Large stabilization effects by intramolecular Beryllium bonds in Ortho-Benzene derivatives

Intramolecular interactions are shown to be key for favoring a given structure in systems with a variety of conformers. In ortho-substituted benzene derivatives including a beryllium moiety, beryllium bonds provide very large stabilizations with respect to non-bound conformers and enthalpy differences above one hundred kJ·mol(−1) are found in the most favorable cases, especially if the newly formed rings are five or six-membered heterocycles. These values are in general significantly larger than hydrogen bonds in 1,2-dihidroxybenzene. Conformers stabilized by a beryllium bond exhibit the typical features of this non-covalent interaction, such as the presence of a bond critical point according to the topology of the electron density, positive Laplacian values, significant geometrical distortions and strong interaction energies between the donor and acceptor quantified by using the Natural Bond Orbital approach. An isodesmic reaction scheme is used as a tool to measure the strength of the beryllium bond in these systems in terms of isodesmic energies (analogous to binding energies), interaction energies and deformation energies. This approach shows that a huge amount of energy is spent on deforming the donor–acceptor pairs to form the new rings

Wolfram Syndrome protein, Miner1, regulates sulphydryl redox status, the unfolded protein response, and Ca2+ homeostasis.

Miner1 is a redox-active 2Fe2S cluster protein. Mutations in Miner1 result in Wolfram Syndrome, a metabolic disease associated with diabetes, blindness, deafness, and a shortened lifespan. Embryonic fibroblasts from Miner1(-/-) mice displayed ER stress and showed hallmarks of the unfolded protein response. In addition, loss of Miner1 caused a depletion of ER Ca(2+) stores, a dramatic increase in mitochondrial Ca(2+) load, increased reactive oxygen and nitrogen species, an increase in the GSSG/GSH and NAD(+)/NADH ratios, and an increase in the ADP/ATP ratio consistent with enhanced ATP utilization. Furthermore, mitochondria in fibroblasts lacking Miner1 displayed ultrastructural alterations, such as increased cristae density and punctate morphology, and an increase in O2 consumption. Treatment with the sulphydryl anti-oxidant N-acetylcysteine reversed the abnormalities in the Miner1 deficient cells, suggesting that sulphydryl reducing agents should be explored as a treatment for this rare genetic disease

Levels and values of circulating endothelial progenitor cells, soluble angiogenic factors, and mononuclear cell apoptosis in liver cirrhosis patients

BACKGROUND: The roles of circulating endothelial progenitor cell (EPC) and mononuclear cell apoptosis (MCA) in liver cirrhosis (LC) patients are unknown. Moreover, vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α are powerful endogenous substances enhancing EPC migration into circulation. We assessed the level and function of EPCs [CD31/CD34 (E(1)), KDR/CD34 (E(2)), CXCR4/CD34 (E(3))], levels of MCA, VEGF and SDF-1α in circulation of LC patients. METHODS: Blood sample was prospectively collected once for assessing EPC level and function, MCA, and plasma levels of VEGF and SDF-1α using flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively, in 78 LC patients and 25 age- and gender-matched healthy controls. RESULTS: Number of EPCs (E(1), E(2), E(3)) was lower (all p < 0.0001), whereas SDF-1α level and MCA were higher (p < 0.001) in study patients compared with healthy controls. Number of EPCs (E(2), E(3)) was higher but MCA was lower (all p < 0.05) in Child's class A compared with Child's class B and C patients, although no difference in VEGF and SDF-1α levels were noted among these patients. Chronic hepatitis B and esophageal varices bleeding were independently, whereas chronic hepatitis C, elevated aspartate aminotransferase (AST), and decompensated LC were inversely and independently correlated with circulating EPC level (all p < 0.03). Additionally, angiogenesis and transwell migratory ability of EPCs were reduced in LC patients than in controls (all p < 0.001). CONCLUSION: The results of this study demonstrated that level, angiogenic capacity, and function of circulating EPCs were significantly reduced, whereas plasma levels of SDF-1α and circulating MCA were substantially enhanced in cirrhotic patients

Fak56 functions downstream of integrin alphaPS3betanu and suppresses MAPK activation in neuromuscular junction growth

Background: Focal adhesion kinase (FAK) functions in cell migration and signaling through activation of the mitogen-activated protein kinase (MAPK) signaling cascade. Neuronal function of FAK has been suggested to control axonal branching; however, the underlying mechanism in this process is not clear. Results: We have generated mutants for the Drosophila FAK gene, Fak56. Null Fak56 mutants display overgrowth of larval neuromuscular junctions (NMJs). Localization of phospho-FAK and rescue experiments suggest that Fak56 is required in presynapses to restrict NMJ growth. Genetic analyses imply that FAK mediates the signaling pathway of the integrin αPS3βν heterodimer and functions redundantly with Src. At NMJs, Fak56 downregulates ERK activity, as shown by diphospho-ERK accumulation in Fak56 mutants, and suppression of Fak56 mutant NMJ phenotypes by reducing ERK activity. Conclusion: We conclude that Fak56 is required to restrict NMJ growth during NMJ development. Fak56 mediates an extracellular signal through the integrin receptor. Unlike its conventional role in activating MAPK/ERK, Fak56 suppresses ERK activation in this process. These results suggest that Fak56 mediates a specific neuronal signaling pathway distinct from that in other cellular processes

Diagnostic efficacy of the triglyceride–glucose index in the prediction of contrast-induced nephropathy following percutaneous coronary intervention

IntroductionContrast-induced nephropathy (CIN) is a common complication of percutaneous coronary intervention (PCI). Identifying patients at high CIN risk remains challenging. The triglyceride-glucose (TyG) index may help predict CIN but evidence is limited. We conducted a meta-analysis to evaluate the diagnostic value of TyG index for CIN after PCI.MethodsA systematic literature search was performed in MEDLINE, Cochrane, and EMBASE until August 2023 (PROSPERO registration: CRD42023452257). Observational studies examining TyG index for predicting CIN risk in PCI patients were included. This diagnostic meta-analysis aimed to evaluate the accuracy of the TyG index in predicting the likelihood of CIN. Secondary outcomes aimed to assess the pooled incidence of CIN and the association between an elevated TyG index and the risk of CIN.ResultsFive studies (Turkey, n=2; China, n=3) with 3518 patients (age range: 57.6 to 68.22 years) were included. The pooled incidence of CIN was 15.3% [95% confidence interval (CI) 11-20.8%]. A high TyG index associated with increased CIN risk (odds ratio: 2.25, 95% CI 1.82-2.77). Pooled sensitivity and specificity were 0.77 (95% CI 0.59-0.88) and 0.55 (95% CI 0.43-0.68) respectively. Analysis of the summary receiver operating characteristic (sROC) curve revealed an area under the curve of 0.69 (95% CI 0.65-0.73). There was a low risk of publication bias (p = 0.81).ConclusionThe TyG index displayed a noteworthy correlation with the risk of CIN subsequent to PCI. However, its overall diagnostic accuracy was found to be moderate in nature. While promising, the TyG index should not be used in isolation for CIN screening given the heterogeneity between studies. In addition, the findings cannot be considered conclusive given the scarcity of data. Further large-scale studies are warranted to validate TyG cutoffs and determine how to optimally incorporate it into current risk prediction models.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023452257, identifier CRD42023452257

Biodistribution and pharmacokinetics of 188Re-liposomes and their comparative therapeutic efficacy with 5-fluorouracil in C26 colonic peritoneal carcinomatosis mice

Chia-Che Tsai1, Chih-Hsien Chang1, Liang-Cheng Chen1, Ya-Jen Chang1, Keng-Li Lan2, Yu-Hsien Wu1, Chin-Wei Hsu1, I-Hsiang Liu1, Chung-Li Ho1, Wan-Chi Lee1, Hsiao-Chiang Ni1, Tsui-Jung Chang1, Gann Ting3, Te-Wei Lee11Institute of Nuclear Energy Research, Taoyuan, 2Cancer Center, Taipei Veterans General Hospital, Taipei, 3National Health Research Institutes, Taipei, Taiwan, ROCBackground: Nanoliposomes are designed as carriers capable of packaging drugs through passive targeting tumor sites by enhanced permeability and retention (EPR) effects. In the present study the biodistribution, pharmacokinetics, micro single-photon emission computed tomography (micro-SPECT/CT) image, dosimetry, and therapeutic efficacy of 188Re-labeled nanoliposomes (188Re-liposomes) in a C26 colonic peritoneal carcinomatosis mouse model were evaluated.Methods: Colon carcinoma peritoneal metastatic BALB/c mice were intravenously administered 188Re-liposomes. Biodistribution and micro-SPECT/CT imaging were performed to determine the drug profile and targeting efficiency of 188Re-liposomes. Pharmacokinetics study was described by a noncompartmental model. The OLINDA|EXM&amp;reg; computer program was used for the dosimetry evaluation. For therapeutic efficacy, the survival, tumor, and ascites inhibition of mice after treatment with 188Re-liposomes and 5-fluorouracil (5-FU), respectively, were evaluated and compared.Results: In biodistribution, the highest uptake of 188Re-liposomes in tumor tissues (7.91% &amp;plusmn; 2.02% of the injected dose per gram of tissue [%ID/g]) and a high tumor to muscle ratio (25.8 &amp;plusmn; 6.1) were observed at 24 hours after intravenous administration. The pharmacokinetics of 188Re-liposomes showed high circulation time and high bioavailability (mean residence time [MRT] = 19.2 hours, area under the curve [AUC] = 820.4%ID/g*h). Micro-SPECT/CT imaging of 188Re-liposomes showed a high uptake and targeting in ascites, liver, spleen, and tumor. The results were correlated with images from autoradiography and biodistribution data. Dosimetry study revealed that the 188Re-liposomes did not cause high absorbed doses in normal tissue but did in small tumors. Radiotherapeutics with 188Re-liposomes provided better survival time (increased by 34.6% of life span; P &amp;lt; 0.05), tumor and ascites inhibition (decreased by 63.4% and 83.3% at 7 days after treatment; P &amp;lt; 0.05) in mice compared with chemotherapeutics of 5-fluorouracil (5-FU).Conclusion: The use of 188Re-liposomes for passively targeted tumor therapy had greater therapeutic effect than the currently clinically applied chemotherapeutics drug 5-FU in a colonic peritoneal carcinomatosis mouse model. This result suggests that 188Re-liposomes have potential benefit and are safe in treating peritoneal carcinomatasis of colon cancer.Keywords: biodistribution, dosimetry, 5-fluorouracil, micro-SPECT/CT, 188Re-liposome