Downregulation of RCN1 inhibits esophageal squamous cell carcinoma progression and M2 macrophage polarization.

Reticulocalbin 1 (RCN1) is a calcium-binding protein involved in the regulation of calcium homeostasis in the endoplasmic reticulum. The aim of this study was to explore the clinical value and biological role of RCN1 in esophageal squamous cell carcinoma (ESCC). In addition, we investigated the effect of RCN1 on the polarization of tumor-associated macrophages (TAMs).

IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of β cells.

Recessive mutations in IER3IP1 (immediate early response 3 interacting protein 1) cause a syndrome of microcephaly, epilepsy, and permanent neonatal diabetes (MEDS). IER3IP1 encodes an endoplasmic reticulum (ER) membrane protein, which is crucial for brain development; however, the role of IER3IP1 in β cells remains unknown. We have generated two mouse models with either constitutive or inducible IER3IP1 deletion in β cells, named IER3IP1-βKO and IER3IP1-iβKO, respectively.

Clinical Characteristics of Patients With MODY: A Literature Review and Retrospective Chart Review.

The clinical manifestation of hepatocyte nuclear factor-1-alpha () maturity-onset diabetes of the young (MODY) is highly variable. This study aims to investigate the clinical characteristics of patients with MODY in general, by geographical regions (Asian or non-Asian), mutations, and islet autoantibody status. A literature review and a chart review of patients with MODY were performed.

A Novel Nonsense Mutation Causes Inefficient Preproinsulin Translocation Into the Endoplasmic Reticulum.

Preproinsulin (PPI) translocation across the membrane of the endoplasmic reticulum (ER) is the first and critical step of insulin biosynthesis. Inefficient PPI translocation caused by signal peptide (SP) mutations can lead to β-cell failure and diabetes. However, the effect of proinsulin domain on the efficiency of PPI translocation remains unknown.

Prediction model of random forest for the risk of hyperuricemia in a Chinese basic health checkup test.

Objectives: The present study aimed to develop a random forest (RF) based prediction model for hyperuricemia (HUA) and compare its performance with the conventional logistic regression (LR) model.

Methods: This cross-sectional study recruited 91,690 participants (14,032 with HUA, 77,658 without HUA). We constructed a RF-based prediction model in the training sets and evaluated it in the validation sets.

Evolution of insulin at the edge of foldability and its medical implications.

Proteins have evolved to be foldable, and yet determinants of foldability may be inapparent once the native state is reached. Insight has emerged from studies of diseases of protein misfolding, exemplified by monogenic diabetes mellitus due to mutations in proinsulin leading to endoplasmic reticulum stress and β-cell death. Cellular foldability of human proinsulin requires an invariant Phe within a conserved crevice at the receptor-binding surface (position B24).

[Preliminary result of stents implantation for spontaneous isolated dissection of the superior mesenteric artery: a prospective single-arm study].

To access the efficacy of stents for spontaneous isolated dissection of the superior mesenteric artery (SIDSMA). The study is a prospective single-arm study which has been registered on Clinical Trials (NCT03916965). Clinical data and follow-up information of the SIDSMA patients who received stent implantation in the First Affiliated Hospital of Zhejiang University during April 1, 2019 and September 30, 2019 were collected.

Liraglutide improves obesity-induced renal injury by alleviating uncoupling of the glomerular VEGF-NO axis in obese mice.

Obesity-related kidney disease is associated with generalized endothelial dysfunction. Liraglutide, a glucagon-like peptide-1 agonist, has cardiovascular-renal protective effects in patients with diabetes. In this study, the ability of liraglutide to reduce urinary albumin excretion by alleviating glomerular vascular endothelial growth factor-nitric oxide (VEGF-NO) axis uncoupling was assessed in high fat diet-induced obese mice.

Role of Proinsulin Self-Association in Mutant Gene-Induced Diabetes of Youth.

Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin (PI) in the endoplasmic reticulum (ER) drive the molecular pathogenesis of mutant gene-induced diabetes of youth (MIDY). How these abnormal interactions are initiated remains unknown. Normally, PI-WT dimerizes in the ER.

Gender-Specific Differences on the Association of Hypertension with Subclinical Thyroid Dysfunction.

Objective: Both hypertension and subclinical thyroid dysfunction (STD) have high prevalence and clinical importance, but their relationship is still a matter of debate. We aimed to explore gender-specific difference on the association between hypertension and STD in Chinese.

Methods: We recruited 13,380 ostensible healthy participants (8,237 men and 5,143 women).

"Register-shift" insulin analogs uncover constraints of proteotoxicity in protein evolution.

Globular protein sequences encode not only functional structures (the native state) but also protein foldability, a conformational search that is both efficient and robustly minimizes misfolding. Studies of mutations associated with toxic misfolding have yielded insights into molecular determinants of protein foldability. Of particular interest are residues that are conserved yet dispensable in the native state.

A Meta-Analysis of Pregnancy Outcomes With Levothyroxine Treatment in Euthyroid Women With Thyroid Autoimmunity.

Context: Thyroid autoimmunity (TAI), the most common cause of (sub)clinical hypothyroidism, is associated with adverse pregnancy outcomes. The benefits of levothyroxine (LT4) intervention in women with TAI remain controversial.

Objective: The purpose of this analysis is to determine the effect of LT4 on pregnancy outcomes in euthyroid women with TAI.

No obvious association exists between red blood cell distribution width and thyroid function.

We aimed to explore gender impacts on the associations between red blood cell distribution width (RDW) and thyroid function in the Chinese population. Gender impacts on the associations between RDW and thyroid function in 8424 males and 5198 females were investigated. RDW was found significantly lower in males than in females.

THE ASSOCIATION BETWEEN BODY MASS INDEX AND SUBCLINICAL THYROID DYSFUNCTION IN DIFFERENT SEXES OF CHINESE.

To study subclinical thyroid dysfunction (SCTD)-subclinical hyperthyroidism and subclinical hypothyroidism-in Chinese patients in relation to body mass index (BMI) and to determine whether a difference between sexes exists. This cross-sectional study recruited 13,503 healthy participants (8,345 male, 5,158 female) who participated in a health examination. Clinical data, including anthropometric measurements and serum parameters, were collected.

Misfolded proinsulin impairs processing of precursor of insulin receptor and insulin signaling in β cells.

Insulin resistance in classic insulin-responsive tissues is a hallmark of type 2 diabetes (T2D). However, the pathologic significance of β-cell insulin resistance and the underlying mechanisms contributing to defective insulin signaling in β cells remain largely unknown. Emerging evidence indicates that proinsulin misfolding is not only the molecular basis of mutant -gene-induced diabetes of youth (MIDY) but also an important contributor in the development and progression of T2D.

Impaired Glucose-Stimulated Proinsulin Secretion Is an Early Marker of β-Cell Impairment Before Prediabetes Stage.

Context: Evidence indicates that there is substantial impairment/loss of β-cell function/mass even before prediabetes. Elevated plasma proinsulin is a sign of β-cell dysfunction in patients with diabetes/prediabetes. However, the dynamic changes of glucose stimulated proinsulin secretion (GSPS) among nondiabetic individuals remain obscure.

Gender- and Age-Specific Differences in the Association of Hyperuricemia and Hypertension: A Cross-Sectional Study.

Objective: Both hyperuricemia and hypertension have important clinical implications, but their relationship in terms of gender and age is still a matter of debate. In this study, we aimed to explore gender- and age-specific differences in this association between hyperuricemia and hypertension in a Chinese population.

Methods: A total of 78596 ostensibly healthy subjects (47781 men and 30815 women) were recruited.

A left femoral artery to right femoral vein bypass graft for hemodialysis access: A case report.

Rationale: As survival prospects improve for long-term patients with hemodialysis, it is common for patients to exhaust all upper extremity access options before other avenues need exploration. The purpose of this case report was to describe our experience in creating a prosthetic graft between left femoral artery and right femoral vein in a patient with history of central venous occlusion and bilateral femoral neck fracture.

Patient Concerns: A female patient with hemodialysis exhausted all upper extremity access options along with bilateral femoral neck fracture.

Association between platelet distribution width and serum uric acid in Chinese population.

Platelet distribution width (PDW) is a simple and inexpensive parameter, which could predict activation of coagulation efficiently. And it has been confirmed to have a significant role in many diseases. We aimed to explore the association between PDW and hyperuricemia in a large Chinese cohort.

Biosynthesis, structure, and folding of the insulin precursor protein.

Insulin synthesis in pancreatic β-cells is initiated as preproinsulin. Prevailing glucose concentrations, which oscillate pre- and postprandially, exert major dynamic variation in preproinsulin biosynthesis. Accompanying upregulated translation of the insulin precursor includes elements of the endoplasmic reticulum (ER) translocation apparatus linked to successful orientation of the signal peptide, translocation and signal peptide cleavage of preproinsulin-all of which are necessary to initiate the pathway of proper proinsulin folding.

Perfluorooctanoic acid impaired glucose homeostasis through affecting adipose AKT pathway.

Perfluorooctanoic acid (PFOA) is commonly applied in manufactured products, and its potential health risk is concerned greatly. Increasing evidences have indicated PFOA-induced liver dysfunction. However, detailed molecular mechanism has not been completely identified.

Positive charge in the n-region of the signal peptide contributes to efficient post-translational translocation of small secretory preproteins.

Increasing evidence indicates that many small secretory preproteins can undergo post-translational translocation across the membrane of the endoplasmic reticulum. Although the cellular machinery involved in post-translational translocation of small secretory preproteins has begun to be elucidated, the intrinsic signals contained within these small secretory preproteins that contribute to their efficient post-translational translocation remain unknown. Here, we analyzed the eukaryotic secretory proteome and discovered the small secretory preproteins tend to have a higher probability to harbor the positive charge in the n-region of the signal peptide (SP).

Competitive Inhibition of the Endoplasmic Reticulum Signal Peptidase by Non-cleavable Mutant Preprotein Cargos.

Upon translocation across the endoplasmic reticulum (ER) membrane, secretory proteins are proteolytically processed to remove their signal peptide by signal peptidase (SPase). This process is critical for subsequent folding, intracellular trafficking, and maturation of secretory proteins. Prokaryotic SPase has been shown to be a promising antibiotic target.

Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes.

To maintain copious insulin granule stores in the face of ongoing metabolic demand, pancreatic beta cells must produce large quantities of proinsulin, the insulin precursor. Proinsulin biosynthesis can account for up to 30-50% of total cellular protein synthesis of beta cells. This puts pressure on the beta cell secretory pathway, especially the endoplasmic reticulum (ER), where proinsulin undergoes its initial folding, including the formation of three evolutionarily conserved disulfide bonds.

INS-gene mutations: from genetics and beta cell biology to clinical disease.

A growing list of insulin gene mutations causing a new form of monogenic diabetes has drawn increasing attention over the past seven years. The mutations have been identified in the untranslated regions of the insulin gene as well as the coding sequence of preproinsulin including within the signal peptide, insulin B-chain, C-peptide, insulin A-chain, and the proteolytic cleavage sites both for signal peptidase and the prohormone convertases. These mutations affect a variety of different steps of insulin biosynthesis in pancreatic beta cells.