Distinctive Microbial Signatures and Gut-Brain Crosstalk in Pediatric Patients with Coeliac Disease and Type 1 Diabetes Mellitus

Coeliac disease (CD) and Type 1 diabetes mellitus (T1DM) are immune-mediated diseases. Emerging evidence suggests that dysbiosis in the gut microbiome plays a role in the pathogenesis of both diseases and may also be associated with the development of neuropathy. The primary goal in this cross-sectional pilot study was to identify whether there are distinct gut microbiota alterations in children with CD (n = 19), T1DM (n = 18) and both CD and T1DM (n = 9) compared to healthy controls (n = 12). Our second goal was to explore the relationship between neuropathy (corneal nerve fiber damage) and the gut microbiome composition. Microbiota composition was determined by 16S rRNA gene sequencing. Corneal confocal microscopy was used to determine nerve fiber damage. There was a significant difference in the overall microbial diversity between the four groups with healthy controls having a greater microbial diversity as compared to the patients. The abundance of pathogenic proteobacteria Shigella and E. coli were significantly higher in CD patients. Differential abundance analysis showed that several bacterial amplicon sequence variants (ASVs) distinguished CD from T1DM. The tissue transglutaminase antibody correlated significantly with a decrease in gut microbial diversity. Furthermore, the Bacteroidetes phylum, specifically the genus Parabacteroides was significantly correlated with corneal nerve fiber loss in the subjects with neuropathic damage belonging to the diseased groups. We conclude that disease-specific gut microbial features traceable down to the ASV level distinguish children with CD from T1DM and specific gut microbial signatures may be associated with small fiber neuropathy. Further research on the mechanisms linking altered microbial diversity with neuropathy are warranted.     

The Role of CaMKII and ERK Signaling in Addiction

Nicotine is the predominant addictive compound of tobacco and causes the acquisition of dependence through its interactions with nicotinic acetylcholine receptors and various neurotransmitter releases in the central nervous system. The Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) play a pivotal role in synaptic plasticity in the hippocampus. CaMKII is involved in long-term potentiation induction, which underlies the consolidation of learning and memory; however, the roles of CaMKII in nicotine and other psychostimulant-induced addiction still require further investigation. This article reviews the molecular mechanisms and crucial roles of CaMKII and ERK in nicotine and other stimulant drug-induced addiction. We also discuss dopamine (DA) receptor signaling involved in nicotine-induced addiction in the brain reward circuitry. In the last section, we introduce the association of polyunsaturated fatty acids and cellular chaperones of fatty acid-binding protein 3 in the context of nicotine-induced addiction in the mouse nucleus accumbens and provide a novel target for the treatment of drug abuse affecting dopaminergic systems.     

Characterization of Dog Glutathione Transferase P1-1, an Enzyme Relevant to Veterinary Medicine

Glutathione transferases (GSTs) form a family of detoxication enzymes instrumental in the inactivation and elimination of electrophilic mutagenic and carcinogenic compounds. The Pi class GST P1-1 is present in most tissues and is commonly overexpressed in neoplastic cells. GST P1-1 in the dog, Canis lupus familiaris, has merits as a marker for tumors and as a target for enzyme-activated prodrugs. We produced the canine enzyme CluGST P1-1 by heterologous bacterial expression and verified its cross-reactivity with antihuman-GST P1-1 antibodies. The catalytic activity with alternative substrates of biological significance was determined, and the most active substrate found was benzyl isothiocyanate. Among established GST inhibitors, Cibacron Blue showed positive cooperativity with an IC₅₀ value of 43 nM. Dog GST P1-1 catalyzes activation of the prodrug Telcyta, but the activity is significantly lower than that of the human homolog.     

Charge Transportation and Chirality in Liquid Crystalline Helical Network Phases of Achiral BTBT-Derived Polycatenar Molecules

First examples of multichain (polycatenar) compounds, based on the π-conjugated [1]benzothieno[3,2-b]benzothiophene unit are designed, synthesized, and their soft self-assembly and charge carrier mobility are investigated. These compounds, terminated by the new fan-shaped 2-brominated 3,4,5-trialkoxybenzoate moiety, form bicontinuous cubic liquid crystalline (LC) phases with helical network structure over extremely wide temperature ranges (>200 K), including ambient temperature. Compounds with short chains show an achiral cubic phase with the double network, which upon increasing the chain length, is at first replaced by a tetragonal 3D phase and then by a mirror symmetry is broken triple network cubic phase. In the networks, the capability of bypassing defects provides enhanced charge carrier mobility compared to imperfectly aligned columnar phases, and the charge transportation is non-dispersive, as only rarely observed for LC materials. At the transition to a semicrystalline helical network phase, the conductivity is further enhanced by almost one order of magnitude. In addition, a mirror symmetry broken isotropic liquid phase is formed beside the 3D phases, which upon chain elongation is removed and replaced by a hexagonal columnar LC phase.     

Targeting S1PRs as a Therapeutic Strategy for Inflammatory Bone Loss Diseases—Beyond Regulating S1P Signaling

As G protein coupled receptors, sphingosine-1-phosphate receptors (S1PRs) have recently gained attention for their role in modulating inflammatory bone loss diseases. Notably, in murine studies inhibiting S1PR2 by its specific inhibitor, JTE013, alleviated osteoporosis induced by RANKL and attenuated periodontal alveolar bone loss induced by oral bacterial inflammation. Treatment with a multiple S1PRs modulator, FTY720, also suppressed ovariectomy-induced osteoporosis, collagen or adjuvant-induced arthritis, and apical periodontitis in mice. However, most previous studies and reviews have focused mainly on how S1PRs manipulate S1P signaling pathways, subsequently affecting various diseases. In this review, we summarize the underlying mechanisms associated with JTE013 and FTY720 in modulating inflammatory cytokine release, cell chemotaxis, and osteoclastogenesis, subsequently influencing inflammatory bone loss diseases. Studies from our group and from other labs indicate that S1PRs not only control S1P signaling, they also regulate signaling pathways induced by other stimuli, including bacteria, lipopolysaccharide (LPS), bile acid, receptor activator of nuclear factor κB ligand (RANKL), IL-6, and vitamin D. JTE013 and FTY720 alleviate inflammatory bone loss by decreasing the production of inflammatory cytokines and chemokines, reducing chemotaxis of inflammatory cells from blood circulation to bone and soft tissues, and suppressing RANKL-induced osteoclast formation.     

Role of the HSP70 Co-Chaperone SIL1 in Health and Disease

Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1′s function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1′s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1′s NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS.     

Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

The low overall survival rate of patients with pancreatic cancer has driven research to seek a new therapeutic protocol. Radiotherapy (RT) is frequently an option in the neoadjuvant or palliative settings for pancreatic cancer treatment. This study explored the effect of RT protocols on the tumor microenvironment (TME) and their consequent impact on anti-programmed cell death ligand-1 (PD-L1) therapy. Using a murine orthotopic pancreatic tumor model, UN-KC-6141, RT-disturbed TME was examined by immunohistochemical staining. The results showed that ablative RT is more effective than fractionated RT at recruiting T cells. On the other hand, fractionated RT induces more myeloid-derived suppressor cell infiltration than ablative RT. The RT-disturbed TME presents a higher perfusion rate per vessel. The increase in vessel perfusion is associated with a higher amount of anti-PD-L1 antibody being delivered to the tumor. Animal survival is increased by anti-PD-L1 therapy after ablative RT, with 67% of treated animals surviving more than 30 days after tumor inoculation compared to a median survival time of 16.5 days for the control group. Splenocytes isolated from surviving animals were specifically cytotoxic for UN-KC-6141 cells. We conclude that the ablative RT-induced TME is more suited than conventional RT-induced TME to combination therapy with immune checkpoint blockade.     

Process parameters influence on zone refining and thermodynamics analysis of 1,2-diphenylethane

Effective distribution coefficients of 9 impurities in 1,2-diphenylethane have been calculated by directional crystallization under different ambient frozen temperature. The effect of varied zone size, temperature difference between the melt and ambient frozen environment, number of zone on purity of 1,2-diphenylethane have been also investigated during the process of zone refining. The results indicate that the product purity in the intermediate purified region with varied zone size is higher 0.04%-0.2% than that with constant zone size. The product purity increases with temperature difference between the melt and ambient frozen environment. The appropriate temperature difference is adopted 50℃. The product purity in the intermediate region of sample bar with 2 molten zones is higher 0.05%-0.43% than that with 1 molten zone. In addition, the change of enthalpy and entropy between impurities and 1,2-diphenylethane have been determined.