = 0.049, respectively). ROC curve revealed that the cutoff values of fibrinogen and FDP to predict sarcopenia risk were 2.54 g/L and 1.15 µg/mL, respectively. CONCLUSIONS: In hospitalized old patients, serum fibrinogen and FDP levels are elevated in sarcopenia patients than those without sarcopenia. Fibrinogen and FDP are associated with sarcopenia in a concentration-dependent manner.

Type 2 diabetes-induced overactivation of P300 contributes to skeletal muscle atrophy by inhibiting autophagic flux.

AIMS: Although autophagy impairment is a well-established cause of muscle atrophy and P300 has recently been identified as an important regulator of autophagy, the effects of P300 on autophagy and muscle atrophy in type 2 diabetes (T2D) remain unexplored. We aimed at characterizing the role of P300 in diabetic muscle and its underlying mechanism. MAIN METHODS: Protein levels of phosphorylated P300, total P300, acetylated histone H3, LC3, p62 and myosin heavy chain, and mRNA levels of Atrogin-1 and MuRF1 were analyzed in palmitic acid (PA)-treated myotubes and db/db mice. Autophagic flux was assessed using transmission electron microscopy, immunofluorescence and mRFP-GFP-LC3 lentivirus transfection in cells. Muscle weight, blood glucose and grip strength were measured in mice. Hematoxylin and eosin (H&E) staining was performed to determine changes in muscle fiber size. To investigate the effects of P300 on autophagy and myofiber remodeling, a P300 specific inhibitor, c646, was utilized. 3-Methyladenine (3-MA) was utilized to inhibit autophagosomes formation, and chloroquine (CQ) was used to block autophagic flux. KEY FINDINGS: Phosphorylation of P300 in response to PA enhanced its activity and subsequently suppressed autophagic flux, leading to atrophy-related morphological and molecular changes in myotubes. Inhibition of P300 reestablished autophagic flux and ameliorated PA-induced myotubes atrophy. However, this effect was largely abolished by co-treatment with the autophagy inhibitor CQ. In vivo results demonstrated that inhibition of P300 partially rescued muscle wasting in db/db mice, accompanied with autophagy reactivation. SIGNIFICANCE: The findings revealed that T2D-induced overactivation of P300 contributes to muscle atrophy by blocking autophagic flux.

Comparative Proteome Analysis of Epicardial and Subcutaneous Adipose Tissues from Patients with or without Coronary Artery Disease.

BACKGROUND AND AIMS: Owing to its unique anatomical structure and metabolism, epicardial adipose tissue (EAT) has attracted amount of attention in coronary artery disease (CAD) research. Here, we analyzed differences in proteome composition in epicardial (EAT) and subcutaneous adipose tissues (SAT) from patients with or without CAD. METHODS: EAT and SAT samples were collected from 6 CAD patients and 6 non-CAD patients. Isobaric Tagging for Relative and Absolute Quantitation (iTRAQ) analysis combined with liquid chromatography tandem-mass spectrometry (LC-MS/MS) was performed to identify the differentially expressed proteins. RESULTS: In total, 2348 proteins expressed in EAT and 2347 proteins expressed in SAT were separately identified. 385 differentially expressed proteins were found in EAT and 210 proteins were found in SAT in CAD patients compared to non-CAD patients. Many proteins differentially expressed in EAT of CAD patients were involved in biological functions associated with CAD development such as cell-to-cell signaling and interaction, inflammatory response, and lipid metabolism. Differential expressions of proteins (MMP9, S100A9, and clusterin) in EAT or SAT were involved in several signaling pathways such as mitochondrial dysfunction, acute phase inflammation, and LXR/RXR activation, which was confirmed by western blotting, and similar results were obtained. CONCLUSIONS: The largest profiles of differentially expressed proteins in EAT and SAT between CAD patients and non-CAD patients were identified. The significant signal pathways, mitochondrial dysfunction, and LXR/RXR activation, which differential proteins were involved in, were firstly found to play roles in EAT of CAD patients, and clusterin was firstly found to be upregulated in EAT of CAD patients.

Inhibition of TLR9 attenuates skeletal muscle fibrosis in aged sarcopenic mice via the p53/SIRT1 pathway.

Sarcopenia is an age-related syndrome characterized by a gradual loss of muscle mass and function, but its pathophysiological mechanism remains unclear. Skeletal muscle extracellular matrix (ECM) remodeling is an important pathological change in sarcopenia, and fibrosis is the most obvious manifestation of this change. We found that the expression of the immunoreceptor Toll-like receptor 9 (TLR9) is significantly increased in skeletal muscle in aged mice and is positively related to muscle fibrosis. Moreover, in previous reports, the longevity gene Sirt1 was reported to attenuate ECM deposition and improve muscle function. In this study, we hypothesized that TLR9 modulated skeletal muscle fibrosis via Sirt1. We used TLR9 knockout (TLR9 KO) mice and C57 mice, and grip strength and body composition were compared at different ages. We found that TLR9 knockout significantly attenuated skeletal muscle fibrosis and improved muscle function in aged mice. Furthermore, silent information regulator 1 (Sirt1) activity in mice was inhibited by Ex527, which is a specific inhibitor of Sirt1. Negative Sirt1 regulation via the activation of TLR9-related signaling pathways participated in skeletal muscle fibrosis in the sarcopenic mice, and this process might mediated by the Sirt1/Smad signaling pathway. Our findings revealed that fibrosis changes in the gastrocnemius muscle in sarcopenic mice are closely related to TLR9 activation, and TLR9 modulation could be a therapeutic strategy for combating sarcopenia during aging.

Metformin attenuates diabetes-induced tau hyperphosphorylation in vitro and in vivo by enhancing autophagic clearance.

Diabetes mellitus (DM) can increase the risk of Alzheimer's disease (AD) in patients. However, no effective approaches are available to prevent its progression and development. Recently, autophagy dysfunction was identified to be involved in the pathogenesis of neurodegenerative diseases. This study was designed to investigate the effect of metformin on hyperphosphorylated tau proteins in diabetic encephalopathy (DE) by regulating autophagy clearance. db/db mice were randomly divided into four groups, db/+ mice were used as control group. Twelve-week old male db/db mice received consecutive intraperitoneal injection of 200 mg/kg/d metformin or (and) 10 mg/kg/d chloroquine for eight weeks. Morris water maze (MWM) tests were performed to test cognitive functions before the mice were euthanized. Metformin attenuated cognitive impairment in db/db mice, reduced hyperphosphorylated tau proteins, restored the impaired autophagy in diabetic mice, all of which were reversed by inhibiting of autophagy activity. In high glucose-cultured HT22 cells, metformin increased autophagy in a dose-dependent manner. Besides, metformin enhanced autophagy activity in an AMPK dependent manner. These data show that metformin may reduce tauopathy and improve cognitive impairment in db/db mice by modulating autophagy through the AMPK dependent pathway. These findings highlight metformin as a new therapeutic strategy for the treatment of DE.

The effect of exercise, resveratrol or their combination on Sarcopenia in aged rats via regulation of AMPK/Sirt1 pathway.

Sarcopenia is an age-related syndrome characterized by progressive loss of muscle mass and function. Exercise is an important strategy to prolong life and increase muscle mass, and resveratrol has been shown a variety beneficial effects on skeletal muscle. In the present study, we investigated the potential efficacy of using short-term exercise (six weeks), resveratrol (150mg/kg/day), or combined exercise+resveratrol (150mg/kg/day) on gastrocnemius muscle mass, grip strength, cross-sectional area and microscopic morphology in aged rats, and explored the potential mechanism at the apoptosis level. Six months old SD rats were used as young control group and 24months old SD rats were adopted as aged group. After six weeks intervention, the data provide evidence that exercise, resveratrol or their combination significantly increase the relative grip strength and muscle mass in aged rats (P<0.05). Electron microscopy discovered a significant increase in sarcomere length, I-band and H-zone in aged rats (P<0.05), and exercise, resveratrol or their combination significantly reduced the increasement (P<0.05). Moreover, light microscopy revealed a significant increase on Feret's diameter and cross-sectional area (CSA) in aged rats (P<0.05), but exercise and resveratrol did not show significant effects on them (P>0.05). Furthermore, exercise, resveratrol or their combination significantly increased the expression of p-AMPK and SIRT1, decreased the expression of acetyl P53 and Bax/Bcl-2 ratio in aged rats (P<0.05). These findings show that aged rats show significant changes in gastrocnemius muscle morphology and ultrastructure, and the protective effects of exercise, resveratrol and their combination are probably associated with anti-apoptotic signaling pathways through activation of AMPK/Sirt1.

Angiotensin-(1-7) administration attenuates Alzheimer's disease-like neuropathology in rats with streptozotocin-induced diabetes via Mas receptor activation.

Diabetes mellitus (DM) is associated with cognitive deficits and an increased risk of Alzheimer's disease (AD). Recently, a newly identified heptapeptide of the renin-angiotensin system (RAS), angiotensin-(1-7) [Ang-(1-7)], was found to protect against brain damage. This study investigated the effects of Ang-(1-7) on diabetes-induced cognitive deficits. Sprague-Dawley rats were randomly divided into four groups. Diabetes was induced via single i.p. streptozotocin (STZ) injections. Ten weeks after diabetes induction, rats in each group received an intracerebral-ventricular (ICV) infusion of either vehicle, Ang-(1-7) alone, or Ang-(1-7)+A779 daily for two weeks. At the end of the study, Morris water maze (MWM) tests were performed to test cognitive functions before the rats were euthanized. Ang-(1-7) treatment significantly reduced escape latencies in diabetic rats in acquisition trials and markedly enhanced platform area crossing frequency and time spent in the target quadrant in probe trials (3.0±0.39 vs. 1.0±0.33, 39.39±1.11% vs. 25.62±3.07%, respectively, P<0.01). Ang-(1-7) treatment ameliorated damage to the ultrastructure of hippocampal synapses, reduced the expression of hippocampal phospho-tau at Ser396 (P<0.01), Ser404 (P<0.01) and Ser202/Thr205 (P<0.05), and decreased amyloid-ß oligomer and both soluble and insoluble ß-amyloid peptide 1-42 (Aß 1-42) and Aß 1-40 levels (P<0.01). These protective effects were significantly reversed by the co-administration of A779. These findings show that Ang-(1-7) is a promising therapeutic target for diabetes-induced cognitive impairment. The neuroprotective effects of Ang-(1-7) were mainly through Mas receptor (MasR) activation.

[Effects of ghrelin on hippocampal DKK-1 expression and cognitive function in rats with diabetes mellitus].

OBJECTIVE: To explore the effects of ghrelin on learning and memory abilities and expressions of DKK-1 and ß-catenin in the hippocampus of diabetic rats. METHODS: Sixty male SD rats were randomly assigned into 4 groups, namely the control group, diabetic group, ghrelin-treated diabetic group (DM1 group), and ghrelin- and D-lys3-GHRP-6 (a GHSR-1a receptor antagonist)-treated diabetic group (DM2 group). Diabetic rat models were established by a single intraperitoneal injection of streptozotocin (65 mg/kg). The learning and memory abilities of the rats were assessed with Morris water maze (MWM) test. The ultrastructure of the hippocampal CA1 area of the rats were observed with electron microscopy. Serum levels of DKK-1 were examined by ELISA, and the expressions of DKK-1 and ß-catenin in the hippocampus were examined by quantitative real-time PCR and Western blotting. RESULTS: Compared with the control group, the diabetic rats exhibited significantly impaired learning and memory abilities (P<0.05), increased expression of DKK-1 and lowered ß-catenin expression in the hippocampus (P<0.05), significant ultrastructural injuries and disordered arrangement of neurons with the nuclear pycnosis in the hippocampal CA1 area. Ghrelin treatment of the diabetic rats obviously improved their learning and memory abilities (P<0.05), reduced DKK-1 and increased ß-catenin expressions (P<0.05), ameliorated ultrastructural damages in the hippocampal CA1 area and restored normal neuronal alignment with clear cell layers. Such effects of ghrelin were antagonized by treatment with D-lys3-GHRP-6 in the diabetic rats. CONCLUSION: Ghrelin can alleviate learning and memory dysfunction in diabetic rats possibly by down-regulating the expressions of DKK-1 and activating the WNT signaling pathways.