Corn Peptides Alleviate Nonalcoholic Fatty Liver Fibrosis in Mice by Inhibiting NLRP3 Inflammasome Activation and Regulating Gut Microbiota.

This study aimed to investigate the effects of corn gluten-derived soluble epoxide hydrolase (sEH) inhibitory peptides on nonalcoholic fatty liver fibrosis induced by a high-fat diet and carbon tetrachloride in mice. Mice treated with corn peptides at doses of 500 or 1000 mg/kg/d for 4 weeks exhibited reduced sEH activity in serum and liver, enhanced lipid metabolism, and decreased lipid accumulation and oxidative stress. Corn peptides effectively downregulated the mRNA levels of Pro-IL-1ß, Pro-IL-18, NOD-like receptor protein 3 (NLRP3), ASC, Pro-caspase-1, Caspase-1, and GSDMD in the liver. This hepatoprotective effect of corn peptides by inhibiting NLRP3 inflammasome activation was further validated in H2O2-induced HepG2 cells. Moreover, corn peptides restored the composition of the gut microbiota and promoted short-chain fatty acid production. This study provides evidence that corn-derived sEH inhibitory peptides have hepatoprotective activity against nonalcoholic fatty liver fibrosis by suppressing NLRP3 inflammasome activation and modulating gut microbiota.

Rational optimization of glycoprotein E (gE)-encoding mRNA for improved Varicella-zoster Virus mRNA vaccine development.

The past decades have seen increasingly rapid advances in the field of mRNA technology and its successful applications in prophylactic vaccine development [1,2]. Recently, we reported on the development of a novel Varicella-zoster virus (VZV) mRNA vaccine (named as ZOSAL) that contains mRNAs encoding for full-length gE immunogen (623 aa) encapsulated into a novel lipid nanoparticle (LNP) system [3]. In mice and rhesus macaques, ZOSAL induced superior virus-specific immunity over licensed subunit vaccine Shingrix, which potentiated the power of mRNA platform in next-generation VZV vaccine development [3].

D-Limonene Inhibits Pichia kluyveri Y-11519 in Sichuan Pickles by Disrupting Metabolism.

The Pichia kluyveri, a proliferation commonly found in Sichuan pickles (SCPs), can accelerate the growth and reproduction of spoilage bacteria, causing off-odor development and decay. Although D-limonene, a common natural preservative, effectively restricts P. kluyveri, its inhibitory mechanism remains unclear. This study aimed to elucidate this molecular mechanism by investigating the impact on basic P. kluyveri metabolism. The findings revealed that D-limonene inhibited P. kluyveri growth and disrupted the transcription of the genes responsible for encoding the enzymes involved in cell wall and membrane synthesis, oxidative phosphorylation, glycolysis, and the tricarboxylic acid (TCA) cycle pathway. The results indicated that these events disrupted crucial metabolism such as cell wall and membrane integrity, adenosine triphosphate (ATP) synthesis, and reactive oxygen species (ROS) balance. These insights provided a comprehensive understanding of the inhibitory effect of D-limonene on the growth and reproduction of P. kluyveri while highlighting its potential application in the SCP industry.

Research on FBG Tactile Sensing Shape Recognition Based on Convolutional Neural Network.

Shape recognition plays a significant role in the field of robot perception. In view of the low efficiency and few types of shape recognition of the fiber tactile sensor applied to flexible skin, a convolutional-neural-network-based FBG tactile sensing array shape recognition method was proposed. Firstly, a sensing array was fabricated using flexible resin and 3D printing technology. Secondly, a shape recognition system based on the tactile sensing array was constructed to collect shape data. Finally, shape classification recognition was performed using convolutional neural network, random forest, support vector machine, and k-nearest neighbor. The results indicate that the tactile sensing array exhibits good sensitivity and perception capability. The shape recognition accuracy of convolutional neural network is 96.58%, which is 6.11%, 9.44%, and 12.01% higher than that of random forest, k-nearest neighbor, and support vector machine. Its F1 is 96.95%, which is 6.3%, 8.73%, and 11.94% higher than random forest, k-nearest neighbor, and support vector machine. The research of FBG shape sensing array based on convolutional neural network provides an experimental basis for shape perception of flexible tactile sensing.

Characteristics of Umami Taste of Soy Sauce Using Electronic Tongue, Amino Acid Analyzer, and MALDI-TOF MS.

The objective of this study was to investigate the umami characteristics of soy sauce using electronic tongue evaluation and amino acid composition and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis. The soy sauce peptides were isolated from soy sauce using XAD-16 macroporous resin combined with ethanol solution. The results showed that the soy sauce peptide fraction eluted by 60% ethanol (SS-60%) exhibited a prominent umami taste, and the umami scores were highly positively correlated with the amino acid nitrogen contents of soy sauces. The umami scores of SS-60% were significantly positively correlated with the contents of free amino acids. Especially, Phe showed the highest positive correlation with the umami scores. In addition, five characteristic ion peaks with m/z at 499, 561, 643, 649, and 855 were identified in the peptide mass fingerprinting. Therefore, this study provides new insights into the umami characteristics for the taste evaluation and reality identification of soy sauce.

Inhibitory effect and mechanism of oregano essential oil on Listeria monocytogenes cells, toxins and biofilms.

Listeria monocytogenes (L. monocytogenes) is a prevalent foodborne pathogen with a remarkable capacity to form biofilms on utensil surfaces. The Listeriolysin O (LLO) exhibits hemolytic activity, which is responsible for causing human infections. In this study, we investigated the inhibitory effect and mechanism of oregano essential oil (OEO) on L. monocytogenes, evaluated the effects on its biofilm removal and hemolytic activity. The minimum inhibitory concentration (MIC) of OEO against L. monocytogenes was 0.03 % (v/v). L. monocytogenes was treated with OEO at 3/2 MIC for 30 min the bacteria was decreased below the detection limit (10 CFU/mL) in PBS and TSB (the initial bacterial load was about 6.5 log CFU/mL). The level of L. monocytogenes in minced pork co-cultured with OEO (15 MIC) about 2.5 log CFU/g lower than that in the untreated group. The inhibitory mechanisms of OEO against planktonic L. monocytogenes encompassed perturbation of cellular morphology, elevation in reactive oxygen species levels, augmentation of lipid oxidation extent, hyperpolarization of membrane potential, and reduction in intracellular ATP concentration. In addition, OEO reduced biofilm coverage on the surface of glass slides by 62.03 % compared with the untreated group. Meanwhile, OEO (1/8 MIC) treatment reduced the hemolytic activity of L. monocytogenes to 24.6 % compared with the positive control. Molecular docking suggested carvacrol and thymol might reduce the hemolytic activity of L. monocytogenes. The results of this study demonstrate that OEO exhibits inhibitory effects against L. monocytogenes, biofilms and LLO, which had potential as natural antimicrobial for the inhibition of L. monocytogenes.

A group 3 medulloblastoma stem cell program is maintained by OTX2-mediated alternative splicing.

OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein-protein interactions and regulates a stem cell splicing program. OTX2 can directly or indirectly bind RNA and this may be partially independent of its DNA regulatory functions. OTX2 controls a pro-tumorigenic splicing program that is mirrored in human cerebellar rhombic lip origins. Among the OTX2-regulated differentially spliced genes, PPHLN1 is expressed in the most primitive rhombic lip stem cells, and targeting PPHLN1 splicing reduces tumour growth and enhances survival in vivo. These findings identify OTX2-mediated alternative splicing as a major determinant of cell fate decisions that drive group 3 MB progression.

One-step fabrication of dipeptide-based bifunctional polymer for individual enrichment of glycopeptides and phosphopeptides from serum.

A dipeptide-based bifunctional material immobilized with Ti4+ (denoted as APE-MBA-VPA-Ti4+) was developed using precipitation polymerization. This polymer combines hydrophilic interaction liquid chromatography (HILIC) and immobilized metal affinity chromatography (IMAC) enrichment strategies, allowing for the individual and simultaneous enrichment of glycopeptides and phosphopeptides. It demonstrated high sensitivity (0.1 fmol µL-1 for glycopeptides, 0.005 fmol µL-1 for phosphopeptides), strong selectivity (molar ratio HRP: BSA = 1:1000, ß-casein: BSA = 1:2500), consistent reusability (10 cycles) and satisfactory recovery rate (93.5 ± 1.8 % for glycopeptides, 91.6 ± 0.6 % for phosphopeptides) in the individual enrichment. Utilizing nano LC-MS/MS technology, the serum of liver cancer patients was analyzed after enrichment individually, resulting in the successful capture of 333 glycopeptides covering 262 glycosylation sites, corresponding to 131 glycoproteins, as well as 67 phosphopeptides covering 57 phosphorylation sites, related to 48 phosphoproteins. In comparison, the serum of normal healthy individuals yielded a total of 283 glycopeptides covering 244 glycosylation sites corresponding to 126 glycoproteins, as well as 66 phosphopeptides covering 56 phosphorylation sites related to 37 phosphoproteins. Label-free quantification identified 10 differentially expressed glycoproteins and 8 differentially expressed phosphoproteins in the serum of liver cancer patients. Among them, glycoproteins (HP, BCHE, AGT, C3, and PROC) and phosphoproteins (ZYX, GOLM1, GP1BB, CLU, and TNXB) showed upregulation and displayed potential as biomarkers for liver cancer.

Ameliorative effects of the mixed aqueous extract of Aurantii Fructus Immaturus and Magnoliae Officinalis Cortex on loperamide-induced STC mice.

Aurantii fructus immaturus (AFI) and Magnoliae Officinalis Cortex (MOC) have been used to treat constipation in China for thousands of years. In this study, a mouse model of slow transit constipation (STC) was established by gavage of loperamide at a dose of 10 mg/kg bw/day for seven days. Seventy-two mice were randomly allocated to six groups (control, STC model, 3 g/kg AFI + MOC, 6 g/kg AFI + MOC, 12 g/kg AFI + MOC, and mosapride). A mixed aqueous extract of AFI and MOC was administered to the STC mice at the corresponding doses from the first day of modelling. Body weight, faecal water content, gastrointestinal transit time, and intestinal propulsion rate were evaluated. Serum levels of neurotransmitters and gastrointestinal hormones, colonic expression of aquaporins (AQP), and interstitial cells of Cajal (ICC) were assessed using ELISA, immunohistochemistry, and Western blot analysis. The abundance and diversity of the gut microbiota were analysed by 16S rRNA gene sequencing. The mixed aqueous extract significantly increased faecal water content and intestinal propulsion rate and shortened gastrointestinal transit time in STC mice. Furthermore, the administration of AFI and MOC significantly decreased serum vasoactive intestinal peptide (VIP), nitric oxide (NO), and somatostatin (SS) levels and increased serum motilin (MTL) levels in STC mice. The protein expression levels of AQP3 and AQP4 in the colon tissue of STC mice significantly decreased following AFI + MOC treatment, whereas those of AQP9 significantly increased. Moreover, the AFI + MOC treatment led to an increase in the number and functionality of ICCs. In addition, the relative abundances of Ruminococcus and Oscillospira increased in response to the administration of AFI + MOC in STC mice. In conclusion, the mixed aqueous extract of AFI and MOC promoted defaecation and increased intestinal mobility in STC mice. Its mechanisms of action involve modulatory effects on neurotransmitters, gastrointestinal hormones, AQPs, and ICCs. AFI + MOC treatment also improved the diversity and abundance of the gut microbiota in STC mice, particularly short-chain fatty acid-producing bacteria, which may play an important role in its beneficial effect on constipation.

Septin 9 expression regulates 'don't eat me' signals and identifies an immune-epithelial class of intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and aggressive liver cancer with limited therapeutic options. Precise classification and immunotherapy are perspectives to improve the treatments. We reported the role of septin 9 in apico-basal polarity and epithelial-to-mesenchymal transition (EMT). Here, we aim to elucidate its role in iCCA. We analyzed single-cell transcriptomes from human iCCA tumor cells based on phenotype and cell state. Knockdown of the septin 9 gene (SEPT9) was done using small interfering RNA (siRNA); interferon-γ (IFN-γ) stimulation was performed using different CCA cells; gene expressions were analyzed by reverse transcription and real-time PCR analysis (RT-qPCR); and immunofluorescence, immunoblotting, and flow cytometry were performed to assess the expression of proteins. The differential distributions of SEPT9 and vimentin (VIM) gene expressions allowed us to define specific cellular trajectories of malignant cells and thus identified distinct clusters of iCCA cells. One cluster was enriched in VIM and extracellular-matrix (ECM) remodeling molecules, and another had high expression of SEPT9 and genes from the 'don't eat me' signal involved in immune escape. This antagonism between SEPT9 and VIM was confirmed by in vitro experiments. Notably, SEPT9 and 'don't eat me' gene expressions were inversely correlated to those of vimentin and the EMT markers. SEPT9 expression was upregulated by IFN-γ and SEPT9 knockdown decreased expression of 'don't eat me' signal genes and increased expression of mesenchymal markers. Cancer Cell Line Encyclopedia (CCLE) transcriptome database analyses confirmed that iCCA cells enriched in septin 9 exhibit epithelial-like features. This study revealed septin 9 as a cytoskeleton element of iCCA epithelial-like cells and a regulator of the immune system response. It also brings new insights into the enigmatic relationship between EMT and immune response. Notably, we decoded a potential mechanism that could sensitize patients to immunotherapies.

Surface-Engineered Polygonatum Sibiricum Polysaccharide CaCO3 Microparticles as Novel Vaccine Adjuvants to Enhance Immune Response.

Micro- and nanoparticles delivery systems have been widely studied as vaccine adjuvants to enhance immunogenicity and sustain long-term immune responses. Polygonatum sibiricum polysaccharide (PSP) has been widely studied as an immunoregulator in improving immune responses. In this study, we synthesized and characterized cationic modified calcium carbonate (CaCO3) microparticles loaded with PSP (PEI-PSP-CaCO3, CTAB-PSP-CaCO3), studied the immune responses elicited by PEI-PSP-CaCO3 and CTAB-PSP-CaCO3 carrying ovalbumin (OVA). Our results demonstrated that PEI-PSP-CaCO3 significantly enhanced the secretion of IgG and cytokines (IL-4, IL-6, IFN-γ, and TNF-α) in vaccinated mice. Additionally, PEI-PSP-CaCO3 induced the activation of dendritic cells (DCs), T cells, and germinal center (GC) B cells in draining lymph nodes (dLNs). It also enhanced lymphocyte proliferation, increased the ratio of CD4+/CD8+ T cells, and elevated the frequency of CD3+ CD69+ T cells in spleen lymphocytes. Therefore, PEI-PSP-CaCO3 microparticles induced a stronger cellular and humoral immune response and could be potentially useful as a vaccine delivery and adjuvant system.

Olink Proteomics-Based Exploration of Immuno-Oncology-Related Biomarkers Leading to Lung Adenocarcinoma Progression.

INTRODUCTION: It is crucial to investigate the distinct proteins that contribute to the advancement of lung cancer. MATERIAL AND METHODS: We analyzed the expression levels of 92 immuno-oncology-related proteins in 96 pairs of lung adenocarcinoma tissue samples using Olink proteomics. The differentially expressed proteins (DEPs) were successively screened in tumor and paraneoplastic groups, early and intermediate-late groups by a nonparametric rank sum test, and the distribution and expression levels of DEPs were determined by volcano and heat maps, etc., and the area under the curve was calculated. RESULTS: A total of 24 DEPs were identified in comparisons between tumor and paracancerous tissues. Among them, interleukin-8 (IL8) and chemokine (C-C motif) ligand 20 (CCL20) as potential markers for distinguishing tumor tissues. Through further screening, it was found that interleukin-6 (IL6) and vascular endothelial growth factor A (VEGFA) may be able to lead to tumor progression through the JaK-STAT signaling pathway, Toll-like receptor signaling pathway and PI3K/AKT signaling pathway. Interestingly, our study revealed a down-regulation of IL6 and VEGFA in tumor tissues compared to paracancerous tissues. CONCLUSIONS: IL8 + CCL20 (AUC: 0.7056) have the potential to differentiate tumor tissue from paracancerous tissue; IL6 + VEGFA (AUC: 0.7531) are important protein markers potentially responsible for tumor progression.

A General Strategy toward Self-assembled Nanovaccine Based on Cationic Lentinan to Induce Potent Humoral and Cellular Immune Responses.

Adjuvants play a critical role in the induction of effective immune responses by vaccines. Here, a self-assembling nanovaccine platform that integrates adjuvant functions into the delivery vehicle is prepared. Cationic Lentinan (CLNT) is mixed with ovalbumin (OVA) to obtain a self-assembling nanovaccine (CLNTO nanovaccine), which induces the uptake and maturation of bone marrow dendritic cells (BMDCs) via the toll-like receptors 2/4 (TLR2/4) to produce effective antigen cross-presentation. CLNTO nanovaccines target lymph nodes (LNs) and induce a robust OVA-specific immune response via TLR and tumor necrosis factor (TNF) signaling pathways, retinoic acid-inducible gene I (RIG-I) receptor, and cytokine-cytokine receptor interactions. In addition, CLNTO nanovaccines are found that promote the activation of follicular helper T (Tfh) cells and induce the differentiation of germinal center (GC) B cells into memory B cells and plasma cells, thereby enhancing the immune response. Vaccination with CLNTO nanovaccine significantly inhibits the growth of ovalbumin (OVA)-expressing B16 melanoma cell (B16-OVA) tumors, indicating its great potential for cancer immunotherapy. Therefore, this study presents a simple, safe, and effective self-assembling nanovaccine that induces helper T cell 1 (Th1) and helper T cell (Th2) immune responses, making it an effective vaccine delivery system.

Transcutaneous auricular vagus nerve stimulation improves anxiety symptoms and cortical activity during verbal fluency task in Parkinson's disease with anxiety.

OBJECTIVE: To investigate the effect of 20/4Hz transcutaneous auricular vagus nerve stimulation (taVNS) on anxiety symptoms in Parkinson's disease (PD) and the potential neural mechanism. METHODS: In the current randomized, double-blind, sham-controlled trial, 30 PD patients with anxiety (PD-A), 30 PD patients without anxiety (PD-nA), and 30 healthy controls (HCs) were enrolled. PD-A patients were randomly (1:1) allotted to real taVNS stimulation group (RS) or sham stimulation group (SS) to explore the efficacy of a two-week treatment of taVNS to promote anxiety recovery. Simultaneously, all participants were measured activation in the bilateral prefrontal cortex during verbal fluency task (VFT) using functional near-infrared spectroscopy. RESULTS: PD-A patients showed significantly decreased oxyhemoglobin in the left triangle part of the inferior frontal gyrus (IFG) during VFT, which was negatively related to the severity of anxiety symptoms. After two-week treatment of taVNS, the interaction of group and time had significant effect on HAMA scores (F = 18.476, p < 0.001, η2 = 0.398). In RS group, compared with baseline, HAMA scores decreased significantly in the post-treatment and follow-up condition (both p < 0.001). Meanwhile, in RS group, HAMA scores were lower than those in SS group in the post-treatment and follow-up condition (p = 0.006, <0.001, respectively). Furthermore, the 20/4Hz taVNS remarkably ameliorated anxiety symptoms in PD patients, directly correlated with the increased activation of the left triangle part of the IFG during VFT in RS group. CONCLUSION: Our results depicted that taVNS could ameliorate the anxiety symptoms of PD-A patients and regulated the function of the left triangle part of the IFG.

Controlling the speed of antigens transport in dendritic cells improves humoral and cellular immunity for vaccine.

Vaccines are an effective intervention for preventing infectious diseases. Currently many vaccine strategies are designed to improve vaccine efficacy by controlling antigen release, typically involving various approaches at the injection site. Yet, strategies for intracellular slow-release of antigens in vaccines are still unexplored. Our study showed that controlling the degradation of antigens in dendritic cells and slowing their transport from early endosomes to lysosomes markedly enhances both antigen-specific T-cell immune responses and germinal center B cell responses. This leads to the establishment of sustained humoral and cellular immunity in vivo imaging and flow cytometry indicated this method not only prolongs antigen retention at the injection site but also enhances antigen concentration in lymph nodes, surpassing traditional Aluminium (Alum) adjuvants. Additionally, we demonstrated that the slow antigen degradation induces stronger follicular helper T cell responses and increases proportions of long-lived plasma cells and memory B cells. Overall, these findings propose that controlling the speed of antigens transport in dendritic cells can significantly boost vaccine efficacy, offering an innovative avenue for developing highly immunogenic next-generation vaccines.

PemK's Arg24 is a crucial residue for PemIK toxin-antitoxin system to induce the persistence of Weissella cibaria against ciprofloxacin stress.

The toxin-antitoxin (TA) system plays a key role in bacteria escaping antibiotic stress with persistence, however, the mechanisms by which persistence is controlled remain poorly understood. Weissella cibaria, a novel probiotic, can enters a persistent state upon encountering ciprofloxacin stress. Conversely, it resumes from the persistence when ciprofloxacin stress is relieved or removed. Here, it was found that PemIK TA system played a role in transitioning between these two states. And the PemIK was consisted of PemK, an endonuclease toxic to mRNA, and antitoxin PemI which neutralized its toxicity. The PemK specifically cleaved the U↓AUU in mRNA encoding enzymes involved in glycolysis, TCA cycle and respiratory chain pathways. This cleavage event subsequently disrupted the crucial cellular processes such as hydrogen transfer, electron transfer, NADH and FADH2 synthesis, ultimately leading to a decrease in ATP levels and an increase in membrane depolarization and persister frequency. Notably, Arg24 was a critical active residue for PemK, its mutation significantly reduced the mRNA cleavage activity and the adverse effects on metabolism. These insights provided a clue to comprehensively understand the mechanism by which PemIK induced the persistence of W. cibaria to escape ciprofloxacin stress, thereby highlighting another novel aspect PemIK respond for antibiotic stress.

Effects of Polymers on Cocrystal Growth in a Drug-Drug Coamorphous System: Relations between Glass-to-Crystal Growth and Surface-Enhanced Crystal Growth.

Coamorphous and cocrystal drug delivery systems provide attractive crystal engineering strategies for improving the solubilities, dissolution rates, and oral bioavailabilities of poorly water-soluble drugs. Polymeric additives have often been used to inhibit the unwanted crystallization of amorphous drugs. However, the transformation of a coamorphous phase to a cocrystal phase in the presence of polymers has not been fully elucidated. Herein, we investigated the effects of low concentrations of the polymeric excipients poly(ethylene oxide) (PEO) and poly(vinylpyrrolidone) (PVP) on the growth of carbamazepine-celecoxib (CBZ-CEL) cocrystals from the corresponding coamorphous phase. PEO accelerated the growth rate of the cocrystals by increasing the molecular mobility of the coamorphous system, while PVP had the opposite effect. The coamorphous CBZ-CEL system exhibited two anomalously fast crystal growth modes: glass-to-crystal (GC) growth in the bulk and accelerated crystal growth at the free surface. These two fast growth modes both disappeared after doping with PEO (1-3% w/w) but were retained in the presence of PVP, indicating a potential correlation between the two fast crystal growth modes. We propose that the different effects of PEO and PVP on the crystal growth modes arose from weaker effects of the polymers on cocrystallization at the surface than in the bulk. This work provides a deep understanding of the mechanisms by which polymers influence the cocrystallization kinetics of a multicomponent amorphous phase and highlights the importance of polymer selection in stabilizing coamorphous systems or preparing cocrystals via solid-based methods.

The mitochondrial stress-induced protein carboxyl-terminal alanine and threonine tailing (msiCAT-tailing) promotes glioblastoma tumorigenesis by modulating mitochondrial functions.

The rapid and sustained proliferation in cancer cells requires accelerated protein synthesis. Accelerated protein synthesis and disordered cell metabolism in cancer cells greatly increase the risk of translation errors. ribosome-associated quality control (RQC) is a recently discovered mechanism for resolving ribosome collisions caused by frequent translation stalls. The role of the RQC pathway in cancer initiation and progression remains controversial and confusing. In this study, we investigated the pathogenic role of mitochondrial stress-induced protein carboxyl-terminal terminal alanine and threonine tailing (msiCAT-tailing) in glioblastoma (GBM), which is a specific RQC response to translational arrest on the outer mitochondrial membrane. We found that msiCAT-tailed mitochondrial proteins frequently exist in glioblastoma stem cells (GSCs). Ectopically expressed msiCAT-tailed mitochondrial ATP synthase F1 subunit alpha (ATP5α) protein increases the mitochondrial membrane potential and blocks mitochondrial permeability transition pore (MPTP) formation/opening. These changes in mitochondrial properties confer resistance to staurosporine (STS)-induced apoptosis in GBM cells. Therefore, msiCAT-tailing can promote cell survival and migration, while genetic and pharmacological inhibition of msiCAT-tailing can prevent the overgrowth of GBM cells. Highlights: The RQC pathway is disturbed in glioblastoma (GBM) cellsmsiCAT-tailing on ATP5α elevates mitochondrial membrane potential and inhibits MPTP openingmsiCAT-tailing on ATP5α inhibits drug-induced apoptosis in GBM cellsInhibition of msiCAT-tailing impedes overall growth of GBM cells.

Accelerated stability modeling of recrystallization from amorphous solid Dispersions: A Griseofulvin/HPMC-AS case study.

Amorphous solid dispersions (ASDs) represent an important approach for enhancing oral bioavailability for poorly water soluble compounds; however, assuring that these ASDs do not recrystallize to a significant extent during storage can be time-consuming. Therefore, various efforts have been undertaken to predict ASD crystallization levels with kinetic models. However, only limited success has been achieved due to limits on crystal content quantification methods and the complexity of crystallization kinetics. To increase the prediction accuracy, the accelerated stability assessment program (ASAP), employing isoconversion (time to hit a specification limit) and a modified Arrhenius approach, are employed here for predictive shelf-life modeling. In the current study, a model ASD was prepared by spray drying griseofulvin and HPMC-AS-LF. This ASD was stressed under a designed combinations of temperature, relative humidity and time with the conditions set to ensure stressing was carried out below the glass transition temperature (Tg) of the ASD. Crystal content quantification method by X-ray powder diffraction (XRPD) with sufficient sensitivity was developed and employed for stressed ASD. Crystallization modeling of the griseofulvin ASD using ASAPprime® demonstrated good agreement with long-term (40 °C/75 %RH) crystallinity levels and support the use of this type of accelerated stability studies for further improving ASD shelf-life prediction accuracy.

Analysis of 15 bile acids in human plasma based on C18 functionalized magnetic organic polymer nanocomposite coupled with liquid chromatography-tandem mass spectrometry.

Because of the "enterohepatic circulation" of bile acid, liver damage can be reflected by monitoring the content of bile acid in the serum of the organism. To monitor the concentration of 15 bile acids in plasma samples, a new technique of PRiME (process, ruggedness, improvement, matrix effect, ease of use) pass-through cleanup procedure combined with high performance liquid chromatography-tandem quadrupole mass spectrometry (HPLC-MS/MS) was developed. The sorbent used in the PRiME pass-through cleanup procedure is a new type of magnetic organic resin composite nano-material modified by C18 (C18-PS-DVB-GMA-Fe3O4), which has high cleanup efficiency of plasma samples. It also shows good performance in the separation and analysis of 15 kinds of bile acids. Under the optimal conditions, the results show higher cleanup efficiency of C18-PS-DVB-GMA-Fe3O4 with recoveries in the range of 82.1-115 %. The limit of quantitative (LOQs) of 15 bile acids were in the range of 0.033 µg/L-0.19 µg/L, and the RSD values of 15 bile acids were in the range of 3.00-11.9 %. Validation results on linearity, specificity, accuracy and precision, as well as on the application to analysis of 15 bile acids in 100 human plasma samples demonstrate the applicability to clinical studies.