Biological & pharmaceutical bulletin最新文献

Opioid receptors and their endogenous ligands are novel targets for the treatment of depression. The nociception (NOP) receptor is structurally similar to the opioid receptor, but NOP is known to have a low affinity for the opioid receptor subtypes μ, δ, and κ. In previous studies, we synthesized peptides with a high affinity for opioid receptors and investigated their antidepressant-like effects in mice. However, we have not yet examined whether NOP-related analogs have antidepressant-like effects. Herein, we synthesized NOP analogs (peptide-1-peptide-8) by solid-phase peptide synthesis using the 9-fluorenylmethyloxycarbony (Fmoc) method with Acetyl-Arg-Tyr-Tyr-Arg-Ile-Arg-NH₂ (Ac-RYYRIR-NH₂) as the lead compound. We examined the affinities and antagonistic activities of the analogs for the NOP receptor using receptor-binding and mouse vas deferens assays, and their effects on the duration of immobile behavior in a tail suspension test. Peptide-6 showed a high affinity and antagonistic activity for the NOP receptor. The intracerebroventricular administration of peptide-6 in mice shortened the duration of immobile behavior, whereas the co-administration of NOP inhibited this effect. Moreover, intracerebroventricular administration of the selective NOP receptor antagonist J-113397 showed antidepressant-like effects in mice. These data suggest that peptide-6 exerts an antidepressant-like effect via inactivation of the central NOP receptor in mice and may represent a lead compound for the development of antidepressant drugs in the future.

Cerebral ischemia/reperfusion (I/R) injury caused by resumed blood flow to an infarcted area contributes to poor patient prognosis due to a lack of treatment strategies. While the blood-brain barrier (BBB) is the greatest barrier for drug delivery to the brain, temporary disruption to the BBB after brain I/R injury allows for delivery of cerebroprotective drug-encapsulated nanoparticles into the brain parenchyma. However, issues remain with delivering drugs to the I/R region using nanoparticles, such as the limited therapeutic time window due to BBB repair over time. To overcome these challenges, we developed nanoparticles specifically targeting the I/R environment. Human umbilical vein endothelial cells (HUVECs) were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R), an in vitro I/R model. Low-density lipoprotein receptor (LDLR) mRNA was upregulated early during the reoxygenation process. Furthermore, immunostaining of OGD/R-treated cells showed an increase in LDLR expression. Next, we constructed a peptide that mimics the LDLR binding recognition site on LDL, and modified liposomes to display the peptide on their surface. Peptide-modified liposomes showed targeting ability to the LDLR on cells. Accumulation of peptide-modified liposomes was significantly increased in OGD/R treated cells compared with controls, and was reduced by blocking LDLR using its antibody. These results demonstrate upregulation of LDLR and LDLR-mediated liposome uptake in OGD/R stressed cells. In conclusion, LDLR binding recognition site mimicking peptide-modified liposomes are a useful drug carrier that can recognize I/R injured endothelial cells.

A major oxidized base, 8-oxo-7,8-dihydroguanine (G^O, 8-hydroxyguanine), is involved in cancer initiation. G^O induces untargeted base substitution (action-at-a-distance) mutations as well as targeted G→T transversions in human cells. Uracil also induces similar untargeted mutations. An abasic site is the common product of their specific DNA glycosylases (OGG1 and UNG2, respectively) and is an expected intermediate of the untargeted mutation pathway. Subsequently, the DNA strand is nicked by AP endonuclease. In this study, a shuttle plasmid containing a true (natural) abasic site was introduced into human U2OS cells. The frequency of action-at-a-distance mutations was much lower for the abasic site than that for uracil, although the abasic site is considered the mutational intermediate of the latter. Moreover, nicked DNA containing a 5'-phosphate induced untargeted mutations less frequently than that without a 5'-phosphate, and their mutation frequencies were much higher than that of the abasic site. The unexpectedly low mutagenic potential of the true abasic site suggests that the mechanism of action-at-a-distance mutations is complex.

Delirium is an acute, potentially life-threatening condition characterized by altered attention, disorganized thinking, and changes in consciousness. It frequently occurs in hospitalized patients with acute heart failure (AHF). In this meta-analysis, we aimed to identify risk factors for delirium in patients with AHF (AHF-D). We evaluated all original studies on delirium occurrence in patients hospitalized for AHF. On March 11, 2024, we searched PubMed, Scopus, Ichushi, and the Cochrane Library. Data extracted included: first author's name, publication year, inclusion/exclusion criteria, study design, delirium assessment methods, odds ratios with 95% confidence intervals, standardized mean differences, and other relevant findings. Of 2436 screened studies, 6 met eligibility criteria (3867 patients with AHF; 796 with delirium [20.6%] and 3071 without). Risk factors for AHF-D included older age; low body mass index; the use of mechanical ventilation/noninvasive positive pressure ventilation; comorbidities (previous stroke, dementia, and depression); use of antipsychotics and benzodiazepines; and laboratory findings on admission (elevated heart rate, B-type natriuretic peptide, blood urea nitrogen, serum creatinine, and low serum albumin and sodium levels). We identified 14 risk factors for AHF-D. These findings may help clinicians identify patients at high risk of developing AHF prior to delirium onset.

Oligodendroglia encompass oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs). In the grey matter of the cortex, nearly all OPCs divide slowly, yet they do not differentiate solely into mature OLs, leaving the exact role of these OPCs in the grey matter enigmatic. Oligodendroglia were traced using the sex-determining region Y-related high mobility group-box 10 (Sox10) Cre-ER^T2 reporter mice. We compared the effect of tamoxifen dissolved in different solvents on the fate of Sox10 cells. We also compared the effect of tamoxifen dosage on the fate of Sox10 cells. The differentiation of labeled red fluorescent protein (RFP) cells was analyzed using immunofluorescence staining. Two groups of RFP cells, type A Sox10 (Sox10-A) cells and type B Sox10 (Sox10-B) cells, were identified in the cortex, striatum, hippocampus, thalamus, and hypothalamus. Sox10-A cells differentiate into platelet-derived growth factor receptor-β+, CD13+ pericytes, and smooth muscle myosin heavy chain 11+ smooth muscle cells when the mice received ethanol or high-dose tamoxifen. Sox10-B cells transform into glutamatergic neurons when the mice received high-dose tamoxifen. Sox10-B cells include perineuronal OPCs and OLs. This investigation provides evidence that a substantial proportion of oligodendroglia in the grey matter serve as mural cell precursors and neuronal precursors. These two phenomena may contribute to our understanding of the fate of oligodendroglia.

Trastuzumab, a therapeutic drug for patients with breast cancer, is one of the most effective and commonly used anticancer drugs for breast cancer. However, its adverse effects include cardiotoxicity, and there is a risk of developing conditions such as arrhythmia, cardiomyopathy, and heart failure. The adverse cardiac effects associated with trastuzumab are now widely recognized, and their mechanisms are beginning to be partially understood. One of the mechanisms has been suggested to be related to the suppressive action of trastuzumab on the erythroblastic oncogene B2 receptor, which acts protectively on the myocardium. Diagnosis can be made by assessing cardiac function with echocardiography, as well as measuring serum troponin I and N-terminal pro-B-type natriuretic peptide levels as biomarkers, and magnetic resonance imaging diagnosis may be helpful for early detection. As for therapeutic and prophylactic drugs, β-blockers and angiotensin-converting enzyme inhibitors, which are used to treat heart failure, have been shown to be effective, while recently, angiotensin receptor/neprilysin and sodium-glucose cotransporter 2 inhibitors are expected to be effective. Furthermore, the cardioprotective effects of proprotein convertase subtilisin/kexin type 9 inhibitors, which are used to treat lipid disorders, have also been attracting attention. This review will summarize the mechanisms, diagnostic methods, and treatment/preventive methods of cardiotoxicity associated with antihuman epidermal growth factor receptor 2 therapies, including trastuzumab.

Pigmentation is one of the most prominent side effects caused by anticancer drugs, especially in female patients, as these changes in appearance can decrease QOL. A typical drug causing such pigmentation is 5-fluorouracil (5-FU); we have previously shown that 5-FU-induced pigmentation is associated with increased adrenocorticotropic hormone (ACTH) and reactive oxygen species (ROS) levels. In male Hos:HRM-2 mice, 5-FU administration resulted in pigmentation appearing in the genital area, accompanied by elevations in neutrophils, ACTH, and ROS. By contrast, female mice showed increases in neutrophils and noradrenaline, but not in ACTH or ROS levels; furthermore, they did not develop pigmentation. In addition, estradiol levels were markedly decreased in female mice, which may have enhanced neutrophil apoptosis and suppressed ROS production. In addition, noradrenaline reflects the stress response and may contribute to the decrease in estradiol, suggesting the hypothalamus-pituitary-adrenal axis and sex hormones may interact in the formation of sex differences. These results suggest that sex differences exist in the development of 5-FU-induced hyperpigmentation and that fluctuations in estradiol and associated changes in neutrophils, ROS, and ACTH may underlie this phenomenon.

Increased accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) causes a rise in intraocular pressure (IOP), which is a primary risk factor for glaucoma. Hyaluronan (HA) is essential for forming the ECM network, but it is unclear whether HA metabolism plays a role in IOP control. In this study, we focused on the hyaluronan-binding protein involved in hyaluronan depolymerization (HYBID, also referred to as cell migration inducing hyaluronidase 1 (CEMIP)/KIAA1199), which is an HA-degrading enzyme. Hybid knockout (KO) mice exhibited IOP elevation [IOP on average +2.14 mmHg at 7 weeks old, +1.54 mmHg at 8 weeks old vs. IOP of wildtype (WT) mice]. In addition, fibronectin and HA accumulated in the TM of Hybid KO mice. In cultured human TM cells (HTMCs), HYBID knockdown with HYBID siRNA increased HA and fibronectin protein but the expression of fibronectin mRNA was not altered. In addition, in HYBID knockdown HTMCs, matrix metalloproteinase (MMP)-1 and tissue inhibitor of metalloproteinase (TIMP) 3 were increased and MMP-9 was decreased. These results indicated that HYBID knockdown did not contribute to fibronectin production but inhibited ECM degradation through decreased MMP-9 expression and increased TIMP3 expression, leading to reduced MMP-2 and MMP-9 activity. These findings may offer new perspectives on the underlying mechanisms of glaucoma associated with fibrosis and potentially contribute to the development of novel glaucoma therapeutics.

Radiation therapy exerts its therapeutic effect by killing cells via the induction of DNA double-strand breaks (DSBs) in malignant tumors, but cancer cells can repair damaged DNA, leading to radiation resistance (radioresistance). Therefore, a radiosensitizing effect can be expected by suppressing mechanism(s) involved in DNA repair after irradiation. Here, we show that the P2Y12 receptor is involved in the radioresistance of mouse B16 melanoma cells, and that P2Y12 antagonist treatment decreases the radioresistance both in vitro and in vivo by inhibiting DNA repair after γ-irradiation. P2Y12 receptor antagonists Clopidogrel and PSB0739 increased cellular sites of unrepaired DNA by suppressing the DNA damage response (DDR) after γ-irradiation and enhanced radiation-induced proliferative death in B16 melanoma cells. On the other hand, ADP (a P2Y12 receptor agonist) enhanced DDR after γ-irradiation and increased radioresistance. Knockdown of the P2Y12 receptor resulted in an increase of unrepaired DNA damage and enhanced proliferative death after γ-irradiation. Suppression of the P2Y12 receptor also contributed to the enhancement of the cancer-killing effect of γ-irradiation, even in fractionated irradiation samples in which the cancer-killing effect decreased due to sublethal damage recovery. Finally, PSB0739 significantly enhanced the antitumor effect of γ-irradiation in vivo. Our results suggest that P2Y12 receptor antagonists are promising candidates as radiosensitizers to improve radiation therapy.

Chronic kidney disease (CKD) is a serious chemotherapy-associated clinical condition. CKD complicates the pharmacokinetics of anticancer drugs, requiring personalized dosing strategies to minimize toxicity. S-1 and oxaliplatin (the SOX regimen) are widely used for gastrointestinal cancer treatment. However, the specific association between systemic drug exposure and renal biomarker levels in CKD remains unclear. This study evaluated the pharmacokinetics of S-1 and oxaliplatin in 2 CKD model rats (5/6 nephrectomy and adenine-induced) and examined their relationships with renal biomarkers. S-1 (2 mg/kg as tegafur) and oxaliplatin (5 mg/kg) were administered separately, and plasma levels of tegafur, 5-fluorouracil (5-FU), 5-chloro-2,4-dihydropyridine, oxaliplatin, and platinum were measured by LC-tandem MS. Systemic exposure to S-1 and oxaliplatin was higher in the CKD model rats than in the normal group, with 5-FU levels being particularly higher in the adenine-induced model than in the 5/6 nephrectomy model. The area under the curve values of 5-FU and platinum were strongly correlated with plasma creatinine (P_Cr) levels (r = 0.79 and 0.88, respectively). Population pharmacokinetic analysis identified P_Cr as a significant covariate of 5-FU clearance. A nomogram constructed using P_Cr-based simulations demonstrated the feasibility of individualized S-1 dosing. Overall, our findings suggest that P_Cr is a practical biomarker to guide S-1 dose optimization and highlight the importance of pharmacokinetics-based strategies for patients with cancer and CKD.