Advanced glycation end products (AGEs) are generated by nonenzymatic modifications of macromolecules (proteins, lipids, and nucleic acids) by saccharides (glucose, fructose, and pentose) via Maillard ...reaction. The formed AGE molecules can be catabolized and cleared by glyoxalase I and II in renal proximal tubular cells. AGE-related diseases include physiological aging, neurodegenerative/neuroinflammatory diseases, diabetes mellitus (DM) and its complications, autoimmune/rheumatic inflammatory diseases, bone-degenerative diseases, and chronic renal diseases. AGEs, by binding to receptors for AGE (RAGEs), alter innate and adaptive immune responses to induce inflammation and immunosuppression via the generation of proinflammatory cytokines, reactive oxygen species (ROS), and reactive nitrogen intermediates (RNI). These pathological molecules cause vascular endothelial/smooth muscular/connective tissue-cell and renal mesangial/endothelial/podocytic-cell damage in AGE-related diseases. In the present review, we first focus on the cellular and molecular bases of AGE-RAGE axis signaling pathways in AGE-related diseases. Then, we discuss in detail the modes of action of newly discovered novel biomolecules and phytochemical compounds, such as Maillard reaction and AGE-RAGE signaling inhibitors. These molecules are expected to become the new therapeutic strategies for patients with AGE-related diseases in addition to the traditional hypoglycemic and anti-hypertensive agents. We particularly emphasize the importance of "metabolic memory", the "French paradox", and the pharmacokinetics and therapeutic dosing of the effective natural compounds associated with pharmacogenetics in the treatment of AGE-related diseases. Lastly, we propose prospective investigations for solving the enigmas in AGE-mediated pathological effects.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We propose a diagnostic for finite temperature topological order using "topological entanglement negativity," the long-range component of a mixed-state entanglement measure. As a demonstration, we ...study the toric code model in d spatial dimensions for d=2,3,4, and find that when topological order survives thermal fluctuations, it possesses a nonzero topological entanglement negativity, whose value is equal to the topological entanglement entropy at zero temperature. Furthermore, we show that the Gibbs state of 2D and 3D toric code at any nonzero temperature, and that of 4D toric code above a certain critical temperature, can be expressed as a convex combination of short-range entangled pure states, consistent with the absence of topological order.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
During rheumatoid arthritis (RA) treatment, long-term injection of antitumor necrosis factor α antibodies (anti-TNFα Abs) may induce on-target toxicities, including severe infections (tuberculosis TB ...or septic arthritis) and malignancy. Here, we used an immunoglobulin G1 (IgG1) hinge as an Ab lock to cover the TNFα-binding site of Infliximab by linking it with matrix metalloproteinase (MMP) -2/9 substrate to generate pro-Infliximab that can be specifically activated in the RA region to enhance the selectivity and safety of treatment. The Ab lock significantly inhibits the TNFα binding and reduces the anti-idiotypic (anti-Id) Ab binding to pro-Infliximab by 395-fold, 108-fold compared with Infliximab, respectively, and MMP-2/9 can completely restore the TNFα neutralizing ability of pro-Infliximab to block TNFα downstream signaling. Pro-Infliximab was only selectively activated in the disease site (mouse paws) and presented similar pharmacokinetics (PKs) and bio-distribution to Infliximab. Furthermore, pro-Infliximab not only provided equivalent therapeutic efficacy to Infliximab but also maintained mouse immunity against Listeria infection in the RA mouse model, leading to a significantly higher survival rate (71%) than that of the Infliximab treatment group (0%). The high-selectivity pro-Infliximab maintains host immunity and keeps the original therapeutic efficiency, providing a novel strategy for RA therapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this prospective study, Han Chinese subjects who were candidates for carbamazepine therapy were screened for the HLA-B*1502 allele because of its association with the Stevens–Johnson syndrome and ...toxic epidermal necrolysis.
The Stevens–Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), are two of the most serious adverse reactions caused by drugs. SJS is characterized by high fever, malaise, and a rapidly developing, blistering exanthema of macular papules and target-like lesions, accompanied by mucosal involvement. This condition is associated with a rate of death of approximately 5%. TEN has a similar presentation, with even more extensive skin detachment and a death rate of 25 to 35%.
1
Carbamazepine, an anticonvulsant and specific analgesic agent for trigeminal neuralgia, is the most common cause of SJS–TEN in Southeast Asian countries.
2
We previously . . .
Echinacoside is a major compound of Cistanche Herb and has glutamate release-inhibiting activity in the brain. Given the involvement of excitotoxicity caused by massive glutamate in the ...pathophysiology of epilepsy, we explored the antiepileptic effect of echinacoside on kainic acid-induced seizures in rats. The rats were intraperitoneally administrated echinacoside for 30 min prior to intraperitoneal injection with kainic acid. The results showed that kainic acid induced seizure-like behavioral patterns, increased glutamate concentrations, caused neuronal loss and microglial activation, and stimulated proinflammatory cytokine gene expression in the hippocampus. These kainic acid-induced alternations were found to be attenuated by echinacoside pretreatment. Furthermore, decreased Akt and glycogen synthase kinase 3β (GSK3β) phosphorylation as well as Bcl-2 expression in the hippocampus was reversed by the echinacoside pretreatment. These results demonstrate that echinacoside exert its antiepileptic and neuroprotective actions in a kainic acid rat model through suppressing inflammatory response and activating the Akt/GSK3β signaling. Therefore, the present study suggests that echinacoside is the potentially useful in the prevention of epilepsy.
The preparation of long-range entangled states using unitary circuits is limited by Lieb-Robinson bounds, but circuits with projective measurements and feedback (“adaptive circuits”) can evade such ...restrictions. We introduce three classes of local adaptive circuits that enable low-depth preparation of long-range entangled quantum matter characterized by gapped topological orders and conformal field theories (CFTs). The three classes are inspired by distinct physical insights, including tensor-network constructions, the multiscale entanglement renormalization ansatz, and parton constructions. A large class of topological orders, including chiral topological order, can be prepared in constant depth or time, and one-dimensional CFT states and non-Abelian topological orders with both solvable and nonsolvable groups can be prepared in depth scaling logarithmically with system size. We also build on a recently discovered correspondence between symmetry-protected topological phases and long-range entanglement to derive efficient protocols for preparing symmetry-enriched topological order and arbitrary Calderbank-Shor-Steane codes. Our work illustrates the practical and conceptual versatility of measurement for state preparation.
Objectives
This study aimed to investigate the clinical outcomes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) under rituximab induction and reinduction therapy in ...Taiwan.
Methods
We performed a retrospective study in patients with GPA or MPA receiving rituximab therapy from August 2008 to July 2020 in seven medical centers in Taiwan. The clinical characteristics and outcomes of these patients were analyzed.
Results
In total, 53 patients (18 with GPA and 35 with MPA) were included. Kidney involvement (82.9% vs. 22.2%, p < .001) and initial creatinine (3.25 ± 2.37 vs. 1.07 ± 0.82, p < .001) were significantly higher in MPA. Within 24 weeks after the first course of rituximab, there were seven deaths (five due to infection and two due to active disease) in patients with MPA (7/35, 20%) compared to 0 in patients with GPA. Of 33 patients receiving rituximab for kidney involvement, 23 survived and were free from renal replacement therapy at 24 weeks. Their chronic kidney disease (CKD) stages improved in 2 but progressed in 7, while 24 had stable CKD stages. Death or end‐stage renal disease (ESRD) was associated with infection and higher initial creatinine. Reinduction therapy for relapse was required in 18 (39.1%) of 46 survivors, which was associated with anti‐proteinase 3 (PR3) positive (odds ratio 3.667, p = .049) and younger age with a cutoff of 49.4 (AUC = 0.679, p = .030, sensitivity = 66.67%, specificity = 75%).
Conclusion
Significant mortality occurred after rituximab induction, especially in patients with MPA. In survivors, age younger than 50 and anti‐PR3 positive were associated with the risk of relapse requiring reinduction.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Polymorphonuclear neutrophils (PMNs) are traditionally regarded as professional phagocytic and acute inflammatory cells that engulf the microbial pathogens. However, accumulating data have suggested ...that PMNs are multi-potential cells exhibiting many important biological functions in addition to phagocytosis. These newly found novel activities of PMN include production of different kinds of cytokines/chemokines/growth factors, release of neutrophil extracellular traps (NET)/ectosomes/exosomes and trogocytosis (membrane exchange) with neighboring cells for modulating innate, and adaptive immune responses. Besides, PMNs exhibit potential heterogeneity and plasticity in involving antibody-dependent cellular cytotoxicity (ADCC), cancer immunity, autoimmunity, inflammatory rheumatic diseases, and cardiovascular diseases. Interestingly, PMNs may also play a role in ameliorating inflammatory reaction and wound healing by a subset of PMN myeloid-derived suppressor cells (PMN-MDSC). Furthermore, PMNs can interact with other non-immune cells including platelets, epithelial and endothelial cells to link hemostasis, mucosal inflammation, and atherogenesis. The release of low-density granulocytes (LDG) from bone marrow initiates systemic autoimmune reaction in systemic lupus erythematosus (SLE). In clinical application, identification of certain PMN phenotypes may become prognostic factors for severe traumatic patients. In the present review, we will discuss these newly discovered biological and pathobiological functions of the PMNs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Increasing frequency of human exposure to PEG-related products means that healthy people are likely to have pre-existing anti-PEG antibodies (pre-αPEG Ab). However, the influence of pre-αPEG Abs on ...the pharmacokinetics (PK) and therapeutic efficacy of LipoDox is unknown.
We generated two pre-αPEG Ab mouse models. First, naïve mice were immunized with PEGylated protein to generate an endogenous αPEG Ab titer (endo αPEG). Second, monoclonal αPEG Abs were passively transferred (αPEG-PT) into naïve mice to establish a αPEG titer. The naïve, endo αPEG and αPEG-PT mice were intravenously injected with
in-labeled LipoDox to evaluate its PK. Tumor-bearing naïve, endo αPEG and αPEG-PT mice were intravenously injected with
in-labeled LipoDox to evaluate its biodistribution. The therapeutic efficacy of LipoDox was estimated in the tumor-bearing mice.
The areas under the curve (AUC)
of LipoDox in endo αPEG and αPEG-PT mice were 11.5- and 15.6- fold less, respectively, than that of the naïve group. The biodistribution results suggested that pre-αPEG Ab can significantly reduce tumor accumulation and accelerate blood clearance of
In-labeled LipoDox from the spleen. The tumor volumes of the tumor-bearing endo αPEG and αPEG-PT mice after treatment with LipoDox were significantly increased as compared with that of the tumor-bearing naïve mice.
Pre-αPEG Abs were found to dramatically alter the PK and reduce the tumor accumulation and therapeutic efficacy of LipoDox. Pre-αPEG may have potential as a marker to aid development of personalized therapy using LipoDox and achieve optimal therapeutic efficacy.
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