Therapeutic Options of Crystallin Mu and Protein Disulfide Isomerase A3 for Cuprizone-Induced Demyelination in Mouse Hippocampus.

This study investigates the changes in hippocampal proteomic profiles during demyelination and remyelination using the cuprizone model. Employing two-dimensional gel electrophoresis and liquid chromatography-tandem mass spectrometry for protein profiling, we observed significant alterations in the expression of ketimine reductase mu-crystallin (CRYM) and protein disulfide isomerase A3 precursor (PDIA3) following exposure to and subsequent withdrawal from cuprizone. Immunohistochemical staining validated these protein expression patterns in the hippocampus, revealing that both PDIA3 and CRYM were downregulated in the hippocampal CA1 region during demyelination and upregulated during remyelination. Additionally, we explored the potential protective effects of CRYM and PDIA3 against cuprizone-induced demyelination by synthesizing cell-permeable Tat peptide-fusion proteins (Tat-CRYM and Tat-PDIA3) to facilitate their crossing through the blood-brain barrier. Our results indicated that administering Tat-CRYM and Tat-PDIA3 mitigated the reduction in proliferating cell and differentiated neuroblast counts compared to the group receiving cuprizone alone. Notably, Tat-PDIA3 demonstrated significant effects in enhancing myelin basic protein expression alongside phosphorylation of CREB in the hippocampus, suggesting its potential therapeutic role in the prevention or treatment of demyelination, and by extension, in conditions such as multiple sclerosis.

Stereotactic body radiotherapy plus rucosopasem in locally advanced or borderline resectable pancreatic cancer: GRECO-2 phase II study design.

Ablative doses of stereotactic body radiotherapy (SBRT) may improve pancreatic cancer outcomes but may carry greater potential for gastrointestinal toxicity. Rucosopasem, an investigational selective dismutase mimetic that converts superoxide to hydrogen peroxide, can potentially increase tumor control of SBRT without compromising safety. GRECO-2 is a phase II, multicenter, randomized, double-blind, placebo-controlled trial of rucosopasem in combination with SBRT in locally advanced or borderline resectable pancreatic cancer. Patients will be randomized to rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT fraction (5 × 10 Gy). The primary end point is overall survival. Secondary end points include progression-free survival, locoregional control, time to metastasis, surgical resection rate, best overall response, in-field local response and acute and long-term toxicity.

The use of high doses of radiation delivered directly to tumors (stereotactic body radiation therapy [SBRT]) may improve survival compared with lower doses of radiation in patients with pancreatic cancer, but it may increase side effects. Rucosopasem, an investigational new drug being developed, can potentially improve the ability of SBRT to treat tumors without decreasing safety. In a previous study, median overall survival was improved when patients were treated with SBRT plus avasopasem, a drug that works the same way as rucosopasem. GRECO-2 is a clinical trial of rucosopasem used in combination with SBRT for treatment of localized pancreatic cancer. Patients will be randomly selected to receive either rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT treatment. The main result being studied is overall survival. Additional results include amount of time before tumors start to grow, how often patients get tumors surgically removed, best overall response and long-term safety. Clinical Trial Registration: NCT04698915 (ClinicalTrials.gov).

Evaluation of Multiplex Rapid Antigen Test for the Detection of SARS-CoV-2 and Influenza A/B in Respiratory Samples.

BACKGROUND: There is little data about the performance of multiplex rapid antigen tests (RATs) on the detection of SARS-CoV-2, influenza A (Flu A), and influenza B (Flu B). This study is to evaluate the performance of Panbio COVID-19/Flu A&B rapid panel (Abbott Diagnostics, Korea) and analyze the factors influencing its sensitivity. METHODS: Nasopharyngeal swabs were collected and stored at the Korea University Anam hospital. In total, 400 residual samples from nasopharyngeal swabs were examined. The diagnostic accuracy of RAT was compared to that of RT-qPCR using the Allplex SARS-CoV-2/FluA/FluB/RSV Assay (Seegene, Seoul, South Korea). RESULTS: Panbio COVID-19/Flu A&B rapid panel showed the sensitivities of 88.0%, 92.0%, and 100% for SARS-CoV-2, Flu A, and Flu B, respectively, and specificities of 100% for all. The agreements with previously licensed single-plex RATs were shown to be high. In the analysis of variables affecting sensitivity, inappropriate sampling time after symptom onset (STASO) and high cycle threshold (Ct value) were shown to negatively affect the sensi-tivity. CONCLUSIONS: In conclusion, the multiplex RAT is useful for diagnosing SARS-CoV-2 and Flu A/B, but more clinical studies are needed.

Porphyran Attenuates Neuronal Loss in the Hippocampal CA1 Subregion Induced by Ischemia and Reperfusion in Gerbils by Inhibiting NLRP3 Inflammasome-Mediated Neuroinflammation.

Porphyran, a sulfated polysaccharide found in various species of marine red algae, has been demonstrated to exhibit diverse bioactivities, including anti-inflammatory effects. However, the protective effects of porphyran against cerebral ischemia and reperfusion (IR) injury have not been investigated. The aim of this study was to examine the neuroprotective effects of porphyran against brain IR injury and its underlying mechanisms using a gerbil model of transient forebrain ischemia (IR in the forebrain), which results in pyramidal cell (principal neuron) loss in the cornu ammonis 1 (CA1) subregion of the hippocampus on day 4 after IR. Porphyran (25 and 50 mg/kg) was orally administered daily for one week prior to IR. Pretreatment with 50 mg/kg of porphyran, but not 25 mg/kg, significantly attenuated locomotor hyperactivity and protected pyramidal cells located in the CA1 area from IR injury. The pretreatment with 50 mg/kg of porphyran significantly suppressed the IR-induced activation and proliferation of microglia in the CA1 subregion. Additionally, the pretreatment significantly inhibited the overexpressions of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing protein-3 (NLRP3) inflammasome complex, and pro-inflammatory cytokines (interleukin 1 beta and interleukin 18) induced by IR in the CA1 subregion. Overall, our findings suggest that porphyran exerts neuroprotective effects against brain IR injury, potentially by reducing the reaction (activation) and proliferation of microglia and reducing NLRP3 inflammasome-mediated neuroinflammation.

Therapeutic Potential of 4-Hexylresorcinol in Preserving Testicular Function in Streptozotocin-Induced Diabetic Rats.

It is known that many diabetic patients experience testicular atrophy. This study sought to investigate the effect of 4-hexylresorcinol (4HR) on testicular function in rats with streptozotocin (STZ)-induced diabetes, focusing on testicular weight, sperm motility, histological alterations, and serum testosterone levels to understand the efficacy of 4HR on testes. Our findings reveal that 4HR treatment significantly improves testicular health in diabetic rats. Notably, the STZ group exhibited a testicular weight of 1.22 ± 0.48 g, whereas the STZ/4HR group showed a significantly enhanced weight of 1.91 ± 0.26 g (p < 0.001), aligning closely with the control group's weight of 1.99 ± 0.17 g and the 4HR group's weight of 2.05 ± 0.24 g, indicating no significant difference between control and 4HR groups (p > 0.05). Furthermore, the STZ/4HR group demonstrated significantly improved sperm motility compared to the STZ group, with apoptotic indicators notably reduced in the STZ/4HR group relative to the STZ group (p < 0.05). These results underscore the therapeutic potential of 4HR for maintaining testicular function under diabetic conditions.

Neuroprotective Effects of Aucubin against Cerebral Ischemia and Ischemia Injury through the Inhibition of the TLR4/NF-κB Inflammatory Signaling Pathway in Gerbils.

Aucubin, an iridoid glycoside, possesses beneficial bioactivities in many diseases, but little is known about its neuroprotective effects and mechanisms in brain ischemia and reperfusion (IR) injury. This study evaluated whether aucubin exhibited neuroprotective effects against IR injury in the hippocampal CA1 region through anti-inflammatory activity in gerbils. Aucubin (10 mg/kg) was administered intraperitoneally once a day for one week prior to IR. Neuroprotective effects of aucubin were assessed by neuronal nuclei (NeuN) immunofluorescence and Floro-Jade C (FJC) histofluorescence. Microgliosis and astrogliosis were evaluated using immunohistochemistry with anti-ionized calcium binding adapter protein 1 (Iba1) and glial fibrillary acidic protein (GFAP). Protein levels of proinflammatory cytokines interleukin1 beta (IL1ß) and tumor necrosis factor alpha (TNFα) were assayed using enzyme-linked immunosorbent assay and Western blot. Changes in toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway were assessed by measuring levels of TLR4, inhibitor of NF-κB alpha (IκBα), and NF-κB p65 using Western blot. Aucubin treatment protected pyramidal neurons from IR injury. IR-induced microgliosis and astrogliosis were suppressed by aucubin treatment. IR-induced increases in IL1ß and TNFα levels were significantly alleviated by the treatment. IR-induced upregulation of TLR4 and downregulation of IκBα were significantly prevented by aucubin treatment, and IR-induced nuclear translocation of NF-κB was reversed by aucubin treatment. Briefly, aucubin exhibited neuroprotective effects against brain IR injury, which might be related to the attenuation of neuroinflammation through inhibiting the TLR-4/NF-κB signaling pathway. These results suggest that aucubin pretreatment may be a potential approach for the protection of brain IR injury.

Postsynthetically Modified Alkoxide-Exchanged Ni2(OR)2BTDD: Synergistic Interactions of CO2 with Open Metal Sites and Functional Groups.

Postsynthetic modifications (PSMs) of metal-organic frameworks (MOFs) play a crucial role in enhancing material performance through open metal site (OMS) functionalization or ligand exchange. However, a significant challenge persists in preserving open metal sites during ligand exchange, as these sites are inherently bound by incoming ligands. In this study, for the first time, we introduced alkoxides by exchanging bridging chloride in Ni2Cl2BTDD (BTDD=bis (1H-1,2,3,-triazolo [4,5-b],-[4',5'-i]) dibenzo[1,4]dioxin) through PSM. Rietveld refinement of synchrotron X-ray diffraction data indicated that the alkoxide oxygen atom bridges Ni(II) centers while the OMSs of the MOF are preserved. Due to the synergy of the existing OMS and introduced functional group, the alkoxide-exchanged MOFs showed CO2 uptakes superior to the pristine MOF. Remarkably, the tert-butoxide-substituted Ni_T exhibited a nearly threefold and twofold increase in CO2 uptake compared to Ni2Cl2BTDD at 0.15 and 1 bar, respectively, as well as high water stability relative to the other exchanged frameworks. Furthermore, the Grand Canonical Monte Carlo simulations for Ni_T suggested that CO2 interacts with the OMS and the surrounding methyl groups of tert-butoxide groups, which is responsible for the enhanced CO2 capacity. This work provides a facile and unique synthetic strategy for realizing a desirable OMS-incorporating MOF platform through bridging ligand exchange.

High Hydrogen Storage in Trigonal Prismatic Monomer-Based Highly Porous Aromatic Frameworks.

Hydrogen storage is crucial in the shift toward a carbon-neutral society, where hydrogen serves as a pivotal renewable energy source. Utilizing porous materials can provide an efficient hydrogen storage solution, reducing tank pressures to manageable levels and circumventing the energy-intensive and costly current technological infrastructure. Herein, two highly porous aromatic frameworks (PAFs), C-PAF and Si-PAF, prepared through a Yamamoto C─C coupling reaction between trigonal prismatic monomers, are reported. These PAFs exhibit large pore volumes and Brunauer-Emmett-Teller areas, 3.93 cm3 g-1 and 4857 m2 g-1 for C-PAF, and 3.80 cm3 g-1 and 6099 m2 g-1 for Si-PAF, respectively. Si-PAF exhibits a record-high gravimetric hydrogen delivery capacity of 17.01 wt% and a superior volumetric capacity of 46.5 g L-1 under pressure-temperature swing adsorption conditions (77 K, 100 bar → 160 K, 5 bar), outperforming benchmark hydrogen storage materials. By virtue of the robust C─C covalent bond, both PAFs show impressive structural stabilities in harsh environments and unprecedented long-term durability. Computational modeling methods are employed to simulate and investigate the structural and adsorption properties of the PAFs. These results demonstrate that C-PAF and Si-PAF are promising materials for efficient hydrogen storage.

Biomarker Analysis from a Phase I/Ib Study of Regorafenib and Nivolumab in Mismatch Repair-Proficient Advanced Refractory Colorectal Cancer.

Previously, we reported the modest but durable anticancer activity of regorafenib/nivolumab in mismatch repair-proficient (pMMR) refractory colorectal cancer in our I/Ib study. Our finding suggests the necessity of biomarkers for better selection of patients. Baseline clinical and pathological characteristics, blood and tumor samples from the patients in the trial were collected and evaluated to discover potential biomarkers. The obtained samples were assessed for immunohistochemistry, ELISA and RNA sequencing. Their correlations with clinical outcome were analyzed. A high albumin level was significantly associated with improved progression-free survival (PFS), overall survival (OS) and disease control. Non-liver metastatic disease showed prolonged PFS and OS. Low regulatory T-cell (Treg) infiltration correlated with prolonged PFS. Low MIP-1ß was associated with durable response and improved OS significantly. Upregulation of 23 genes, including CAPN9, NAPSA and ROS1, was observed in the durable disease control group, and upregulation of 10 genes, including MRPS18A, MAIP1 and CMTR2, was associated with a statistically significant improvement of PFS. This study suggests that pretreatment albumin, MIP-1ß, non-liver metastatic disease and Treg infiltration may be potential predictive biomarkers of regorafenib/nivolumab in pMMR colorectal cancer. Further studies are needed to confirm these findings.

Protective effect of Tat fused HPCA protein on neuronal cell death caused by ischemic injury.

Background: Bain ischemia is a disease that occurs for various reasons, induces reactive oxygen species (ROS), and causes fatal damage to the nervous system. Protective effect of HPCA on ischemic injury has not been extensively studied despite its significance in regulating calcium homeostasis and promoting neuronal survival in CA1 region of the brain. Objective: We investigate the role of HPCA in ischemic injury using a cell-permeable Tat peptide fused HPCA protein (Tat-HPCA). Methods: Western blot analysis determined the penetration of Tat-HPCA into HT-22 cells and apoptotic signaling pathways. 5-CFDA, AM, DCF-DA, and TUNEL staining confirmed intracellular ROS production and DNA damage. The intracellular Ca2+ was measured in primary cultured neurons treated with H2O2. Protective effects were examined using immunohistochemistry and cognitive function tests by passive avoidance test and 8-arm radial maze test. Results: Tat-HPCA effectively penetrated into HT-22 cells and inhibited H2O2-induced apoptosis, oxidative stress, and DNA fragmentation. It also effectively inhibited phosphorylation of JNK and regulated the activation of Caspase, Bax, Bcl-2, and PARP, leading to inhibition of apoptosis. Moreover, Ca2+ concentration decreased in cells treated with Tat-HPCA in primary cultured neurons. In an animal model of ischemia, Tat-HPCA effectively penetrated the hippocampus, inhibited cell death, and regulated activities of astrocytes and microglia. Additionally, Cognitive function tests show that Tat-HPCA improves neurobehavioral outcomes after cerebral ischemic injury. Conclusion: These results suggest that Tat-HPCA might have potential as a therapeutic agent for treating oxidative stress-related diseases induced by ischemic injury, including ischemia.

Advancing the early detection of canine cognitive dysfunction syndrome with machine learning-enhanced blood-based biomarkers.

Up to half of the senior dogs suffer from canine cognitive dysfunction syndrome (CCDS), the diagnosis method relies on subjective questionnaires such as canine cognitive dysfunction rating (CCDR) scores. Therefore, the necessity of objective diagnosis is emerging. Here, we developed blood-based biomarkers for CCDS early detection. Blood samples from dogs with CCDR scores above 25 were analyzed, and the biomarkers retinol-binding protein 4 (RBP4), C-X-C-motif chemokine ligand 10 (CXCL10), and NADPH oxidase 4 (NOX4) were validated against neurodegenerative models. Lower biomarker levels were correlated with higher CCDR scores, indicating cognitive decline. Machine-learning analysis revealed the highest predictive accuracy when analyzing the combination of RBP4 and NOX4 using the support vector machine algorithm and confirmed potential diagnostic biomarkers. These results suggest that blood-based biomarkers can notably improve CCDS early detection and treatment, with implications for neurodegenerative disease management in both animals and humans.

Association between body mass index and three-year outcome of acute myocardial infarction.

Body mass index (BMI), as an important risk factor related to metabolic disease. However, in some studies higher BMI was emphasized as a beneficial factor in the clinical course of patients after acute myocardial infarction (AMI) in a concept known as the "BMI paradox." The purpose of this study was to investigate how clinical outcomes of patients treated for AMI differed according to BMI levels. A total of 10,566 patients in the Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH) from May 2010 to June 2015 were divided into three BMI groups (group 1: BMI < 22 kg/m2, group 2: ≥ 22 and < 26 kg/m2, and group 3: ≥ 26 kg/m2). The primary outcome was major adverse cardiac and cerebrovascular event (MACCE) at 3 years of follow-up. At 1 year of follow-up, the incidence of MACCE in group 1 was 10.1% of that in group 3, with a hazard ratio (HR) of 2.27, and 6.5% in group 2, with an HR of 1.415. This tendency continued up to 3 years of follow-up. The study demonstrated that lower incidence of MACCE in the high BMI group of Asians during the 3-year follow-up period compared to the low BMI group. The results implied higher BMI could exert a positive effect on the long-term clinical outcomes of patients with AMI undergoing percutaneous coronary intervention (PCI).

Support Through Remote Observation and Nutrition Guidance (STRONG), a digital health intervention to reduce malnutrition among pancreatic cancer patients: A study protocol for a pilot randomized controlled trial.

Background: Malnutrition is a common and distressing condition among pancreatic cancer patients. Fewer than a quarter of pancreatic cancer patients receive medical nutrition therapy (MNT), important for improving nutritional status, weight maintenance, quality of life and survival. System, provider, and patient level barriers limit access to MNT. We propose to examine the feasibility of a 12-week multi-level, digital health intervention designed to expand MNT access among pancreatic cancer patients. Methods: Individuals with advanced pancreatic cancer starting chemotherapy (N = 80) will be 1:1 randomized to the intervention or usual care. The Support Through Remote Observation and Nutrition Guidance (STRONG) intervention includes system-level (e.g., routine malnutrition and screening), provider-level (e.g., dietitian training and web-based dashboard), and patient-level strategies (e.g., individualized nutrition plan, self-monitoring of dietary intake via Fitbit, ongoing goal monitoring and feedback). Individuals receiving usual care will be referred to dietitians based on their oncologists' discretion. Study assessments will be completed at baseline, 4-, 8-, 12-, and 16-weeks. Results: Primary outcomes will be feasibility (e.g., recruitment, retention, assessment completion) and acceptability. We will collect additional implementation outcomes, such as intervention adherence, perceived usability, and feedback on intervention quality via an exit interview. We will collect preliminary data on outcomes that may be associated with the intervention including malnutrition, quality of life, treatment outcomes, and survival. Conclusion: This study will advance our knowledge on the feasibility of a digital health intervention to reduce malnutrition among individuals with advanced pancreatic cancer. Trial registration: NCT05675059, registered on December 9, 2022.