Drug Discoveries and Therapeutics最新文献

Hematologic abnormalities are the most common symptoms of Shwachman-Diamond syndrome (SDS). The causative gene for SDS is the Shwachman-Bodian-Diamond syndrome (SBDS) gene; however, the function of SBDS and pathogenesis of each condition in SDS are largely unknown. SBDS is known to be localized at mitotic spindles and stabilizes microtubules. Previously, we demonstrated that SBDS is ubiquitinated and subsequently degraded in the mitotic phase, thereby accelerating mitotic progression. In this study, we examined mitosis in a myeloid cell model of SDS (SDS cells). 4',6-Diamidino-2-phenylindole (DAPI)-stained chromosome observation and cell cycle analysis of nocodazole-synchronized cells revealed that the SDS cells have abnormally rapid mitosis. In addition, many lagging chromosomes and micronuclei were detected. Moreover, the phosphorylation of threonine tyrosine kinase, the crucial kinase of the spindle assembly checkpoint (SAC), was suppressed. Chromosomal instability caused by SAC dysfunction may cause a variety of clinical conditions, including hematologic tumors in patients with SDS.

The case reports a woman in her 70s, with type 2 diabetes and chronic kidney disease in G4 stage. The patient had elevated HbA1c, and she was switched from linagliptin, a dipeptidyl peptidase 4 inhibitor, to dulaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA). Thereafter, the HbA1c level decreased; however, since the dulaglutide supply became a problem, the patient was switched to tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA. To date, no clinical studies have evaluated the efficacy and safety of switching from GLP-1RA to GIP/GLP-1RA, but we report this case because efficacy was observed in this patient. The therapeutic effects after switching to tirzepatide included decrease in HbA1c, increase in eGFR, and decrease in BUN, when compared to when dulaglutide was used. A change from dulaglutide to tirzepatide, could inhibit renal impairment progression and improve renal function.

A comparative evaluation of the brand-name drug Mycospor and six generic drugs (IWAKI, Bifonol, F, YD, Sawai, and TEVA), all comprising a cream formulation containing the antifungal drug bifonazole, was performed based on physicochemical measurements. The pH of the various formulations was significantly higher for the generics Bifonol (pH 7.1), Sawai (pH 6.7), and TEVA (pH 7.3) and significantly lower for YD (pH 4.3) than for the brand-name drug Mycospor (pH 5.5). The viscosity of the various formulations was significantly higher for TEVA (25,011 mPa·s) versus Mycospor (22,376 mPa·s) and significantly lower for IWAKI, Bifonol, F, YD, and Sawai, with Bifonol (8,572 mPa·s) being particularly low. Considering the hysteresis loop area obtained for the shear rate vs. shear stress, which represents the thixotropic properties, and using the value of Mycospor as the reference for 100%, YD (179%), Sawai (557%), and TEVA (201%) showed significantly higher values. Furthermore, the membrane permeability of bifonazole at 24 hours was significantly higher for Bifonol (309 μg/mL) and F (182 μg/mL) and significantly lower for Sawai (124 μg/mL) and TEVA (92 μg/mL) than for Mycospor (153 μg/mL). Finally, optical micrographs showed that the dispersion of particles was similar in the various formulations, but the particles of F and TEVA were uniformly dispersed with a smaller particle size than the other formulations. Overall, significant differences were observed in the formulation characteristics between the brand-name drug and generic drugs, which were attributed to differences in the manufacturing process and the types of additives.

Skin exposed to ultraviolet light produces hydrogen peroxide (H₂O₂) and reactive oxygen species (ROS) that cause protein denaturation and other disorders. We investigated whether electrolytic-reduction ion water (ERI), which has reducing properties and has been reported to protect skin, exhibits antioxidant activity in skin keratinocytes. The antioxidant activity of ERI was first examined using DPPH assay and Electron Spin Resonance to test for radicals, and using the Amplex Red method to test for H₂O₂. Concentration-dependent scavenging of hydroxyl radical but no H₂O₂ depletion were detected. An investigation of the expression of heme oxygenase-1, which is upregulated by oxidative response in cells, showed an increase through H₂O₂ oxidation, which was inhibited by ERI in a concentration-dependent manner. This suggests that ERI directly removes ROS. Quantitative real-time polymerase chain reaction analysis was performed to determine whether ERI regulates the expression of aquaporin 3 (AQP3), a known H₂O₂ transporter. This analysis revealed that ERI enhances AQP3 expression in a concentration-dependent manner and is involved in the transport of intracellular H₂O₂ to the extracellular space. In addition, ERI inhibited H₂O₂-induced cytotoxicity in a concentration-dependent manner. These results suggest that ERI protects keratinocytes from ROS by directly scavenging them and indirectly by eliminating them through the promotion of the efflux of intracellular H₂O₂.

Fever is one of the most common complications in stroke patients and can generally be classified as either infectious or non-infectious. Infectious fevers are commonly caused by pulmonary infections, urinary tract infections, and secondary infections associated with medical interventions such as endotracheal intubation, urinary catheterization, and nasogastric tubes. Non-infectious fevers primarily manifest as central fevers, although in rare cases, they may also result from drug-induced causes. Existing research indicates that the most common cause of central fever is brainstem hemorrhage, followed by hemorrhage in the basal ganglia and thalamus, then cerebellar hemorrhage, large cortical infarction, and basilar artery occlusion, with intraventricular hemorrhage being relatively rare. Stroke patients' body temperatures can rise to 39°C within 12 hours after onset and peak within 24 hours. In this case, a stroke patient with acute cerebral infarction and secondary thalamic hemorrhage developed new sensory abnormalities in the left limbs and intermittent fever during hospitalization. Despite the use of antibiotics targeting a pulmonary infection, the patient's fever did not show significant improvement. Gabapentin was added to the treatment regimen to address the sensory abnormalities. Surprisingly, within four hours of gabapentin administration, the patient's body temperature normalized and remained stable during subsequent monitoring. This observation led us to hypothesize that gabapentin may have a potential role in alleviating central fever.

This study aimed to evaluate the effect of astaxanthin compound nutrient (ACN) complementary therapy on pregnancy outcomes in polycystic ovary syndrome (PCOS) patients undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). This study enrolled 92 patients with PCOS who were continuously supplemented with ACN for three months prior to IVF/ICSI treatment from 2021 to 2023, and selected 92 patients who did not receive the treatment during the same period as controls. Baseline characteristics, ovulation induction outcomes, and pregnancy outcomes were compared between the two groups. In addition, the body mass index (BMI), anti-Müllerian hormone (AMH), antral follicle counting (AFC), fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of insulin resistant (HOME-IR), and basal sex hormones of the supplementary group patients before and after treatment were compared. The results showed that there were no significant differences in the patient's duration of stimulation, total gonadotropin dose, peak E2 levels, and number of retrieved oocytes between the two groups. However, the number of 2 pronucleus (PN) fertilization, transferable embryos, and high-quality embryos was significantly higher in the ACN group compared with the control group. For both fresh and frozen embryo transplantation, positive pregnancy outcomes increased in PCOS patients who received supplementation of ACN for 3 months. In addition, after 3 months of supplementing with ACN, the patient's BMI, AMH, fasting insulin, HOME-IR, basal luteinising hormone (bLH), and basal testosterone (bT) decreased compared to before treatment. This study suggested that ACN improved insulin resistance, hormone levels, embryo quality and pregnancy outcomes in PCOS patients.

In this study, we aimed to examine whether a wheelchair cushion placed directly atop a sling seat or deflection of the sling seat compensated by a pad along with the placement of a wheelchair cushion changed sitting pressure. Additionally, we examined whether these additions changed sitting comfort. For twenty healthy adults who consented to participate, measurements were taken for three types of cushions, each with and without padding, under six conditions. The cushion types tested included air (cushion A), urethane foam (cushion U), and three-dimensional thermoplastic elastomer (cushion T). A pressure distribution measurement equipment was used for the measurements. Following the measurement, the comfort of the wheelchair cushion was measured. The ischial area pressure of the cushion A pad was significantly lower than that without the pad. Cushions U and T were for ischial area pressure with a pad, resulting in a decreasing trend in ischial area pressure with a pad compared to that without a pad; however, the difference was insignificant. For all cushions, sitting comfort was significantly better in all groups with padding than in those without. In conclusion, ischial pressure can be dispersed by placing a pad on the seat surface of a wheelchair cushion, and pads were suggested to improve sitting comfort for all cushions.

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is deeply involved in the development and higher function of the nervous system, including learning and memory. By contrast, a reduction in BDNF levels is associated with various neurological disorders such as dementia and depression. Therefore, the inducers of Bdnf expression might be valuable in ameliorating or protecting against a decline in brain functions. We previously reported that, through high-throughput screening to identify inducers of Bdnf expression in Bdnf-luciferase transgenic mice, several herbal extracts induced Bdnf expression in cortical neurons. In the present study, we found that Panax notoginseng root extract (PNRE) potently induced Bdnf expression in primary cultured cortical neurons primarily via the L-type voltage-dependent Ca²⁺ channel (L-VDCC) and calcineurin. PNRE promoted nuclear translocation of cAMP-responsive element-binding protein-regulated transcription coactivator 1 (CRTC1). These findings suggest that PNRE activates the L-VDCC/calcineurin/CRTC1 axis, which is the primary signaling pathway involved in the neuronal activity-dependent expression of Bdnf. Moreover, we demonstrated that PNRE increased the dendritic complexity of cortical neurons in vitro. Thus, by upregulating Bdnf expression, PNRE is a potential candidate for improving cognitive impairment seen in several kinds of dementia.

A pandemic known as anti-microbial resistance (AMR) poses a challenge to contemporary medicine. To stop AMR's rise and quick worldwide spread, urgent multisectoral intervention is needed. This review will provide insight on new and developing treatment approaches for AMR. Future therapy options may be made possible by the development of novel drugs that make use of developments in "omics" technology, artificial intelligence, and machine learning. Vaccines, immunoconjugates, antimicrobial peptides, monoclonal antibodies, and nanoparticles may also be intriguing options for treating AMR in the future. Combination therapy may potentially prove to be a successful strategy for combating AMR. To lessen the impact of AMR, ideas like drug repurposing, antibiotic stewardship, and the one health approach may be helpful.

The silkworm Nocardia infection model has been established as a useful animal model for screening the pathogenicity of Nocardia and evaluating the therapeutic effects of antimicrobial agents against Nocardia infection. No histopathological analysis of silkworms infected with Nocardia farcinica has yet been performed. In this study, we performed histological analyses on organs of silkworms infected with N. farcinica. One day after infection with N. farcinica, the organism developed a branching filamentous form from coccid cells in the hemolymph. In addition, we evaluated effective doses (ED₅₀) values by treating infected silkworms with amikacin 30 seconds and 24 hours after infection and found that the ED₅₀ values treated within 30 seconds and 24 hours after infection were 4.1 μg/larva and 5.6 μg/larva, respectively. Evaluation of treatment with amikacin against the infected silkworms was unaffected by the growth process form of Nocardia. These results suggest that the silkworm Nocardia infection model is a useful tool for evaluating the antimicrobial therapy in the growth process of the N. farcinica.