Mesenchymal stem cell (MSC) is a promising tool for the therapy of immune disorders. However, their efficacy and mechanisms in treating allergic skin disorders are less verified. We sought to ...investigate the therapeutic efficacy of human umbilical cord blood-derived MSCs (hUCB-MSCs) against murine atopic dermatitis (AD) and to explore distinct mechanisms that regulate their efficacy. AD was induced in mice by the topical application of Dermatophagoides farinae. Naïve or activated-hUCB-MSCs were administered to mice, and clinical severity was determined. The subcutaneous administration of nucleotide-binding oligomerization domain 2 (NOD2)-activated hUCB-MSCs exhibited prominent protective effects against AD, and suppressed the infiltration and degranulation of mast cells (MCs). A β-hexosaminidase assay was performed to evaluate the effect of hUCB-MSCs on MC degranulation. NOD2-activated MSCs reduced the MC degranulation via NOD2-cyclooxygenase-2 signaling. In contrast to bone marrow-derived MSCs, hUCB-MSCs exerted a cell-to-cell contact-independent suppressive effect on MC degranulation through the higher production of prostaglandin E2 (PGE2 ). Additionally, transforming growth factor (TGF)-β1 production from hUCB-MSCs in response to interleukin-4 contributed to the attenuation of MC degranulation by downregulating FcεRI expression in MCs. In conclusion, the subcutaneous application of NOD2-activated hUCB-MSCs can efficiently ameliorate AD, and MSC-derived PGE2 and TGF-β1 are required for the inhibition of MC degranulation.
This study was a phase 1, single-center, randomized, double-blind, placebo-controlled, single-dosing, and dose-escalating study of intravenous SAL200. It is a new candidate drug for the treatment of ...antibiotic-resistant staphylococcal infections based on a recombinant form of the phage endolysin SAL-1. The study evaluated the pharmacokinetics, pharmacodynamics, and tolerance among healthy male volunteers after the intravenous infusion of single ascending doses of SAL200 (0.1, 0.3, 1, 3, and 10 mg/kg of body weight). SAL200 was well tolerated, and no serious adverse events (AEs) were observed in this clinical study. Most AEs were mild, self-limiting, and transient. The AEs reported in more than three participants were fatigue, rigors, headache, and myalgia. No clinically significant values with respect to the findings of clinical chemistry, hematology, and coagulation analyses, urinalysis, vital signs, and physical examinations were observed, and no notable trends in our electrocardiogram (ECG) results for any tested dose were noticed. A greater-than-dose-proportional increase with regard to systemic exposure and the maximum serum concentration was observed when the SAL200 dose was increased from 0.1 mg/kg to 10 mg/kg. This investigation constitutes the first-in-human phase 1 study of an intravenously administered, phage endolysin-based drug. (This study has been registered at ClinicalTrials.gov under identifier NCT01855048 and at the Clinical Research Information Service https://cris.nih.go.kr/cris/ under identifier KCT0000968.).
Memory stabilization after learning requires translational and transcriptional regulations in the brain, yet the temporal molecular changes that occur after learning have not been explored at the ...genomic scale. We used ribosome profiling and RNA sequencing to quantify the translational status and transcript levels in the mouse hippocampus after contextual fear conditioning. We revealed three types of repressive regulations: translational suppression of ribosomal protein-coding genes in the hippocampus, learning-induced early translational repression of specific genes, and late persistent suppression of a subset of genes via inhibition of estrogen receptor 1 (ESR1/ERα) signaling. In behavioral analyses, overexpressing Nrsn1, one of the newly identified genes undergoing rapid translational repression, or activating ESR1 in the hippocampus impaired memory formation. Collectively, this study unveils the yet-unappreciated importance of gene repression mechanisms for memory formation.
Summary
Background
DWP14012 (fexuprazan), a novel potassium‐competitive acid blocker, is under development for the treatment of acid‐related disorders.
Aims
To compare the pharmacodynamics (PDs), ...pharmacokinetics (PKs) and safety of DWP14012 among healthy subjects of Korean, Caucasian and Japanese descent.
Methods
A randomised, double‐blind, placebo‐controlled, single‐ and multiple‐dose study was conducted. Ten subjects in each dose group (40, 60 or 80 mg for Koreans; 40 or 80 mg for Caucasians; 20, 40 or 80 mg for Japanese) were randomly assigned to DWP14012 or a placebo. Twenty‐four‐hour intragastric pH measurements and serial blood samples were collected for PK/PD evaluation. The PK/PD parameters were compared between each ethnicity.
Results
The extent of gastric acid suppression was similar among the ethnicities; the mean percentages of time that the intragastric pH was above 4 after multiple doses of 40 mg in the Korean, Caucasian and Japanese subjects were 64.3%, 62.8% and 70.3%, respectively, and the corresponding values for the 80 mg dose were 94.8%, 90.6% and 90.6% respectively. The changes in serum gastrin were not clinically significant between all three ethnicities. The systemic exposure of DWP14012 was similar between the three ethnicities after the 40 mg doses but slightly lower in Caucasian and Japanese subjects after the 80 mg doses. Gastric acid suppression by DWP14012 showed a clear exposure‐response relationship in the three ethnicities.
Conclusions
Gastric acid suppression by DWP14012 was similar among the Korean, Caucasian and Japanese subjects in this study, and the PK, PK‐PD relationships and safety were also similar among the three ethnicities. DWP14012 could be used without consideration of ethnicity.
Aims
DWP16001 is a novel sodium–glucose cotransporter‐2 inhibitor under development for the treatment of type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetics, ...pharmacodynamics and safety of DWP16001 after single and multiple doses in healthy subjects.
Methods
A randomized, double‐blind, placebo‐ and active‐controlled, single‐ and multiple‐dose study was conducted. Twelve subjects in each dose group received a single dose (0.2, 0.5, 1.0, 2.0 or 5.0 mg) or multiple doses (0.1, 0.3, 0.5, 1.0 or 2.0 mg once daily for 15 consecutive days) of DWP16001, dapagliflozin 10 mg or placebo at a ratio of 8:2:2. Serial blood and interval urine samples were collected for the pharmacokinetic and pharmacodynamic analyses. The safety and tolerability of DWP16001 were also assessed.
Results
A dose‐dependent increase in the urinary glucose excretion was observed after a single dose, and the steady state urinary glucose excretion was 50–60 g/d after multiple doses in the dose range of 0.3–2.0 mg. DWP16001 was rapidly absorbed with the time to peak plasma concentration of 1.0–3.0 hours, and it exhibited a mean elimination half‐life of 13–29 hours. The systemic exposure to DWP16001 increased proportionally with multiple dose administrations in the range of 0.1–2.0 mg. DWP16001 was well tolerated in all dose groups.
Conclusion
DWP16001 induced glucosuria in a dose‐dependent manner, and systemic exposure was observed after multiple doses. DWP16001 was well tolerated in single oral doses of up to 5.0 mg and in multiple oral doses of up to 2.0 mg.
Reactivated memory undergoes a rebuilding process that depends on de novo protein synthesis. This suggests that retrieval is dynamic and serves to incorporate new information into preexisting ...memories. However, little is known about whether or not protein degradation is involved in the reorganization of retrieved memory. We found that postsynaptic proteins were degraded in the hippocampus by polyubiquitination after retrieval of contextual fear memory. Moreover, the infusion of proteasome inhibitor into the CA1 region immediately after retrieval prevented anisomycin-induced memory impairment, as well as the extinction of fear memory. This suggests that ubiquitin- and proteasome-dependent protein degradation underlies destabilization processes after fear memory retrieval. It also provides strong evidence for the existence of reorganization processes whereby preexisting memory is disrupted by protein degradation, and updated memory is reconsolidated by protein synthesis.
A recent study has suggested that fibroblasts can be converted into mouse-induced neural stem cells (miNSCs) through the expression of defined factors. However, successful generation of human iNSCs ...(hiNSCs) has proven challenging to achieve. Here, using microRNA (miRNA) expression profile analyses, we showed that let-7 microRNA has critical roles for the formation of PAX6/NESTIN-positive colonies from human adult fibroblasts and the proliferation and self-renewal of hiNSCs. HMGA2, a let-7-targeting gene, enables induction of hiNSCs that displayed morphological/molecular features and in vitro/in vivo differentiation potential similar to H9-derived NSCs. Interestingly, HMGA2 facilitated the efficient conversion of senescent somatic cells or blood CD34+ cells into hiNSCs through an interaction with SOX2, whereas other combinations or SOX2 alone showed a limited conversion ability. Taken together, these findings suggest that HMGA2/let-7 facilitates direct reprogramming toward hiNSCs in minimal conditions and maintains hiNSC self-renewal, providing a strategy for the clinical treatment of neurological diseases.
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•Inhibition of let-7 promotes direct reprogramming and self-renewal of hiNSCs•HMGA2, a target of let-7, promotes the rapid and efficient generation of hiNSCs•HMGA2 facilitates the direct reprogramming of human senescent cells and blood cells
Efficient generation of induced neural stem cells (iNSCs) from human somatic cells has remained challenging. Here, Yu et al. show that inhibition of the let-7 microRNA, or expression of its target HMGA2, facilitates SOX2-mediated direct reprogramming of human adult fibroblasts, senescent somatic cells, and blood cells into iNSCs. These hiNSCs display tridifferentiation ability and functionality, which could potentially provide therapeutic treatment for diverse neurological diseases.
Objective
We evaluated the efficacy of endovascular thrombectomy (EVT) on the functional outcome of patients with acute basilar artery occlusion and low posterior circulation acute stroke prognosis ...early computed tomography score (PC‐ASPECTS).
Methods
We identified patients with acute ischemic stroke due to basilar artery occlusion and PC‐ASPECTS of 6 or less, presenting within 24 h between August 2008 and April 2022. The primary outcome was a favorable functional outcome, defined as a modified Rankin Scale (mRS) score of 0–3 at 90 days. The secondary outcomes included an mRS score of 0–2, a favorable shift in the ordinal mRS scale, the occurrence of symptomatic intracranial hemorrhage (sICH), and mortality at 90 days. We compared the outcome of patients treated with EVT and those without EVT, using the inverse probability of treatment weighting methods.
Results
Out of 566 patients, 55.5% received EVT. In the EVT group, 106 (33.8%) achieved favorable outcomes, compared to 56 patients (22.2%) in the conservative group. EVT significantly increased the likelihood of achieving a favorable outcome compared to conservative treatment (relative risk RR 1.39, 95% confidence interval CI, 1.11–1.74, p = 0.004). EVT was associated with a favorable shift in the mRS (RR 1.85, 95% CI, 1.49–2.29, p < 0.001) and reduced mortality without an increase in the risk of sICH. It did not have an impact on achieving an mRS score of 0–2.
Interpretation
Patients with acute basilar artery occlusion and a PC‐ASPECTS of 6 or less might benefit from EVT without an increasing sICH. ANN NEUROL 2024;95:788–799
Because human mesenchymal stem cells (hMSC) have profound immunomodulatory effects, many attempts have been made to use hMSCs in preclinical and clinical trials. For hMSCs to be used in therapy, a ...large population of hMSCs must be generated by in vitro expansion. However, the immunomodulatory changes following the in vitro expansion of hMSCs have not been elucidated. In this study, we evaluated the effect of replicative senescence on the immunomodulatory ability of hMSCs in vitro and in vivo. Late-passage hMSCs showed impaired suppressive effect on mitogen-induced mononuclear cell proliferation. Strikingly, late-passage hMSCs had a significantly compromised protective effect against mouse experimental colitis, which was confirmed by gross and histologic examination. Among the anti-inflammatory cytokines, the production of prostaglandin E2 (PGE2) and the expression of its primary enzyme, cyclooxygenase-2 (COX-2), were profoundly increased by pre-stimulation with interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), and this response was significantly decreased with consecutive passages. We demonstrated that the impaired phosphorylation activity of p38 MAP kinase (p38 MAPK) in late-passage hMSCs led to a compromised immunomodulatory ability through the regulation of COX-2. In conclusion, our data indicate that the immunomodulatory ability of hMSCs gradually declines with consecutive passages via a p38-mediated alteration of COX-2 and PGE2 levels.
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