Secretory Products Research Articles

Beta cell function, insulin resistance and vitamin D status among type 2 diabetes patients in Western Kenya

Serum vitamin D status exerts effects on glucose-insulin-homeostatic states underlying Diabetes-Mellitus, Type 2 (T2DM). This has been described in white and Asian population where low Vitamin D levels predicted future impairments in beta cell function and worsening of insulin resistance. This study aimed to examine the relationship between serum vitamin D, insulin resistance and beta cell function in a sub population of black Kenyan T2DM patients. The primary objective was to determine the levels of serum 25 hydroxy (25-OH) vitamin D, and estimate the insulin resistance, and beta cell function among T2DM patients at Moi Teaching and Referral Hospital (MTRH). This was a cross sectional study. 124 T2DM patients attending the MTRH Diabetes clinic between February and May 2016 were enrolled. Patients on insulin therapy and/or thiazolidinediones were excluded. Anthropometric, clinical and demographic data was obtained. Samples were drawn for estimation of serum 25-OH vitamin D, fasting insulin levels and fasting blood glucose levels. HOMA (Homeostatic model of assessment) model was used to estimate Beta cell secretion (HOMA-B) and insulin resistance (HOMA-IR); while the Disposition index {(DI) hyperbola product of insulin sensitivity (1/HOMA-IR) and beta cell secretion} was used to estimate the beta cell function. The relationships between serum vitamin D, insulin resistance and beta cell function were explored using a linear regression model. The study participants had a mean age of 56.2 (± 9.2) years, and a mean BMI of 26.9 kg/m2 (4.3). Forty nine percent (n = 61) were males. Vitamin D deficiency was present in 71.1% (n = 88) of the respondents. Relatively low levels of insulin resistance and higher levels of beta cell dysfunction were observed {median HOMA-IR of 2.3 (0.7, 6.5) and Disposition Index (DI) of 25.5 (14.3, 47.2)}. Vitamin D levels exhibited a low positive correlation with DI [r = 0.22 (95% CI: 0.03, 0.37)], but was not significantly correlated with HOMA-IR [r = 0.07(95% CI: − 0.11, 0.25)]. These results indicate that beta cell dysfunction rather than insulin resistance as the predominant defect among black T2DM patients seeking care at the MTRH diabetes clinic. Vitamin D deficiency is also prevalent among them and exhibits a low positive correlation with beta cell dysfunction. There was no correlation observed between Vitamin D deficiency and insulin resistance.

Pseudocnidae of ribbon worms (Nemertea): ultrastructure, maturation, and functional morphology.

The fine structure of mature pseudocnidae of 32 species of nemerteans, representatives of 20 genera, six families, and two classes was investigated with scanning and transmission electron microscopy. Pseudocnidae are composed of four layers (cortex, medulla, precore layer, and core) in most species investigated, but the degree of development and position of each layer can vary between different species. The secretion products comprising immature pseudocnidae segregate into separate layers: a thin envelope, which subsequently separates into the cortex and medulla and an extensive internal layer. We distinguish two pseudocnida types: type I is characterized by a two-layered core and type II by a three-layered core. Type I pseudocnidae are present in archinemertean species, Carinoma mutabilis, and in all pilidiophoran species, except Heteronemertea sp. 5DS; type II pseudocnidae occur in all studied species of Tubulanidae and the basal Heteronemertea sp. 5DS. Based on the structure of the discharged pseudocnidae observed in eleven species of palaeonemerteans and in eight species of pilidiophorans, we distinguish three different mechanisms (1–3) of core extrusion/discharge with the following characteristics and distribution: (1) the outer core layer is everted simultaneously with the tube-like layer and occurs in type I pseudocnidae of most species; (2) the extruded core is formed by both eversion of the outer core layer and medullar layer, and occurs in type I pseudocnidae of Micrura cf. bella; (3) the eversion of the outer core layer begins together with the core rod and core rod lamina and occurs in type II pseudocnidae. Morpho-functional comparison with other extrusomes (cnidae, sagittocysts, rhabdtites, and paracnids) confirm that pseudocnidae are homologous structures that are unique to nemerteans.

Human Placental NADPH Oxidase Mediates sFlt-1 and PlGF Secretion in Early Pregnancy: Exploration of the TGF-β1/p38 MAPK Pathways.

Preeclampsia, a hypertensive disorder occurring during pregnancy, is characterized by excessive oxidative stress and trophoblast dysfunction with dysregulation of soluble Fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) production. Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase (Nox) is the major source of placental superoxide in early pregnancy and its activation with the subsequent formation of superoxide has been demonstrated for various agents including Transforming Growth Factor beta-1 (TGF-β1), a well-known p38 MAPK pathway activator. However, the bridge between Nox and sFlt-1 remains unknown. The purpose of this study was to explore the possible signaling pathway of TGF-β1/Nox/p38 induced sFlt-1 production in human chorionic villi (CV). Methods: Human chorionic villi from first trimester placenta (7–9 Gestational Weeks (GW)) were treated with TGF-β1 or preincubated with p38 inhibitor, SB203580. For NADPH oxidase inhibition, CV were treated with diphenyleneiodonium (DPI). The protein levels of phospho-p38, p38, phospho-Mothers Against Decapentaplegic homolog 2 (SMAD2), and SMAD2 were detected by Western blot. The secretion of sFlt-1 and PlGF by chorionic villi were measured with Electrochemiluminescence Immunologic Assays, and NADPH oxidase activity was monitored by lucigenin method. Results: We demonstrate for the first time that NADPH oxidase is involved in sFlt-1 and PlGF secretion in first trimester chorionic villi. Indeed, the inhibition of Nox by DPI decreases sFlt-1, and increases PlGF secretions. We also demonstrate the involvement of p38 MAPK in sFlt-1 secretion and Nox activation as blocking the p38 MAPK phosphorylation decreases both sFlt-1 secretion and superoxide production. Nevertheless, TGF-β1-mediated p38 activation do not seem to be involved in regulation of the first trimester placental angiogenic balance and no crosstalk was found between SMAD2 and p38 MAPK pathways. Conclusions: Thus, the placental NADPH oxidase play a major role in mediating the signal transduction cascade of sFlt-1 production. Furthermore, we highlight for the first time the involvement of p38 activation in first trimester placental Nox activity.

Disruption of alpha-tubulin releases carbon catabolite repression and enhances enzyme production in Trichoderma reesei even in the presence of glucose

BackgroundTrichoderma reesei is a filamentous fungus that is important as an industrial producer of cellulases and hemicellulases due to its high secretion of these enzymes and outstanding performance in industrial fermenters. However, the reduction of enzyme production caused by carbon catabolite repression (CCR) has long been a problem. Disruption of a typical transcriptional regulator, Cre1, does not sufficiently suppress this reduction in the presence of glucose.ResultsWe found that deletion of an α-tubulin (tubB) in T. reesei enhanced both the amount and rate of secretory protein production. Also, the tubulin-disrupted (ΔtubB) strain had high enzyme production and the same enzyme profile even if the strain was cultured in a glucose-containing medium. From transcriptome analysis, the ΔtubB strain exhibited upregulation of both cellulase and hemicellulase genes including some that were not originally induced by cellulose. Moreover, cellobiose transporter genes and the other sugar transporter genes were highly upregulated, and simultaneous uptake of glucose and cellobiose was also observed in the ΔtubB strain. These results suggested that the ΔtubB strain was released from CCR.ConclusionTrichoderma reesei α-tubulin is involved in the transcription of cellulase and hemicellulase genes, as well as in CCR. This is the first report of overcoming CCR by disrupting α-tubulin gene in T. reesei. The disruption of α-tubulin is a promising approach for creating next-generation enzyme-producing strains of T. reesei.

Microbial Production of Biodegradable Lactate-Based Polymers and Oligomeric Building Blocks From Renewable and Waste Resources.

Polyhydroxyalkanoates (PHAs) are naturally occurring biopolymers produced by microorganisms. PHAs have become attractive research biomaterials in the past few decades owing to their extensive potential industrial applications, especially as sustainable alternatives to the fossil fuel feedstock-derived products such as plastics. Among the biopolymers are the bioplastics and oligomers produced from the fermentation of renewable plant biomass. Bioplastics are intracellularly accumulated by microorganisms as carbon and energy reserves. The bioplastics, however, can also be produced through a biochemistry process that combines fermentative secretory production of monomers and/or oligomers and chemical synthesis to generate a repertoire of biopolymers. PHAs are particularly biodegradable and biocompatible, making them a part of today’s commercial polymer industry. Their physicochemical properties that are similar to those of petrochemical-based plastics render them potential renewable plastic replacements. The design of efficient tractable processes using renewable biomass holds key to enhance their usage and adoption. In 2008, a lactate-polymerizing enzyme was developed to create new category of polyester, lactic acid (LA)–based polymer and related polymers. This review aims to introduce different strategies including metabolic and enzyme engineering to produce LA-based biopolymers and related oligomers that can act as precursors for catalytic synthesis of polylactic acid. As the cost of PHA production is prohibitive, the review emphasizes attempts to use the inexpensive plant biomass as substrates for LA-based polymer and oligomer production. Future prospects and challenges in LA-based polymer and oligomer production are also highlighted.

ACE2 and energy metabolism: the connection between COVID-19 and chronic metabolic disorders.

The renin-angiotensin system (RAS) has currently attracted increasing attention due to its potential function in regulating energy homeostasis, other than the actions on cellular growth, blood pressure, fluid, and electrolyte balance. The existence of RAS is well established in metabolic organs, including pancreas, liver, skeletal muscle, and adipose tissue, where activation of angiotensin-converting enzyme (ACE) - angiotensin II pathway contributes to the impairment of insulin secretion, glucose transport, fat distribution, and adipokines production. However, the activation of angiotensin-converting enzyme 2 (ACE2) - angiotensin (1-7) pathway, a novel branch of the RAS, plays an opposite role in the ACE pathway, which could reverse these consequences by improving local microcirculation, inflammation, stress state, structure remolding, and insulin signaling pathway. In addition, new studies indicate the protective RAS arm possesses extraordinary ability to enhance brown adipose tissue (BAT) activity and induces browning of white adipose tissue, and consequently, it leads to increased energy expenditure in the form of heat instead of ATP synthesis. Interestingly, ACE2 is the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is threating public health worldwide. The main complications of SARS-CoV-2 infected death patients include many energy metabolism-related chronic diseases, such as diabetes. The specific mechanism leading to this phenomenon is largely unknown. Here, we summarize the latest pharmacological and genetic tools on regulating ACE/ACE2 balance and highlight the beneficial effects of the ACE2 pathway axis hyperactivity on glycolipid metabolism, as well as the thermogenic modulation.

The Role of Gonadotropin-Releasing Hormone (GnRH) in Endometrial Cancer.

Endometrial cancer (EC) is one of the most common gynecological malignancies. Gonadotropin releasing hormone (GnRH) is a decapeptide first described to be secreted by the hypothalamus to regulate pituitary gonadotropin secretion. In this systematic review, we analyze and summarize the data indicating that most EC express GnRH and its receptor (GnRH-R) as part of an autocrine system regulating proliferation, the cell cycle, and apoptosis. We analyze the available data on the expression and function of GnRH-II, its putative receptor, and its signal transduction. GnRH-I and GnRH-II agonists, and antagonists as well as cytotoxic GnRH-I analogs, have been shown to inhibit proliferation and to induce apoptosis in human EC cell lines in pre-clinical models. Treatment with conventional doses of GnRH-agonists that suppress pituitary gonadotropin secretion and ovarian estrogen production has become part of fertility preserving therapy of early EC or its pre-cancer (atypical endometrial hyperplasia). Conventional doses of GnRH-agonists had marginal activity in advanced or recurrent EC. Higher doses or more potent analogs including GnRH-II antagonists have not yet been used clinically. The cytotoxic GnRH-analog Zoptarelin Doxorubicin has shown encouraging activity in a phase II trial in patients with advanced or recurrent EC, which expressed GnRH-R. In a phase III trial in patients with EC of unknown GnRH-R expression, the cytotoxic GnRH doxorubicin conjugate was not superior to free doxorubicin. Further well-designed clinical trials exploiting the GnRH-system in EC might be useful.

Role of Glycosylation in Lipid-Interacting Properties of Pulmosaposin A, from the Pulmonary Surfactant Protein B Precursor

Pulmonary surfactant, the secretory product of type II pneumocytes, is a complex with a unique protein-lipid composition that lines the alveoli surface. At the air-liquid interface, surfactant reduces surface tension and avoids lung collapse during breathing. Surfactant Protein B (SP-B), an essential component of pulmonary surfactant, is synthesized as a long precursor to prevent from protein aggregation due to its hydrophobicity. The N-terminus of this precursor contains the Pulmosaposin A (or SP-BN), the murine version being originally described as a defensive protein with some bactericidal functions under particular conditions. Moreover, this precursor domain contains, in humans, a glycosylation site apparently related to susceptibility to certain pulmonary pathologies. However, none of these properties have been deeply characterized from a molecular point of view. Here we describe the production of the recombinant human Pulmosaposin A (hSP-BN) in the yeast Pichia pastoris, the isolation of the glycosylated and deglycosylated forms as well as a non-glycosylated mutant. The purified proteins conserved the saposin fold rich in helical content. Toxicity against bacteria could not be observed, a discrepancy with previous results obtained with the murine version expressed in E. coli. Nevertheless, these pulmosaposin variants showed lipid-interacting properties, especially under acidic conditions, which is consistent with their saposin fold as well as with their potential role within the precursor during SP-B maturation and secretion. Results are discussed in terms of the specific role of this lipid-interacting activity as well as the involvement of glycosylation and its relation with pulmonary dysfunction and disease.

Role of mesenchymal stromal cells and their secretory products in kidney regeneration

Kidney diseases are an important medical problem. Kidney injuries are accompanied by oxidative stress, cell death, capillary destruction, inflammation and fibrosis. Mesenchymal stromal cells (MSCs) have a complex effect on the regeneration by producing various regulatory molecules, including those inside extracellular vesicles, and therefore are considered as a promising therapeutic resource for cell therapy of kidney diseases. Their renoprotective effect has been shown in different experimental models, but the results of the clinical trials are ambiguous. Clinical use of MSCs is complicated by their low survival rate in the injured kidney, potential immunogenicity, tumorogenicity and fibrogenicity. Cell-free therapy with the secretory products of MSCs such as conditioned environments or extracellular vesicles is a promising direction for using their regenerative potential. However, introduction of MSCs and their secretory products into medical practice requires further research into the mechanisms of their proregenerative action, improvement of cultivation protocols, and more clinical trials.

Regulatory T cells induced by B cells suppress NLRP3 inflammasome activation and alleviate monosodium urate-induced gouty inflammation

SummaryRegulatory T cells induced by B cells (Treg-of-B cells), a distinct Foxp3- Treg cell subset, have established the roles in the suppression of inflammatory conditions, including asthma and intestinal inflammation. However, little is known about the regulatory effects of Treg-of-B cells on innate immunity. Herein, we examined whether Treg-of-B cells could regulate macrophage function and prevent NLRP3-associated diseases, particularly inflammatory gouty arthritis. Treg-of-B cells, but not thymus-derived Treg or effector T cells, inhibited inflammasome-mediated IL-1β secretion, caspase-1 activation, and NLRP3 production by LPS/ATP stimulation in a cell contact-dependent manner. In addition, Treg-of-B cells inhibited monosodium urate-induced NLRP3 inflammasome activation in vitro via NF-κB signaling. Treg-of-B cells ameliorated gouty inflammation in a mouse air pouch model by reducing neutrophil and leukocyte influx and cytokine and chemokine production. Our results demonstrated that Treg-of-B cells exerted regulatory effects on innate immunity by suppressing NLRP3 inflammasome activation and feasible for future therapeutic applications.

Efficient brazzein production in yeast (Kluyveromyces lactis) using a chemically defined medium.

The sweet-tasting protein brazzein offers considerable potential as a functional sweetener with antioxidant, anti-inflammatory, and anti-allergic properties. Here, we optimized a chemically defined medium to produce secretory recombinant brazzein in Kluyveromyces lactis, with applications in mass production. Compositions of defined media were investigated for two phases of fermentation: the first phase for cell growth, and the second for maximum brazzein secretory production. Secretory brazzein expressed in the optimized defined medium exhibited higher purity than in the complex medium; purification was by ultrafiltration using a molecular weight cutoff, yielding approximately 107mgL-1. Moreover, the total media cost in this defined medium system was approximately 11% of that in the optimized complex medium to generate equal amounts of brazzein. Therefore, the K. lactis expression system is useful for mass-producing recombinant brazzein with high purity and yield at low production cost and indicates a promising potential for applications in the food industry.

Spirocerca lupi Proteomics and Its Role in Cancer Development: An Overview of Spirocercosis-Induced Sarcomas and Revision of Helminth-Induced Carcinomas.

Spirocerca lupi is a parasitic nematode of canids that induces a myriad of clinical manifestations in its host and, in 25% of infections, leads to the formation of sarcomas. The description of the protein composition of the excretory and secretory products (Sl-ESP) of S. lupi has shed light on its possible interactions with the host environment, including migration within the host and mechanisms of immunomodulation. Despite this, the process by which S. lupi induces cancer in the dog remains poorly understood, and some hypotheses have arisen regarding these possible mechanisms. In this review, we discuss the role of specific ESP from the carcinogenic helminths Clonorchis sinensis, Opisthorchis viverrini and Schistosoma haematobium in inducing chronic inflammation and cancer in their host’s tissues. The parasitic worms Taenia solium, Echinococcus granulosus, Heterakis gallinarum, Trichuris muris and Strongyloides stercoralis, which have less-characterized mechanisms of cancer induction, are also analyzed. Based on the pathological findings in spirocercosis and the mechanisms by which other parasitic helminths induce cancer, we propose that the sustained inflammatory response in the dog´s tissues produced in response to the release of Sl-ESP homologous to those of other carcinogenic worms may lead to the malignant process in infected dogs.

Pomelo peel oil alleviates cerebral NLRP3 inflammasome activation in a cardiopulmonary resuscitation rat model.

The NLR family pyrin domain-containing 3 (NLRP3) inflammasome, which is composed of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and pro-caspase-1 protein complexes, is activated by the reactive oxygen species (ROS) that are associated with ischemia-reperfusion (I/R) and are involved in brain damage. Pomelo peel oil (PPO) exhibits antioxidant activity. However, it is unclear whether PPO is able to attenuate NLRP3 inflammasome-induced inflammation and pyroptosis. Healthy male Sprague-Dawley rats were subjected to 7 min of cardiac arrest via trans-esophageal electrical stimulation, followed by cardiopulmonary resuscitation (CPR). The rats were then treated with PPO prior to reperfusion for 24 h. Hematoxylin and eosin staining was used to evaluate brain tissue and cell damage. In the brain tissues, reactive oxygen species (ROS) were assayed, immunofluorescence was used to analyze the expression of NLRP3 and western blotting was performed to determine the expression levels of neuroenolase (NSE), NF-κB, interleukin-1β (IL-1β), gasdermin D (GSDMD) and the NLRP3 inflammasome. Treatment of the rats with PPO significantly decreased the pathological damage of the brain tissue and reduced the expression of NSE, production of ROS and secretion of NF-κB, NLRP3, IL-1β and GSDMD. In conclusion, these results demonstrate the ability of PPO to protect the brain against I/R injury in rats after CPR by a mechanism involving inhibition of the inflammation and pyroptosis mediated by NLRP3 inflammasome activation.

Insulin acutely activates metabolism of primary human monocytes and promotes a proinflammatory phenotype.

Increased glycolysis is a metabolic trait of activated innate immune cells and supports functional changes including cytokine production. Insulin drives glycolysis in nonimmune cells, yet its metabolic effects on human innate immune cells remain unexplored. Potential effects of insulin on immune cell metabolism may occur acutely after a postprandial increase in plasma insulin levels or as a consequence of chronically elevated insulin levels as observed in obese insulin-resistant individuals and patients with diabetes. Here, we investigated the effects of acute and chronic exposure to insulin on metabolism and function of primary human monocytes. Insulin acutely activated the PI3K/Akt/mTOR pathway in monocytes and increased both oxygen consumption and glycolytic rates. Functionally, acute exposure to insulin increased LPS-induced IL-6 secretion and reactive oxygen species production. To model chronically elevated insulin levels in patients with diabetes, we exposed monocytes from healthy individuals for 24 h to insulin. Although we did not find any changes in expression of metabolic genes that are regulated by insulin in non-immune cells, chronic exposure to insulin increased LPS-induced TNFα production and enhanced MCP-1-directed migration. Supporting this observation, we identified a positive correlation between plasma insulin levels and macrophage numbers in adipose tissue of overweight individuals. Altogether, insulin acutely activates metabolism of human monocytes and induces a shift toward a more proinflammatory phenotype, which may contribute to chronic inflammation in patients with diabetes.

Effects of biotin on promoting anammox bacterial activity

Anaerobic ammonium oxidation (anammox) bacteria significantly improve the efficiency and reduce cost of nitrogen removal in wastewater treatment plants. However, their slow growth and vulnerable activity limit the application of anammox technology. In this paper, the enhancement of biotin on the nitrogen removal activity of anammox bacteria in short-term batch experiments was studied. We found that biotin played a significant role in promoting anammox activity within a biotin concentration range of 0.1–1.5 mg/L. At a biotin concentration of 1.0 mg/L, the total nitrogen removal rate (NRR) increased by 112%, extracellular polymeric substance (EPS) secretion and heme production significantly improved, and anammox bacterial biomass increased to maximum levels. Moreover, the predominant genus of anammox bacteria was Candidatus Brocadia.

Common Pitfalls in the Management of Patients with Micronutrient Deficiency: Keep in Mind the Stomach.

Micronutrient deficiencies are relatively common, in particular iron and cobalamin deficiency, and may potentially lead to life-threatening clinical consequences when not promptly recognized and treated, especially in elderly patients. The stomach plays an important role in the homeostasis of some important hematopoietic micronutrients like iron and cobalamin, and probably in others equally important such as ascorbic acid, calcium, and magnesium. A key role is played by the corpus oxyntic mucosa composed of parietal cells whose main function is gastric acid secretion and intrinsic factor production. Gastric acid secretion is necessary for the digestion and absorption of cobalamin and the absorption of iron, calcium, and probably magnesium, and is also essential for the absorption, secretion, and activation of ascorbic acid. Several pathological conditions such as Helicobacter pylori-related gastritis, corpus atrophic gastritis, as well as antisecretory drugs, and gastric surgery may interfere with the normal functioning of gastric oxyntic mucosa and micronutrients homeostasis. Investigation of the stomach by gastroscopy plus biopsies should always be considered in the management of patients with micronutrient deficiencies. The current review focuses on the physiological and pathophysiological aspects of gastric acid secretion and the role of the stomach in iron, cobalamin, calcium, and magnesium deficiency and ascorbate homeostasis.

Melatonin protects against environmental stress-induced fetal growth restriction via suppressing ROS-mediated GCN2/ATF4/BNIP3-dependent mitophagy in placental trophoblasts

Gestational exposure to environmental stress induces fetal growth restriction (FGR), and thereby increasing the risk of infant death and chronic noncommunicable diseases in adults. However, the mechanism by which environmental stress induces FGR remains unclear. Based on case-control study, we found that the reduced level of melatonin (MT), a major secretory product from the pineal gland, was observed in placentae of FGR. This work was to investigate the protective effect of MT on environmental stress-caused FGR and its mechanisms. We used cadmium (Cd) as an environmental stressor to stimulate pregnant mice and thereby establishing a FGR model. The data showed that maternal Cd exposure lowered the P4 concentration in maternal sera, placentae and amniotic fluid, and caused FGR. Correspondingly, the expression of CYP11A1, a critical P4 synthase, was markedly downregulated in Cd-treated placentae. Simultaneously, Cd triggered BNIP3-dependent mitophagy in placental trophoblasts, as determined by the degradation of mitochondrial proteins, including HSP60 and COX IV, and the accumulation of puncta representing co-localization of TOM20 with LC3B or BNIP3 with LC3B. Based on our case-control study, we also found that activated BNIP3-dependent mitophagy and P4 synthesis inhibition occurred in SGA placentae. Most importantly, BNIP3 siRNA reversed Cd-induced P4 synthesis suppression in human placental trophoblasts. It is noteworthy that MT alleviated Cd-caused P4 synthesis suppression and FGR via antagonizing BNIP3-dependent mitophagy in placental trophoblasts. Further results confirmed that MT attenuated Cd-triggered BNIP3-dependent mitophagy via blocking GCN2/ATF4 signaling. Amusingly, Cd triggered oxidative stress and then activating GCN2/ATF4 signaling in placental trophoblasts. As expected, MT obviously suppressed Cd-caused reactive oxygen species (ROS) release. In the present study, we propose a neoteric mechanism by which MT protects against environmental stress-impaired P4 synthesis and fetal growth via suppressing ROS-mediated GCN2/ATF4/BNIP3-dependent mitophagy in placental trophoblasts. As above, MT is a potential therapeutic agent antagonizing environmental stress-induced developmental toxicity.

Updates on the understanding and management of thyroid eye disease.

Thyroid eye disease (TED) is a complex disease associated with myriad clinical presentations, including facial disfigurement, vision loss, and decreased quality of life. Traditionally, steroid therapy and/or radiation therapy were commonly used in the treatment of active TED. While these therapies can help reduce inflammation, they often do not have a sustainable, significant long-term effect on disease outcomes, including proptosis and diplopia. Recent advances in our understanding of the pathophysiology of TED have shifted the focus of treatment toward targeted biologic therapies. Biologics have the advantage of precise immune modulation, which can have better safety profiles and greater efficacy compared to traditional approaches. For instance, the insulin-like growth factor-1 receptor (IGF-1R) has been found to be upregulated in TED patients and to colocalize with the thyroid-stimulating hormone receptor (TSHR), forming a signaling complex. Teprotumumab is an antibody targeted against IGF-1R. By inhibiting the IGF-1R/TSHR signaling pathway, teprotumumab may reduce the production of proinflammatory cytokines, hyaluronan secretion, and orbital fibroblast activation in patients with TED. Due to promising phase II and III clinical trial results, teprotumumab has become the first biologic US Food and Drug Administration (FDA)-approved for the treatment of TED. In addition, there are currently ongoing studies looking at the use of antibodies targeting the neonatal Fc receptor (FcRn) in various autoimmune diseases, including TED. FcRn functions to transport immunoglobulin G (IgG) and prevent their lysosomal degradation. By blocking the recycling of IgG, this approach may dampen the body’s immune response, in particular the pathogenic IgG implicated in some autoimmune diseases. Advances in our understanding of the pathophysiology of TED, therefore, are leading to more targeted therapeutic options, and we are entering an exciting new phase in the management of TED. This review will cover recent insights into the understanding of TED pathophysiology and novel treatment options as well as ongoing studies of new potential treatment options for TED.

Association of Osteocalcin with Metabolic Syndrome and its Correlation with Insulin Resistance

Introduction: Metabolic Syndrome (MetS) is an important public health burden associated with five-fold risk of developing Type 2 Diabetes Mellitus (T2DM) and two fold risk of Cardio Vascular Disease (CVD). Recent studies described that osteoblasts produce osteocalcin which increases insulin secretion and adiponectin production resulting in insulin sensitivity. Aim: To determine the association of serum osteocalcin with MetS and to assess the correlation of insulin resistance Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) with osteocalcin. Materials and Methods: This case-control study was carried out in the Department of Biochemistry at MKCG Medical College, Brahmapur, Odisha, India. By observing the mean and standard deviation from previous studies, with 95% Confidence Interval (CI) and 80% power of study, the sample size was calculated to be 45. Forty eight cases between 20-45 years of age meeting the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria of MetS and 50 age and sex matched healthy individuals were taken as controls. Individuals with any systemic illness or on any kind of medications were excluded from the study. Fasting blood sugar, lipid profile were measured by standard procedures. Serum osteocalcin and serum insulin was estimated by Enzyme-linked Immunosorbent Assay (ELISA) LISA SCAN READER and ROCHE e COBAS 411 electrochemiluminiscence, respectively. Statistical analysis was done in Statistical Package for the Social Sciences (SPSS) 22.0 version software. Results: Serum osteocalcin was found to be lower in cases as compared to controls (7.74±4.62 ng/mL and 23.24±9.74 ng/mL) respectively. Osteocalcin was also found to be significantly negatively correlated with HOMA-IR, Waist Circumference (WC), triglyceride and fasting blood sugar in cases with (r=-0.322, p=0.025), (r=-0.519, p<0.001), (r=-0.401, p=0.005), (r=-0.539, p<0.001), respectively and also in controls with (r=-0.494, p<0.001), (r=-0.176, p=0.245), (r=-0.398, p<0.05), (r=-0.141, p<0.05), respectively. Conclusion: Serum osteocalcin being negatively correlated with insulin resistance may have therapeutic role in prevention of MetS which may be substantiated with further study.

Exosomes Derived from Bone Mesenchymal Stem Cells Alleviate Compression-Induced Nucleus Pulposus Cell Apoptosis by Inhibiting Oxidative Stress.

Oxidative stress is relevant in compression-induced nucleus pulposus (NP) cell apoptosis and intervertebral disc (IVD) degeneration. Exosomes derived from bone mesenchymal stem cells (BMSCs-Exos) are key secretory products of MSCs, with important roles in tissue regeneration. This research is aimed at studying the protective impact of BMSCs-Exos on NP cell apoptosis caused by compression and investigating the underlying mechanisms. Our results indicated that we isolated BMSCs successfully. Exosomes were isolated from the BMSCs and found to alleviate the inhibitory effect that compression has on proliferation and viability in NP cells, decreasing the toxic effects of compression-induced NP cells. AnnexinV/PI double staining and TUNEL assays indicated that the BMSCs-Exos reduced compression-induced apoptosis. In addition, our research found that BMSCs-Exos suppressed compression-mediated NP oxidative stress by detecting the ROS and malondialdehyde level. Furthermore, BMSCs-Exos increased the mitochondrial membrane potential and alleviated compression-induced mitochondrial damage. These results indicate that BMSCs-Exos alleviate compression-mediated NP apoptosis by suppressing oxidative stress, which may provide a promising cell-free therapy for treating IVD degeneration.