Reduced Calcium Levels Research Articles

215. MALNUTRITION AND VITAMIN DEFICIENCIES AFTER ONCOLOGICAL GASTRIC OR ESOPHAGEAL RESECTION

Abstract Background Patients receiving oncological esophagectomy or gastrectomy are known to be at high risk for vitamin and micronutrient deficiency before, during and after surgery. However, there are no clear guidelines for these cancer patients regarding postoperative vitamin supplementation. preoperative malnutrition has been shown to be associated with a higher risk of perioperative complications. In addition, malnutrition has shown to be an independent risk factor for reduced survival in cancer patients and early cancer recurrence. Methods This meta-analysis examines the prevalence of postoperative malnutrition, vitamin, and micronutrient deficiencies in patients who underwent gastrectomy or esophagectomy. A computer-based literature search was performed in several different databases with the The following search terms were used: vitamin, nutrition, deficienc*, malnutrition, osteoporos*, sarcopenia, esophagectom*, oesophagectom*, gastrectomy*, gastric, surg*, resect*, operat*, removal, excision, neoplas*, tumor, tumour, cancer, malign*adenocarcinom* squamous cell carcinom*. Out of 1611 studies, 42 documented relevant information, but only 17 provided 95% confidence intervals. After excluding seven studies due to insufficient data, the meta-analysis included 947 patients from 10 studies. Results The studies recorded vitamin and micronutrient blood levels from 3 months to 10 years post-surgery. The analysis found significant deficiencies in 25-OH Vitamin D3, Vitamin B12, and Serum Calcium levels. Patients had significantly lower Vitamin D3 levels compared to the healthy population, with mean levels in the lower normal range or lower. Serum Calcium levels were also significantly lower than the mean levels of the healthy population but stayed within the normal range. Mean Serum B12 levels were significantly lower than mean B12 levels in the standard population, but standard deviations stayed within the normal range. Serum albumin levels showed no signs of deficiency when compared to the healthy population. Similarly, no deficiency was detected in serum ferritin levels. Other vitamins and micronutrients studies included serum phosphorous, Vitamin A and Vitamin E, but data was insufficient for metanalysis. Discussion The study underscores the need for further research and guidelines to address postoperative nutritional deficiencies in these patients. Particularly, patients often develop a deficiency in Vitamin D3 after surgery, despite supplementation. Vitamin D3 insufficiency may increase perioperative risk and is concerning given the reduced calcium levels and bone marrow density. In conclusion there is a clear need for Vitamin D3 supplementation, both postoperatively and during the perioperative period. The study supports previous data indicating a high prevalence of postoperative micronutrient deficiency in esophagectomy patients. Given the high risk of malnutrition, screening should be a routine part of follow-up care. More data, particularly regarding deficiencies and supplementation after esophagectomy, is necessary.

Effectiveness of oral calcium to prevent citrate-related toxicity during peripheral blood hematopoietic stem cell collection – An experience from a tertiary care center

Abstract: BACKGROUND: Apheresis procedures use citrate as an anticoagulant to ensure the fluidity of extracorporeal blood. Citrate-related toxicities are common adverse effects in peripheral blood stem cell (PBSC) collections as they are lengthy procedures resulting in prolonged citrate exposure. Intravenous (IV) calcium administration during therapeutic apheresis procedures is commonly used to reduce the citrate-related toxicity in adults and pediatric population. Very few literature on the use of oral calcium for the prevention of citrate toxicity during PBSC collection are present. OBJECTIVE: The objective of this study was to evaluate the effect of prophylactic oral calcium in reducing citrate-related toxicities during PBSC collections. MATERIALS AND METHODS: A prospective cross-sectional study was carried out at a tertiary care hospital of Southern India. All participants received calcium carbonate – 1 g before and at each 100 ml of collection. Preprocedure, interim, and postprocedure serum calcium were measured. All procedures were done using Spectra Optia. The ACD (acid-citrate-dextrose) rate were between 1:8 to 1:14 and were adjusted for inlet draw rate. The total blood volume processed between 2.5 to 3 based on body weight. Reduction in calcium levels and adverse reactions due to hypocalcemia were observed. Data were analyzed using SPSS 23 software. RESULTS: The majority of the procedures were undisturbed and tolerable to oral calcium. A total of 97.3% of the study subjects did not experience any symptoms of hypocalcemia. Only 2.7% (One autologous and one allogenic donor) had symptoms attributable to hypocalcemia though they had preprocedure calcium >9 mg/dl. Pre- and postprocedure calcium were compared using a paired t-test which was statistically significant. CONCLUSION: Prophylactic oral calcium in PBSC collection is an effective and easy way to the prevention of citrate-related adverse effects without affecting technical performance and product efficacy.

Vasorelaxant effects of biochemical constituents of various medicinal plants and their benefits in diabetes.

Endothelial function plays a pivotal role in cardiovascular health, and dysfunction in this context diminishes vasorelaxation concomitant with endothelial activity. The nitric oxide-cyclic guanosine monophosphate pathway, prostacyclin-cyclic adenosine monophosphate pathway, inhibition of phosphodiesterase, and the opening of potassium channels, coupled with the reduction of calcium levels in the cell, constitute critical mechanisms governing vasorelaxation. Cardiovascular disease stands as a significant contributor to morbidity and mortality among individuals with diabetes, with adults afflicted by diabetes exhibiting a heightened cardiovascular risk compared to their non-diabetic counterparts. A plethora of medicinal plants, characterized by potent pharmacological effects and minimal side effects, holds promise in addressing these concerns. In this review, we delineate various medicinal plants and their respective biochemical constituents, showcasing concurrent vasorelaxant and anti-diabetic activities.

Development of Clarstatin, a Novel Drug Lead for the Therapy of Autoimmune Uveitis.

We describe the design, synthesis, and activity of a potent thiourea-bridged backbone cyclic peptidomimetic known as Clarstatin, comprising a 5-amino acid sequence (Q/D)1-(R/K)2-X3-X4-A5-(Gln/Asp)1-(Arg/Lys)2-AA3-AA4-Ala5-based on a motif called "shared epitope (SE)", specifically present in specific alleles of the HLA-DRB1 gene. This SE binds to a particular site within the proline reach domain (P-domain) of the cell surface-calreticulin (CS-CRT). CS-CRT is a multifunctional endoplasmic reticulum (ER) calcium-binding protein that is located on the cell surface of T cells and triggers innate immune signaling, leading to the development of inflammatory autoimmune diseases. The development of Clarstatin was based on the parent peptide W-G-D1-K2-S3-G4-A5- derived from the active region of the SE. Following the design based on the cycloscan method, the synthesis of Clarstatin was performed by the Fmoc solid phase peptide synthesis (SPPS) method, purified by HPLC to 96% homogeneity, and its structure was confirmed by LC-MS. Clarstatin reduced calcium levels in Jurkat lymphocyte cultures, ameliorated uveitis in vivo in the experimental autoimmune uveitis (EAU) mice model, and was safe upon acute toxicity evaluation. These findings identify Clarstatin as a promising lead compound for future drug development as a novel class of therapeutic agents in the therapy of uveitis.

VITAMIN D, CALCIUM, AND PHOSPHORUS STATUS IN CHILDREN WITH SPINA BIFIDA

Introduction. Children with spina bifida (SB) are at the highest risk of developing vitamin and mineral deficiencies, including vitamin D, due to a sedentary lifestyle, prolonged indoor stays, and dietary peculiarities. The aim of our study was to determine the dietary intakes of vitamin D, calcium, and phosphorus in children with spina bifida and the concentration of these nutrients in the serum of children with SB. Materials and Methods. The study included 20 children aged 2 to 17 years with congenital neural tube defect (spina bifida). The control group consisted of 67 healthy children aged 6 to 17 years. To determine the dietary intakes of vitamin D, calcium and phosphorus, children or their parents were surveyed using a questionnaire containing questions about the amount of consumption of certain food products over the week. The total amount of vitamin D, calcium, and phosphorus in the weekly diet were calculated, as well as their average daily intakes with food and overall. The concentration of 25-OH vitamin D, calcium, and phosphorus in the blood serum was determined using an enzyme immunoassay. Results. Among the examined children with SB, girls predominated (70.0%). Physical development delay and undernutrition were identified in 3 (15.0%), overweight - in 6 (30.0%) children. Most children with SB exhibited clinical manifestations of mineral metabolism disorders: body proportion disturbances (55.0%), posture disorders (40.0%), scoliosis and/or chest deformity (50.0%), caries (40.0%). Despite the presence of dairy, meat, and fish products in the weekly diet of all children with SB, their quantity was insufficient to meet the daily needs for vitamin D, calcium, and phosphorus. Inadequate intake of vitamin D from food occurred in 70.0% of children, calcium deficiency in 90.0%, phosphorus deficiency in 80.0%, with the alimentary provision of calcium and phosphorus in children with SB being significantly lower than in healthy children (p=0.0027 and p=0.0047, respectively). Optimal levels of vitamin D in the blood serum were observed in only 10.0% of children with SB, which was twice less than in healthy children, while its deficiency was observed 1.5 times more often in children with SB than in healthy children. Half of the patients with SB had reduced calcium levels, and 70.0% had reduced phosphorus levels. Conclusions. The study results demonstrate a wide prevalence of vitamin D deficiency and insufficiency (in 90.0%), calcium and phosphorus deficiency in children with SB, indicating the need for additional intake of these nutrients alongside dietary and lifestyle corrections. Further research on a larger cohort of patients with supplementation regimens is necessary to reduce the risk of complications and improve the quality of life for children with SB.

Regional and Age-Related Variations in Blood Calcium Levels among Patients with Plasmodium falciparum and P. vivax malaria: A Systematic Review and Meta-Analysis

Despite several studies examining the relationship between calcium levels and malaria, inconsistencies and varied results remain in the literature. This study aimed to synthesize the evidence on the association between blood calcium levels and malaria severity. A systematic literature search was conducted in the Embase, Scopus, PubMed, Ovid, and Google Scholar databases. The studies that investigated calcium levels in participants with malaria were reviewed and included for synthesis. The quality of included studies was assessed based on a standardized checklist by the Joanna Briggs Institute (JBI) critical appraisal checklists. The thematic synthesis had been used for qualitative synthesis. For the quantitative synthesis, the meta-analysis was performed to estimate the pooled effect sizes for differences in calcium levels between groups of participants using a random effect model using Hedge’s g as a measure of effect size. Out of the 4574 identified records, 14 studies were reviewed. The thematic synthesis across these studies noted a consistent theme: reduced calcium levels in malaria patients compared to uninfected controls. However, the meta-analysis encompassing three specific analyses—comparing calcium levels between malaria patients and controls, severe and non-severe malaria cases, and fatal cases versus survivors—showed no significant difference in calcium levels. The statistics were as follows: (1) p = 0.15, Hedge’s g: −1.00, 95% CI: −2.37–0.38, I2: 98.97, 9 studies; (2) p = 0.35, Hedge’s g: −0.33, 95% CI: −1.02–0.36, I2: 81.61, 3 studies; and (3) p = 0.71, Hedge’s g: −0.14, 95% CI: −0.91–0.62, I2: 87.05, 3 studies. Subgroup analyses indicated that regional disparities, especially between Africa and Asia, and participant age groups may influence these outcomes. While a trend of decreased calcium levels in malaria patients was observed, the meta-analytical results suggest regional and age-related variations. Further investigations should emphasize these differences to better guide clinical management, prognostic applications, and the crafting of policies concerning malaria’s metabolic effects.

Outcomes of Central Neck Dissection for Papillary Thyroid Carcinoma in Primary Versus Revision Setting.

Surgery in the central compartment after previous thyroidectomy involves an increased risk of injury to critical organs, including the parathyroids and recurrent laryngeal nerve. Contrastingly, primary central neck dissection involves a relatively low operative risk. This study aimed to compare the outcomes of central neck dissection in primary versus revision settings with respect to the lymph node yield and complication rates. This single-center prospective study included patients who underwent primary or revision neck dissection surgery for histologically confirmed thyroid malignancy between January 2018 and January 2022. We included 30 patients who underwent total thyroidectomy with primary central neck dissection and 29 patients who underwent central neck dissection following remote thyroidectomy with or without previous central dissection. There was no significant between-group difference in postoperative complications, including permanent hypocalcemia and recurrent laryngeal nerve injury. However, both groups showed a significant postoperative decrease in calcium levels even though calcium and parathyroid hormone levels were within reference range. Although many surgeons fear revision central neck dissection, it appears to have similar therapeutic outcomes and complication rates as primary neck dissection for papillary thyroid cancer. Specifically, there were no between-group differences in the lymph node yield, hypoparathyroidism, or recurrent laryngeal nerve paralysis. Patients with normocalcemia showed a significant postoperative reduction in calcium levels, suggesting subclinical parathyroid insufficiency.

Factors contributing to poor COVID-19 outcomes in diabetic patients: Findings from a single-center cohort study.

Diabetes Mellitus (DM) is a frequent comorbidity in patients infected with the SARS-CoV-2 virus. The risk of developing severe or critical COVID-19 and higher mortality was observed to be increased in diabetic patients hospitalized due to COVID-19. In this study we aimed to find out the impact of clinical characteristics, comorbidities, laboratory results, and complications on the outcomes of diabetic patients hospitalized due to COVID-19. This article is a retrospective cohort study that include diabetic patients hospitalized with COVID-19 infection. A definition of diabetes was based on the past history of diabetes or if the HbA1c was 6.5% or higher. Demographics, clinical characteristics, comorbidities, laboratory results, and complications were extracted from the electronic medical records. The mortality rate increased with increasing age (from 5.56% in younger patients to 46% in the elderly) and with severity (from 25.71% in moderate cases to 43.77% in critical cases). We found that a critical severity on admission (OR: 5.26, 95% CI: 1.28-21.66, p = 0.0214), a history of stroke (OR: 8.37, 95% CI: 2.2-31.88, p = 0.0018), and low calcium levels on admission (OR: 2.23, 95% CI: 1.01-4.91, p = 0.0475) were significant risk factors predicting higher COVID-19 mortality in diabetic patients. The findings of this study suggest that reduced calcium levels could potentially indicate higher mortality due to COVID-19 in patients with DM. Furthermore, careful monitoring of diabetic patients hospitalized due to COVID-19 infection, especially those with critical disease severity or those with a history of stroke, may improve their outcome and lessen mortality.

Clinical phenotypes and prognosis of IgG4-related diseases accompanied by deteriorated kidney function: a retrospective study.

IgG4-related disease (IgG4-RD) is a multiorgan autoimmune disorder that causes irreversible injury. Deteriorated kidney functions are common but easily ignored complications associated with IgG4-RD. Yet the clinical manifestations and prognosis of this specific entity have not been fully illustrated. Three hundred fifty patients with IgG4-RD were retrospectively enrolled and divided into 119 IgG4-RD with chronic kidney disease (IgG4-RD CKD+) and 231 IgG4-RD without CKD (IgG4-RD CKD-). Demographic clinical and laboratory characteristics and survival of two cohorts were compared using restricted cubic splines, logistic and Cox regression, and Kaplan-Meier analysis. A nomogram was generated for calculating the probability of CKD in IgG4-RD. The spectrum of organ involvement was different between IgG4-RD CKD+ and CKD- cohorts (p<0.001). Lung (26.89%) and retroperitoneum (18.49%) involvement were more common in the IgG4-RD CKD+ cohort. Increased serum potassium and phosphorus, reduced calcium levels, and hypocomplementemia (all p<0.05) were observed in IgG4-RD CKD+. Restricted cubic splines revealed a U-shaped plot regarding associations between serum potassium and CKD. Kaplan-Meier analysis demonstrated significantly lower long-term survival rates in IgG4-RD patients with kidney function at CKD stages 4-5. Cox regression revealed declined kidney functions (G4 HR 6.537 (95% CI: 1.134-37.675)) associated with increased all-cause mortality in IgG4-RD patients. A nomogram was constructed to predict CKD in IgG4-RD promptly with a discrimination (C-index) of 0.846. CKD in IgG4-RD was associated with poor outcomes and electrolyte disturbances. Patients with IgG4-RD should be aware of possible deterioration in kidney function. The nomogram proposed would help to identify the subtle possibility of CKD in IgG4-RD. Key points • IgG4-related diseases with deteriorated kidney function have specific clinical and laboratory characteristics. • It is crucial to recognize and address the negative impact of deteriorating kidney function in IgG4-related diseases to prevent further harm. • The nomogram proposed would help to identify subtle kidney involvement by evaluating the possibility of CKD in IgG4-related diseases.

Calcium Reduction Using Variations of Thickness and Retention Time of Cocoa Shell Activated Carbon

High levels of hardness can lead to increased cases of kidney stones. Hardness levels can be reduced by using activated carbon from the cocoa rind as an adsorbent. The purpose of this research was to determine the variation of activated carbon thickness and optimum retention time in reducing the calcium content of dug well water, to determine the percent decrease in calcium ion levels at the optimum variation, and to determine the significance of the difference in the decreased in calcium levels between the treatment groups. The research method used the principle of adsorption of activated carbon from cocoa shells to calcium ions, which are activated by KOH. There were ten treatment samples with different variations of activated carbon thickness and retention time. The results showed that the thickness of activated carbon of 60 cm with a retention time of 50 minutes had the optimum ability to reduce the calcium content of dug well water. The percentage decrease in calcium levels reached 89,041 % with a decreased concentration of 234 ppm. The result of the statistical test showed a significance value of 0,05. The conclusion of the research is that activated carbon of cocoa shells can reduce calcium levels to the levels of soft water hardness, with variations in activated carbon thickness and retention time having a significant effect.

Prevalence of vitamin D deficiency in seniors – A retrospective study

Vitamin D deficiency is a condition with different causes. It is associated with numerous comorbidities such as autoimmune diseases, bone diseases, cancer, cardiovascular diseases, neurodegenerative diseases, psychiatric diseases, and respiratory infections like COVID-19. Due to its high prevalence all over the world, it is a major task for health care systems worldwide. Through a combination of low sunlight exposure, insufficient nutrition, and age-related changes in skin, liver, and kidney function, especially seniors and nursing home residents, in particular, have a significantly increased risk of developing a vitamin D deficiency. This retrospective study analyzed the prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D]<12ng/ml) amongst selected Austrian nursing home seniors. It also examined whether demographic data and other laboratory values like calcium correlate with vitamin D levels by using the Pearson correlation coefficient. This correlation was graphically illustrated with a scatter plot and regression line. A total of 478 patients admitted to a nursing home in Vienna between January 3, 2017, and August 31, 2020, were included. A total of 106 seniors (22,2%) suffered from a manifest vitamin D deficiency. The vitamin D level of the men was significantly lower than the level of the women (22.9±12.6ng/ml vs. 26.2±14.8ng/ml, p=0.027). The vitamin D serum levels significantly correlated with the serum calcium levels of the participants (r=0.19, p<0.001). 39.5% (189 out of 478) of the nursing home residents had inadequate serum vitamin D levels. In summary, it can be said that the prevalence of vitamin D deficiency among nursing home residents is considerably high. Inadequate vitamin D levels were often associated with reduced calcium levels. Given the high prevalence, the numerous negative health consequences of inadequate levels, and the large therapeutic index, this risk group should get a general supplementation with a dose of 25μg (1000 IU) vitamin D3 per day. In addition, a blood examination should be performed as early as three months after the start of the supplementation therapy. If some residents do not achieve an adequate vitamin D concentration, the substitution has to be adapted to the individual needs to treat them as precisely as possible.

Effect of sevelamer on serum phosphorus levels in chronic kidney disease and hemodialysis patients; a systematic review and meta-analysis

Introduction: Hyperphosphatemia is an independent risk factor for mortality in chronic kidney disease (CKD) patients. Objectives: This systematic review and meta-analysis aimed to investigate the effect of Sevelamer on serum phosphorus levels in CKD and hemodialysis patients. Materials and Methods: The data were obtained after searching the international databases of Cochrane, PubMed, Scopus, Web of Science, and the Google Scholar search engine until February 28, 2023. The heterogeneity of articles was assessed using the I2 index. The data were analyzed in STATA 14, and P values &lt; 0.05 were considered significant. Findings: A total of 22 articles were assessed with a total sample size of 3221. Sevelamer reduced calcium levels in CKD and hemodialysis patients compared with those in the comparison group (standardized mean difference [SMD]: -0.67; 95% CI: -1.23, -0.11); however, sevelamer had no significant effect on serum parathyroid hormone (PTH) levels (SMD: 0.07; 95% CI: -0.39, 0.54) and Ca × P product (SMD: -0.20; 95% CI: -0.41, 0). A significant decrease in serum phosphorus level was observed in patients who had taken sevelamer for a maximum of 12 weeks compared with the comparison group (SMD: -0.27; 95% CI: -0.54, -0.01); however, no significant decrease in serum phosphorus level was observed in patients who had taken sevelamer for more than 12 weeks. A significant decrease in serum phosphorus level was observed in sevelamer users compared to placebo group members (SMD: -0.36; 95% CI: -0.68, -0.05). Conclusion: The administration of sevelamer reduced serum phosphorus levels in CKD and hemodialysis patients compared with those in the placebo group in the short term. Therefore, physicians are recommended to prescribe sevelamer for a maximum period of three months. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO website (ID: CRD42023406804).

Biochemical parameters in patients with Trichomonasvaginalis and Toxoplasma gondii in Erbil-Iraq

This study investigated the biochemical parameters of two parasites, Trichomonasvaginalis and Toxoplasma gondii among females attending the gynaecological out patients clinics in MaternityRizgaryHospital, several health centers and some private clinics in Erbil-Iraq, from 16th July 2007 till 15th July 2008, by using different diagnostic methods. In addition, a comparative study to evaluate the biochemical changes due to tichomoniasis and toxoplasmosis. The serum samples were examined for some biochemical parameters like cholesterol, triglycerides, high density lipoproteins-cholesterol (HDL-C), low density lipoproteins-cholesterol (LDL-C), total proteins, albumin, globulin, with some elements such as calcium, sodium, potassium, chloride, iron, copper and zinc. Infection with Trichomonasvaginalis had no significant effects on the studied biochemical parameters among non-pregnant women. Toxoplasma gondii causes a significant decrease in total protein level among non-pregnant women, while in pregnant women, reduced calcium level was observed

Simvastatin Reduces Doxorubicin-Induced Cardiotoxicity: Effects beyond Its Antioxidant Activity.

This study aimed to evaluate if Simvastatin can reduce, and/or prevent, Doxorubicin (Doxo)-induced cardiotoxicity. H9c2 cells were treated with Simvastatin (10 µM) for 4 h and then Doxo (1 µM) was added, and the effects on oxidative stress, calcium homeostasis, and apoptosis were evaluated after 20 h. Furthermore, we evaluated the effects of Simvastatin and Doxo co-treatment on Connexin 43 (Cx43) expression and localization, since this transmembrane protein forming gap junctions is widely involved in cardioprotection. Cytofluorimetric analysis showed that Simvastatin co-treatment significantly reduced Doxo-induced cytosolic and mitochondrial ROS overproduction, apoptosis, and cytochrome c release. Spectrofluorimetric analysis performed by means of Fura2 showed that Simvastatin co-treatment reduced calcium levels stored in mitochondria and restored cytosolic calcium storage. Western blot, immunofluorescence, and cytofluorimetric analyses showed that Simvastatin co-treatment significantly reduced Doxo-induced mitochondrial Cx43 over-expression and significantly increased the membrane levels of Cx43 phosphorylated on Ser368. We hypothesized that the reduced expression of mitochondrial Cx43 could justify the reduced levels of calcium stored in mitochondria and the consequent induction of apoptosis observed in Simvastatin co-treated cells. Moreover, the increased membrane levels of Cx43 phosphorylated on Ser368, which is responsible for the closed conformational state of the gap junction, let us to hypothesize that Simvastatin leads to cell-to-cell communication interruption to block the propagation of Doxo-induced harmful stimuli. Based on these results, we can conclude that Simvastatin could be a good adjuvant in Doxo anticancer therapy. Indeed, we confirmed its antioxidant and antiapoptotic activity, and, above all, we highlighted that Simvastatin interferes with expression and cellular localization of Cx43 that is widely involved in cardioprotection.

Picolinafen exposure induces ROS accumulation and calcium depletion, leading to apoptosis in porcine embryonic trophectoderm and uterine luminal epithelial cells during the peri-implantation period

The global use of herbicides accounts for more than 48% of total pesticide usage. Picolinafen is a pyridine carboxylic acid herbicide that is predominantly used to control broadleaf weeds in wheat, barley, corn, and soybeans. Despite its widespread use in agriculture, its toxicity in mammals has rarely been studied. In this study, we first identified the cytotoxic effects of picolinafen on porcine trophectoderm (pTr) and luminal epithelial (pLE) cells, which are involved in the implantation process during early pregnancy. Picolinafen treatment significantly decreased the viability of pTr and pLE cells. Our results demonstrate that picolinafen increased the number of sub-G1 phase cells and early/late apoptosis. In addition, picolinafen disrupted mitochondrial function and resulted in the accumulation of intracellular ROS, leading to a reduction in calcium levels in both the mitochondria and cytoplasm of pTr and pLE cells. Moreover, picolinafen was found to significantly inhibit the migration of pTr. These responses were accompanied by the activation of the MAPK and PI3K signal transduction pathways by picolinafen. Our data suggest that the deleterious effects of picolinafen on the viability and migration of pTr and pLE cells might impair their implantation potential.

Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling.

Introduction: More than 50 mutations in the MAPT gene result in heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-Tau). However, early pathogenic events that lead to disease and the degree to which they are common across MAPT mutations remain poorly understood. The goal of this study is to determine whether there is a common molecular signature of FTLD-Tau. Methods: We analyzed genes differentially expressed in induced pluripotent stem cell-derived neurons (iPSC-neurons) that represent the three major categories of MAPT mutations: splicing (IVS10 + 16), exon 10 (p.P301L), and C-terminal (p.R406W) compared with isogenic controls. The genes that were commonly differentially expressed in MAPT IVS10 + 16, p.P301L, and p.R406W neurons were enriched in trans-synaptic signaling, neuronal processes, and lysosomal function. Many of these pathways are sensitive to disruptions in calcium homeostasis. One gene, CALB1, was significantly reduced across the three MAPT mutant iPSC-neurons and in a mouse model of tau accumulation. We observed a significant reduction in calcium levels in MAPT mutant neurons compared with isogenic controls, pointing to a functional consequence of this disrupted gene expression. Finally, a subset of genes commonly differentially expressed across MAPT mutations were also dysregulated in brains from MAPT mutation carriers and to a lesser extent in brains from sporadic Alzheimer disease and progressive supranuclear palsy, suggesting that molecular signatures relevant to genetic and sporadic forms of tauopathy are captured in a dish. The results from this study demonstrate that iPSC-neurons capture molecular processes that occur in human brains and can be used to pinpoint common molecular pathways involving synaptic and lysosomal function and neuronal development, which may be regulated by disruptions in calcium homeostasis.

Combinatorial delivery of CPI444 and vatalanib loaded on PEGylated graphene oxide as an effective nanoformulation to target glioblastoma multiforme: In vitro evaluation.

Glioblastoma multiforme (GBM) is known as the primary malignant and most devastating form of tumor found in the central nervous system of the adult population. The active pharmaceutical component in current chemotherapy regimens is mostly hydrophobic and poorly water-soluble, which hampers clinical implications. Nanodrug formulations using nanocarriers loaded with such drugs assisted in water dispersibility, improved cellular permeability, and drug efficacy at a low dose, thus adding to the overall practical value. Here, we successfully developed a water-dispersible and biocompatible nanocargo (GO-PEG) based on covalently modified graphene oxide (GO) with a 6-armed poly(ethylene glycol) amine dendrimer for effective loading of the two hydrophobic anticancer drug molecules, CPI444 and vatalanib. These drug molecules target adenosine receptor (A2AR), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and type III stem cell receptor tyrosine kinase (c-KIT), which plays a crucial role in cancers. The effective cellular delivery of the drugs when loaded on GO-PEG is attributed to the increased permeability of the drug-nanoconjugate formulation. We observed that this combinatorial drug treatment with nanocargo resulted in a significant reduction in the overall cell survival as supported by reduced calcium levels and stem cell markers such as Oct4 and Nanog, which are two of the prime factors for GBM stem cell proliferation. Furthermore, reduced expression of CD24 upon treatment with nanoformulation impeded cellular migration. Cellular assays confirmed inhibition of cell proliferation, migration, and angiogenic potential of GBM treated with GO-PEG–Drug conjugates. Ultimately, GBM U87 cells assumed programmed cell death at a very low concentration due to nanocarrier-mediated drug delivery along with the chosen combination of drugs. Together, this study demonstrated the advantage of GO-PEG mediated combined delivery of CPI444 and vatalanib drugs with increased permeability, a three-pronged combinatorial strategy toward effective GBM treatment.

Reduced calcium levels and accumulation of abnormal insulin granules in stem cell models of HNF1A deficiency

Mutations in HNF1A cause Maturity Onset Diabetes of the Young (HNF1A-MODY). To understand mechanisms of β-cell dysfunction, we generated stem cell-derived pancreatic endocrine cells with hypomorphic mutations in HNF1A. HNF1A-deficient β-cells display impaired basal and glucose stimulated-insulin secretion, reduced intracellular calcium levels in association with a reduction in CACNA1A expression, and accumulation of abnormal insulin granules in association with SYT13 down-regulation. Knockout of CACNA1A and SYT13 reproduce the relevant phenotypes. In HNF1A deficient β-cells, glibenclamide, a sulfonylurea drug used in the treatment of HNF1A-MODY patients, increases intracellular calcium, and restores insulin secretion. While insulin secretion defects are constitutive in β-cells null for HNF1A, β-cells heterozygous for hypomorphic HNF1A (R200Q) mutations lose the ability to secrete insulin gradually; this phenotype is prevented by correction of the mutation. Our studies illuminate the molecular basis for the efficacy of treatment of HNF1A-MODY with sulfonylureas, and suggest promise for the use of cell therapies.

Magnolol and honokiol target TRPC4 to regulate extracellular calcium influx and relax intestinal smooth muscle

Ethnopharmacological relevanceMagnolia officinalis Cortex (M. officinalis) is a classical traditional Chinese medicine (TCM) widely used to treat digestive system diseases. It effectively regulates gastrointestinal motility to improve abdominal pain, abdominal distension and other symptoms. Magnolol (MAG) and honokiol (HON) are the main pharmacodynamic components responsible for the gastrointestinal activity of M. officinalis. Aim of the studyThe transient receptor potential (TRP) family is highly expressed in the gastrointestinal tract and participates in the regulation of gastrointestinal motility, visceral hypersensitivity, visceral secretion and other physiological activities. In this study, the calcium-lowering mechanisms of MAG and HON contributing to the smooth muscle relaxation associated with TRP are discussed. Materials and methodsThe relaxation smooth muscle effects of MAG and HON were tested by the isolated intestine tone tests. A synthetic MAG probe (MAG-P) was used to target fishing for their possible target. The distribution of MAG on the smooth muscle was identified by a molecular tracer based on chemical biology. Ca2+ imaging and dual-luciferase reporter assays were used to determine the effects on the target proteins. Finally, the calcium-mediating effects of MAG and HON on smooth muscle cells and TRPC4-knockdown cells were compared to verify the potential mechanism. ResultsAfter confirming the smooth muscle relaxation in the small intestine induced by MAG and HON, the relaxation effect was identified mainly due to the downregulation of intracellular calcium by controlling external calcium influx. Although MAG and HON inhibited both TRPV4 and TRPC4 channels to reduce calcium levels, the inhibitory effect on TRPC4 channels is an important mechanism of their smooth muscle relaxation effect, since TRPC4 is widely expressed in the small intestinal smooth muscle cells. ConclusionsThe inhibition of MAG and HON on TRPC4 channels contributes to the relaxation of intestinal smooth muscle.

Treatment options for hypercalcemia after cosmetic oil injections: Lessons from human tissue cultures and a pilot intervention study.

Granuloma formation following self-administered cosmetic oil injections can lead to severe hypercalcemia and renal calcifications due to extra-renal vitamin D activation. This translational study aims to identify Prednisolone sparing therapeutics for hypercalcemia after development of granulomatous disease secondary to paraffin oil injections. Granuloma tissue isolated from five men were cultured ex vivo and treated with selected drugs to block generation of activated vitamin D (1,25(OH)2D3). In a retrospective study, we included data before and during different treatments of 21 men with paraffin oil induced granulomatous hypercalcemia (46 treatment courses) where serum calcium, parathyroid hormone, vitamin D metabolites, creatinine and inflammatory markers were measured. Addition of Ketoconazole or Ciclosporin to granuloma tissue ex vivo culture, significantly suppressed production of 1,25(OH)2D3 after 48h (both p<0.05). Prednisolone was the first treatment option in most men and lowered serum levels of ionized calcium after 1, 2, 3 and 6months compared with baseline (p<0.05). Ketoconazole or Hydroxychloroquine had no significant effect on serum calcium levels and were unable to reduce the concomitant daily Prednisolone doses (p>0.05). Azathioprine did not reduce calcium levels. However, addition of Tacrolimus to Prednisolone treatment enabled a reduction in Prednisolone dose after 3months (p=0.014), but with no additional effect on calcium homeostasis. This study verifies that Prednisolone is an effective treatment and suggests that calcineurin inhibitors may be used as Prednisolone sparing treatment for paraffin oil-induced granulomatous hypercalcemia. Randomized clinical trials are needed to determine clinical efficacy.