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"Shu, Hui"
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Instability Challenges and Stabilization Strategies of Pharmaceutical Proteins
Maintaining the structure of protein and peptide drugs has become one of the most important goals of scientists in recent decades. Cold and thermal denaturation conditions, lyophilization and freeze drying, different pH conditions, concentrations, ionic strength, environmental agitation, the interaction between the surface of liquid and air as well as liquid and solid, and even the architectural structure of storage containers are among the factors that affect the stability of these therapeutic biomacromolecules. The use of genetic engineering, side-directed mutagenesis, fusion strategies, solvent engineering, the addition of various preservatives, surfactants, and additives are some of the solutions to overcome these problems. This article will discuss the types of stress that lead to instabilities of different proteins used in pharmaceutics including regulatory proteins, antibodies, and antibody-drug conjugates, and then all the methods for fighting these stresses will be reviewed. New and existing analytical methods that are used to detect the instabilities, mainly changes in their primary and higher order structures, are briefly summarized.
Journal Article
Spin-neutral currents for spintronics
Electric currents carrying a net spin polarization are widely used in spintronics, whereas globally spin-neutral currents are expected to play no role in spin-dependent phenomena. Here we show that, in contrast to this common expectation, spin-independent conductance in compensated antiferromagnets and normal metals can be efficiently exploited in spintronics, provided their magnetic space group symmetry supports a non-spin-degenerate Fermi surface. Due to their momentum-dependent spin polarization, such antiferromagnets can be used as active elements in antiferromagnetic tunnel junctions (AFMTJs) and produce a giant tunneling magnetoresistance (TMR) effect. Using RuO
2
as a representative compensated antiferromagnet exhibiting spin-independent conductance along the [001] direction but a non-spin-degenerate Fermi surface, we design a RuO
2
/TiO
2
/RuO
2
(001) AFMTJ, where a globally spin-neutral charge current is controlled by the relative orientation of the Néel vectors of the two RuO
2
electrodes, resulting in the TMR effect as large as ~500%. These results are expanded to normal metals which can be used as a counter electrode in AFMTJs with a single antiferromagnetic layer or other elements in spintronic devices. Our work uncovers an unexplored potential of the materials with no global spin polarization for utilizing them in spintronics.
Spin-polarised electric currents have been studied extensively for use in spintronics, while their spin-neutral counterparts have been largely ignored. Here Shao et al show that such spin-neutral currents can be controlled by the Neel vector orientation of an antiferromagnet and detected using an antiferromagnetic tunnel junction.
Journal Article
Hybrid energy storage system for intelligent electric vehicles incorporating improved PSO algorithm
Existing energy storage system is difficult to balance the energy distribution and dynamic response efficiency issues of lithium-ion batteries and supercapacitor, resulting in low energy utilization. Therefore, the study proposes a hybrid energy storage system for intelligent electric vehicles incorporating improved particle swarm optimization. The study analyzes the relationship between vehicle driving speed and power demand through equivalent model, constructs an objective function containing power demand and state of charge, and uses an improved algorithm for optimization and solution. The performance test results indicated that the proposed improved algorithm exhibited the fastest convergence speed by rapidly decreasing the objective function value and approximating the optimal solution within the first 20 iterations in both single-peak and multi-peak functions. The simulation experiments were validated under urban working conditions and highway working conditions, respectively. The results indicated that the energy efficiency in both working conditions was improved to 92.5% and 94.9%, respectively. In addition, good results were achieved in the contribution of supercapacitor, which were 27.2% and 29.6%, respectively. In the test results based on HIL environment, the system proposed by the research institute can also maintain energy efficiency of over 80% under extreme conditions. The findings support the optimal design of intelligent electric vehicle energy storage systems both theoretically and practically, showing that the study’s revised algorithm performs well in both energy allocation efficiency and dynamic response performance.
Journal Article
Autophagy and Tau Protein
Neurofibrillary tangles, which consist of highly phosphorylated tau protein, and senile plaques (SPs) are pathological hallmarks of Alzheimer’s disease (AD). In swollen axons, many autophagic vacuoles are observed around SP in the AD brain. This suggests that autophagy function is disturbed in AD. We used a neuronal cellular model of tauopathy (M1C cells), which harbors wild type tau (4R0N), to assess the effects of the lysosomotrophic agent NH4Cl, and autophagy inhibitors chloroquine and 3 methyladenine (3MA). It was found that chloroquine, NH4Cl and 3MA markedly increased tau accumulation. Thus, autophagy lysosomal system disturbances disturbed the degradation mechanisms of tau protein. Other studies also revealed that tau protein, including aggregated tau, is degraded via the autophagy lysosome system. Phosphorylated and C terminal truncated tau were also reported to disturb autophagy function. As a therapeutic strategy, autophagy upregulation was suggested. Thus far, as autophagy modulators, rapamycin, mTOCR1 inhibitor and its analogues, lithium, metformin, clonidine, curcumin, nicotinamide, bexaroten, and torehalose have been proposed. As a therapeutic strategy, autophagic modulation may be the next target of AD therapeutics.
Journal Article
HBx facilitates ferroptosis in acute liver failure via EZH2 mediated SLC7A11 suppression
Background
Acute liver failure (ALF) is a syndrome of severe hepatocyte injury with high rate of mortality. Hepatitis B virus (HBV) infection is the major cause of ALF worldwide, however, the underlying mechanism by which HBV infection leads to ALF has not been fully disclosed.
Methods
D-GalN-induced hepatocyte injury model and LPS/D-GalN-induced ALF mice model were used to investigate the effects of HBV X protein (HBx) in vitro and in vivo, respectively. Cell viability and the levels of Glutathione (GSH), malondialdehyde (MDA) and iron were measured using commercial kits. The expression of ferroptosis-related molecules were detected by qRT-PCR and western blotting. Epigenetic modification and protein interaction were detected by chromatin immunoprecipitation (ChIP) assay and co-immunoprecipitation (co-IP), respectively. Mouse liver function was assessed by measuring aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The histological changes in liver tissues were monitored by hematoxylin and eosin (H&E) staining, and SLC7A11 immunoreactivity was assessed by immunohistochemistry (IHC) analysis.
Results
D-GalN triggered ferroptosis in primary hepatocytes. HBx potentiated D-GalN-induced hepatotoxicity and ferroptosis in vitro, and it suppressed SLC7A11 expression through H3K27me3 modification by EZH2. In addition, EZH2 inhibition or SLC7A11 overexpression attenuated the effects of HBx on D-GalN-induced ferroptosis in primary hepatocytes. The ferroptosis inhibitor ferrostatin-1 (Fer-1) protected against ALF and ferroptosis in vivo. By contrast, HBx exacerbates LPS/D-GalN-induced ALF and ferroptosis in HBx transgenic (HBx-Tg) mice.
Conclusion
HBx facilitates ferroptosis in ALF via EZH2/H3K27me3-mediated SLC7A11 suppression.
Journal Article
Drug survival of biologics in treating psoriasis: a meta-analysis of real-world evidence
Drug survival of biologics represents their real-world effectiveness and safety. We conducted a meta-analysis of real-world evidence on the drug survival of biologics in treating psoriasis. We searched the PubMed, CENTRAL, and EMBASE databases from inception to 7th October 2017 for studies reporting the annual drug survival for at least 1 year. Two authors independently screened and selected relevant studies, and assessed their risk of bias. A third author was available for arbitrating discrepancies. We conducted a random-effects model meta-analysis to obtain the respective pooled drug survival from year 1 to 4. We conducted subgroup analysis on biologic-naïve subjects, discontinuation for loss of efficacy and adverse effects. We included 37 studies with 32,631 subjects. The drug survival for all biologics decreased with time, dropping from 66% at year 1 to 41% at year 4 for etanercept, from 69% to 47% for adalimumab, from 61% to 42% for infliximab, and from 82% to 56% for ustekinumab. Ustekinumab was associated with the highest drug survival in all and biologic-naïve subjects. Etanercept was associated with the lowest drug survival and was most commonly discontinued for loss of efficacy. Infliximab was most frequently associated with discontinuation for adverse effects. Clinicians may use this study as a reference in treating psoriasis.
Journal Article
Gallic Acid Attenuated LPS-Induced Neuroinflammation: Protein Aggregation and Necroptosis
Gallic acid (3,4,5-trihydroxybenzoic acid, GA), a phenolic acid, is ubiquitous in almost all parts of the plant. In the present study, a neuroinflammatory rat model using intranigral infusion of lipopolysaccharides (LPS, 4 μg/μL) was employed to study the neuroprotective effect of GA which was orally administered daily. Compared with the vehicle-treated rats, systemic administration of GA (100 mg/kg) significantly attenuated LPS-induced increases in glial fibrillary acidic protein (a biomarker of activated astrocytes) and ED-1 (a biomarker of activated microglia), as well as inducible nitric oxide synthase (iNOS, a proinflammatory enzyme) and interleukin-1β (a proinflammatory cytokine), in the LPS-infused substantia nigra (SN) of rat brain. At the same time, GA attenuated LPS-induced elevation in heme oxygenase-1 level (a redox-regulated protein) and α-synuclein aggregation (a hallmark of CNS neurodegeneration), suggesting that GA is capable of inhibiting LPS-induced oxidative stress and protein conjugation. Furthermore, GA prevented LPS-induced caspase 3 activation (a biomarker of programmed cell death) and LPS-induced increases in receptor-interacting protein kinase (RIPK)-1 and RIPK-3 levels (biomarkers of necroptosis), indicating that GA inhibited LPS-induced apoptosis and necroptosis in the nigrostriatal dopaminergic system of rat brain. Moreover, an in vitro study was employed to investigate the anti-inflammatory effect of GA on BV2 microglial cells which were subjected to LPS (1 μg/mL) treatment. Consistently, co-incubation of GA diminished LPS-induced increases in iNOS mRNA and iNOS protein expression in the treated BV-2 cells as well as NO production in the culture medium. The anti-oxidative activity of GA was evaluated using iron-induced lipid peroxidation of brain homogenates. After 3-h incubation at 37 °C, GA was more potent than glutathione and less potent than trolox in inhibiting iron-induced lipid peroxidation. Conclusively, the present study suggests that GA is anti-inflammatory via attenuating LPS-induced neuroinflammation, oxidative stress, and protein conjugation. Furthermore, GA prevented LPS-induced programmed cell deaths of nigrostriatal dopaminergic neurons of the rat brain, suggesting that GA may be neuroprotective by attenuating neuroinflammation in CNS neurodegenerative diseases.
Journal Article
Lysophosphatidylethanolamine Affects Lipid Accumulation and Metabolism in a Human Liver-Derived Cell Line
The physiological functions of lysophosphatidylethanolamine (lysoPE) have not been fully elucidated. In this study, the effects of lysoPE on lipogenesis and lipolysis were investigated in a cultured human liver-derived cell line. The intracellular lipid profile was investigated in detail using liquid chromatography–tandem mass spectrometry (LC-MS/MS) to better understand the underlying mechanism. The expression of genes related to lipid metabolism and catabolism was analyzed using real-time PCR. LysoPE supplementation induced cellular lipid droplet formation and altered triacylglycerol (TAG) profiles. Furthermore, lysoPE downregulated expression of the TAG hydrolyzation regulation factor ATGL, and reduced the expression of fatty acid biosynthesis-related genes SREBP1 and SCD1. LC-MS/MS-based lipidomic profiling revealed that the addition of lysoPE 18:2 increased the PE species containing linoleic acyl, as well as the CE 18:2 species, likely due to the incorporation of linoleic acyl from lysoPE 18:2. Collectively, these findings suggest that lysoPE 18:2 is involved in lipid droplet formation by suppressing lipolysis and fatty acid biosynthesis. Thus, lysoPE might play a pathological role in the induction of fatty liver disease.
Journal Article