OBJECTIVES: To compare the efficacy and safety of daprodustat (DPD) versus darbepoetin alfa (DBPA) in patients with anemia in chronic renal failure. MATERIALS AND METHODS: Randomized controlled trials (RCTs) of DPD and D...OBJECTIVES: To compare the efficacy and safety of daprodustat (DPD) versus darbepoetin alfa (DBPA) in patients with anemia in chronic renal failure. MATERIALS AND METHODS: Randomized controlled trials (RCTs) of DPD and DBPA in anemia were retrieved from PubMed, Embase, Cochrane library, and Web of Science from inception to August 1, 2023. The collected data were analyzed using Stata 15.0. RESULTS: Four RCTs involving 7419 patients (3717 in the DPD group and 3702 in the DBPA group) were included in the study. Meta-analysis revealed that there were no significant differences in the change in hemoglobin level [Standardized Mean Difference (SMD) = 3.23, 95 % CI (-0.25, 6.70)], transferrin saturation [SMD = -0.07, 95 % CI (-0.31, 0.17)], total iron [SMD = 0.24, 95 % CI (-0.05, 0.53))], and incidence of adverse events [ RR = 1.02, 95 % CI (0.98, 1.06)] between the two groups. However, DPD was superior in lowering ferritin level [SMD = -0.05, 95 % CI (-0.10, -0.01)] and improving total iron-binding capacity [SMD = 0.57, 95 % CI (0.46, 0.68)] than DBPA. CONCLUSIONS: DPD is not inferior to DBPA in the treatment of anemia in chronic renal failure.
Vascular smooth muscle cells (VSMCs) modulate blood pressure by adjusting vascular contractility. Specific families of ion channels that are expressed in VSMCs regulate membrane potential and intracellular Ca concentrati...Vascular smooth muscle cells (VSMCs) modulate blood pressure by adjusting vascular contractility. Specific families of ion channels that are expressed in VSMCs regulate membrane potential and intracellular Ca concentration ([Ca]). Subsets of them are known to form molecular complexes with Ca-sensitive molecules via scaffolding proteins such as caveolin and junctophilin. This enables localized and molecular complex-specific signal transduction to regulate vascular contractility. This intracellular region is referred to as a Ca microdomain. When hypertensive stimuli are applied to blood vessels, gene expression of ion channels and scaffold proteins in vascular cells changes dramatically, often leading to membrane depolarization and increased [Ca]. As a result, blood vessels undergo functional remodeling characterized by enhanced contractility. In addition, the transcription of inflammatory genes in vascular cells is also upregulated. This induces leukocyte infiltration into the vascular wall and structural remodeling mediated by VSMC proliferation and extracellular matrix remodeling. This functional and structural remodeling perpetuates the hypertensive state, leading to progressive damage to systemic organs. This review summarizes recent findings on the mechanisms by which Ca microdomains in VSMCs regulate contractility. In addition, the changes in Ca microdomains due to hypertensive stimuli and their contributions to both functional and structural remodeling are summarized.
Conventional wired systems for recording intestinal motility using strain-gauge transducers physically limit animal movement and are not ideal for long-term studies. Here, we developed a wireless recording system that al...Conventional wired systems for recording intestinal motility using strain-gauge transducers physically limit animal movement and are not ideal for long-term studies. Here, we developed a wireless recording system that allows continuous monitoring of intestinal activity in freely moving rats. We also developed a denoising autoencoder that isolates intestinal motility signals from locomotor noise while maintaining a 10-s temporal resolution. The refined data revealed decreased intestinal motility while the rats were behaviorally active. This system has broad applications for in vivo physiological research.
Neovascular age-related macular degeneration (nAMD) is an ocular disease characterized by choroidal neovascularization (CNV), resulting in severe visual impairment. Arctigenin is a natural lignan compound from Arctium la...Neovascular age-related macular degeneration (nAMD) is an ocular disease characterized by choroidal neovascularization (CNV), resulting in severe visual impairment. Arctigenin is a natural lignan compound from Arctium lappa L. and has anti-inflammatory and vascular normalizing effects. Here, we investigated the anti-angiogenic effects of arctigenin on CNV formation. Laser-induced CNV model mice were orally administered arctigenin at 100 mg/kg once a day for 5 days before laser irradiation. Oral administration of arctigenin suppressed CNV formation, vascular leakage, and the proliferation of endothelial cells in the CNV lesions. Treatment with arctigenin at 30 μM attenuated vascular endothelial growth factor (VEGF)-induced cell proliferation of human retinal microvascular endothelial cells (HRMECs). Moreover, arctigenin suppressed the phosphorylation of Src, which is involved in VEGF signaling. Arctigenin also inhibited VEGF-induced mitochondrial respiratory activation. These findings suggested that daily intake of arctigenin may have beneficial effects on nAMD.
Pueraria Mirifica (Willd. Ohwi) is a medicine with anti-inflammatory and lipid-lowering properties. Puerarin is one of the main active components of Pueraria. The aim of this study was to investigate the possible mechani...Pueraria Mirifica (Willd. Ohwi) is a medicine with anti-inflammatory and lipid-lowering properties. Puerarin is one of the main active components of Pueraria. The aim of this study was to investigate the possible mechanisms of Pueraria in the treatment of non-alcoholic fatty liver disease. The therapeutic effect of the drug was demonstrated by serum and liver pathology indicators. The mechanism of action of puerarin was demonstrated by intestinal microbial changes and short-chain fatty acid content tests. The mechanism of puerarin alleviating Metabolic dysfunction-associated steatotic liver disease (MASLD) by regulating intestinal flora was predicted by bioinformatics. The relationship between flora and liver was revealed by q-PCR detection of mRNA expression level of liver metabolic genes. And the mechanism of puerarin action was further verified by intestinal microbial clearance experiments. Puerarin reduced vacuolar-like changes, lipid deposition, and inflammatory cell infiltration in the livers of high-fat diet (HFD) model mice. The gut microbiota abundance and diversity were remodeled, short-chain fatty acid content was increased, and the intestinal mucosal barrier was repaired, accompanied by a reduction in inflammatory cytokines. Puerarin regulated mRNA expression of hepatic lipid metabolism genes to alleviate MASLD. These results suggested that puerarin treats MASLD by treating altering bacterial metabolism and anti-inflammation.
This study was designed to investigate the role of Ligustrum lucidum Ait and Ecliptae Herba on premature ovarian failure (POF) and the underlying mechanisms. In the POF mouse model constructed using cyclophosphamide (CTX...This study was designed to investigate the role of Ligustrum lucidum Ait and Ecliptae Herba on premature ovarian failure (POF) and the underlying mechanisms. In the POF mouse model constructed using cyclophosphamide (CTX), Ligustrum lucidum Ait and Ecliptae Herba increased ovarian index and estradiol (E2) levels and curtailed motility and follicle-stimulating hormone (FSH). Ligustrum lucidum Ait and Ecliptae Herba alleviated ovarian pathological damage in POF mice and promoted the expression of ovarian CD31 and Vascular Endothelial Growth Factor A (VEGFA). Through high-performance liquid chromatography-mass spectrometry (HPLC-MS) and network pharmacology, Specnuezhenide and ecliptasaponin A were identified as the key components of Ligustrum lucidum Ait and Ecliptae Herba in anti-POF action. The important target associated with these components is Estrogen Receptor (ESR) 1. Molecular docking and in vitro experiments showed that Specnuezhenide and ecliptasaponin A can both bind to the ESR protein; knocking down ESR1 inhibited the anti-apoptotic effect of Specnuezhenide and ecliptasaponin A on CTX-induced POF cells. In conclusion, the key components of Ligustrum lucidum Ait and Ecliptae Herba that alleviate POF are Specnuezhenide and ecliptasaponin A, which improve the condition by upregulating ESR1.
Cardiac fibroblasts (CFs) play roles in the maintenance of myocardial tissue structure. Cellular senescence is a state of stable cell cycle arrest. We previously reported that extracellular vesicles (EV) secreted by doxo...Cardiac fibroblasts (CFs) play roles in the maintenance of myocardial tissue structure. Cellular senescence is a state of stable cell cycle arrest. We previously reported that extracellular vesicles (EV) secreted by doxorubicin (DOX, 1000 nM)-induced senescent CFs (D10-EV) caused autophagy in CFs. EV mediate cell-to-cell communication through the transfer of microRNA (miRNA). In this study, we focused on miRNA contained in EV and aimed to elucidate mechanisms underlying the autophagy induction by D10-EV in CFs. Neonatal rat CFs (NRCFs) were treated with DOX for the induction of cellular senescence. EV were isolated from culture media of NRCFs. miRNA was extracted from the EV and miRNA profiles were analyzed using miRNA-seq. Seven miRNAs were significantly decreased, whereas 14 miRNAs were significantly increased in D10-EV compared with the vehicle-treated NRCFs-derived EV. Among the target genes of 14 miRNAs, Rhebl1 was identified. D10-EV significantly increased microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I and decreased protein expression of Ras homolog enriched in brain like 1 (RHEBL1) in NRCFs. Small interfering RNA against Rhebl1 tended to increase LC3-II/LC3-I. In conclusion, we for the first time revealed that the senescent NRCFs-derived EV induced autophagy in NRCFs via the suppression of RHEBL1 protein.
Mechanical allodynia, the pain caused by innocuous tactile stimuli, is a hallmark symptom of neuropathic pain that is often resistant to currently available treatments. Cannabinoids are widely used for pain management; h...Mechanical allodynia, the pain caused by innocuous tactile stimuli, is a hallmark symptom of neuropathic pain that is often resistant to currently available treatments. Cannabinoids are widely used for pain management; however, their therapeutic mechanisms for neuropathic mechanical allodynia remain unclear. Using transgenic rats that enable to optogenetically stimulate touch-sensing Aβ fibers in the skin, we found that the intrathecal administration of the synthetic cannabinoid, WIN 55,212-2, alleviated the Aβ fiber-derived neuropathic allodynia. Furthermore, we injected adeno-associated virus vectors incorporating the rat cannabinoid receptor 1 (CB receptor) (encoded by Cnr1) promoter and tdTomato or short hairpin RNA targeting the CB receptor into the spinal dorsal horn (SDH) and demonstrated that the conditional knockdown of CB receptors in Cnr1 SDH neurons attenuates the anti-allodynic effects of intrathecally administered WIN 55,212-2. Electrophysiological analysis revealed that Cnr1 SDH neurons received excitatory synaptic inputs from the primary afferent Aβ fibers. Collectively, our results suggest that the CB receptors in Cnr1 SDH neurons are molecular and cellular targets of intrathecal WIN 55,212-2 to alleviate neuropathic allodynia.
Jiawei Kongsheng Zhenzhong Pill(JKZP) is based on Kongsheng Zhenzhong Pill contained in the Tang Dynasty's "Thousand Golden Prescriptions," which exhibited good anti-ischemic and antidepressant effects in the previous st...Jiawei Kongsheng Zhenzhong Pill(JKZP) is based on Kongsheng Zhenzhong Pill contained in the Tang Dynasty's "Thousand Golden Prescriptions," which exhibited good anti-ischemic and antidepressant effects in the previous study. However, its specific effects on post-stroke depression (PSD) and the mechanism are not clear. This study aimed to investigate the effects of JKZP in the treatment of PSD and related mechanisms. The decoction of JKZP was first analyzed for its medicinal chemical composition and screened for representative components of JKZP. The Middle cerebral artery occlusion (MCAO) method combined with solitary rearing and chronic unpredictable mild stress (CUMS) was used to establish a rat model of PSD, and to observe the effects of JKZP on the behavior and synaptic plasticity of PSD rats, and to investigate the mechanism of JKZP in the treatment of PSD by detecting the mRNA level, protein expression and activity of Netrin-1/DCC signaling pathway-related proteins. The results showed that the JKZP decoction contained loganin, β-asarone and other pharmaceutical ingredients, which have been reported to protect against cerebral ischemic injury and antidepressant effects. JKZP significantly improved the depression-like behavior of PSD rats and improved the damage to pyramidal neurons in the medial prefrontal cortex (mPFC) of PSD rats. Moreover, JKZP increased the density of dendritic spines in the mPFC of PSD rats, improved synaptic gap width and thickness of the post-synaptic density, and increased the number of synaptic vesicles. The results of Real-Time quantitative reverse transcription PCR (qRT-PCR), Western blotting, and pull-down assays revealed that JKZP increased netrin-1, deleted in colorectal cancer (DCC), and focal adhesion kinase (FAK) mRNA and protein expression, elevated the p-FAK/FAK ratio, and decreased myosin II protein expression and Ras homolog gene family member A (RhoA-GTP) activity in the mPFC of PSD rats. Taken together, JKZP can affect synaptic structural remodeling and improve depressive manifestations and neuronal damage in PSD rats by regulating the expression and activity of signaling molecules related to the netrin-1/DCC signaling pathway.
Kurozu, a traditional Japanese black vinegar (JBV), is produced from steamed unpolished rice, koji, and water through saccharification, alcoholic fermentation, and acetic fermentation. These processes result in a vinegar...Kurozu, a traditional Japanese black vinegar (JBV), is produced from steamed unpolished rice, koji, and water through saccharification, alcoholic fermentation, and acetic fermentation. These processes result in a vinegar rich in amino acids, vitamins, organic acids, and proteins. While Kurozu has demonstrated benefits, including anti-oxidative and anti-adipogenic activities, its effects on health at the organismal level remain poorly understood. This study aimed to evaluate the impact of Kurozu on healthspan of Caenorhabditis elegans (C. elegans) using the C. elegans Health lifespan Auto-monitoring System (C-HAS). Kurozu concentrated liquid (KCL) was tested at concentrations ranging from 0.005% to 0.5%. Results showed that 0.5% KCL significantly extended lifespan and healthspan, particularly when heat-killed (HK) E. coli OP50 was provided as the food source. In contrast, the lifespan- and healthspan-extending effects at 0.5% KCL were abolished when live E. coli was used as the food source. This suggests that active components in KCL may be metabolized by live bacteria, diminishing their beneficial effects. Further reproducibility tests at 0.5% and 1% KCL concentrations confirmed the healthspan-extending effects under conditions of dead bacterial feeding. This study highlights the health-promoting impact of KCL and provides new insights into its role as a functional food ingredient.
We previously demonstrated that the midnolin gene (MIDN) is a risk factor for Parkinson's disease (PD) in Yamagata and British cohorts, and that neurite outgrowth is abolished by MIDN knockout in PC12 cells. Therefore, d...We previously demonstrated that the midnolin gene (MIDN) is a risk factor for Parkinson's disease (PD) in Yamagata and British cohorts, and that neurite outgrowth is abolished by MIDN knockout in PC12 cells. Therefore, drugs that upregulate MIDN may have neurotrophic effects. In this study, acetylcholine increased MIDN promoter activity and gene expression in a concentration-dependent manner in SH-SY5Y cells. These effects were suppressed by atropine and a G inhibitor, YM254890, indicating that muscarinic receptor/G signaling is required for the induction of MIDN by acetylcholine. Our findings suggest that drugs that upregulate MIDN may have therapeutic potential for PD.
Methylglyoxal (MGO), a highly reactive dicarbonyl compound produced via the glycolytic pathway, plays a key role in the pathogenesis of various diabetic complications, such as diabetic retinopathy. Müller cells provide n...Methylglyoxal (MGO), a highly reactive dicarbonyl compound produced via the glycolytic pathway, plays a key role in the pathogenesis of various diabetic complications, such as diabetic retinopathy. Müller cells provide neurotrophic support and maintain retinal homeostasis, including the redox balance. This dysfunction leads to retinal disease. Yes-associated protein (YAP), a major downstream effector of the Hippo pathway, plays a crucial role in regulating cell survival. In this study, we investigated the roles of Müller cell YAP during MGO-induced retinal injury using normal rats intravitreally injected with MGO and a rat Müller cell line (rMC-1). Immunohistochemistry revealed that MGO injection increased the glial fibrillary acidic protein immunoreactivity in Müller cells. The alignment of Müller cell nuclei was disrupted in MGO-treated retinas. YAP increased and activated in Müller cells two days after MGO injection. This increase in YAP levels was independent of the Hippo pathway and partially attributed to the upregulation of YAP mRNA levels. YAP inhibition by verteporfin exacerbated MGO-induced cell damage and decreased Bcl-xL levels in rMC-1 cells. Intravitreal verteporfin injection also enhanced MGO-induced retinal oxidative stress. Overall, our findings suggest that YAP activation in Müller cells alleviates oxidative stress in the retina following MGO-induced retinal injury.
Retinal drug delivery via peripheral administration enhances the safety and efficacy of retinal pharmacotherapy. As retinal drug distribution from the circulating blood is limited by the blood-retinal barrier (BRB), BRB-...Retinal drug delivery via peripheral administration enhances the safety and efficacy of retinal pharmacotherapy. As retinal drug distribution from the circulating blood is limited by the blood-retinal barrier (BRB), BRB-permeable retinal drugs with potent pharmacological effects are needed for peripheral administration. Our previous research indicated carrier-mediated retinal transport of amantadine, which has neuroprotective effects by inhibiting N-methyl-d-aspartate receptors, across the BRB. As several amantadine derivatives are also suggestive to strongly interact with the carrier-mediated amantadine transport at the BRB, these compounds are proposed as candidates for the treatment of retinal diseases after peripheral administration. To find the appropriate retinal drug candidate, neuroprotective effects of compounds interacting with carrier-mediated amantadine transport across the BRB were firstly evaluated using primary-cultured rat cortical neurons. As a result, N'-(1-adamantyl)ethane-1,2-diamine (test compound) exerted the most potent neuroprotective effects. In addition, this test compound indicated neuroprotective effects against retinal damage after intraperitoneal administration in retinal damage rats. Our findings suggest the test compound, which interacts with carrier-mediated amantadine transport across the BRB and protected neurons from excitotoxicity in vitro, is a key agent to develop the pharmacotherapy with peripheral administration of medicines for retinal diseases.
BACKGROUND: As periodontal disease (PD) is an irreversible disorder, preventive dentistry in human and veterinary medicine has become pertinent. This study focused on persimmon tannin (PT) and examined its bactericidal,...BACKGROUND: As periodontal disease (PD) is an irreversible disorder, preventive dentistry in human and veterinary medicine has become pertinent. This study focused on persimmon tannin (PT) and examined its bactericidal, anti-halitosis, and anti-inflammatory effects by focusing on Porphyromonas gulae (P. gulae). METHODS: The direct effects of PT on P. gulae were evaluated in vitro. Pro-inflammatory cytokines secretion induced by P. gulae in the macrophage cell lines were determined. A clinical study in dogs with P. gulae-associated PD was performed by one-month intraoral treatment with 0.1% PT-containing gel. RESULTS: PT exhibited a significant bactericidal effect to P. gulae. The biofilm formation and methyl mercaptan generated by P. gulae was significantly decreased by PT even after a short exposure period. P. gulae-induced proinflammatory cytokine production in macrophage cell lines was inhibited by PT treatment in a dose-dependent manner. In a clinical study of dogs, intraoral treatment with 0.1% PT did not significantly influence the gingivitis and plaque scores, however, the concentrations of hydrogen sulfide and methyl mercaptan were also significantly decreased by the PT treatment. Although there was no anti-bacterial in vitro, P. gulae activity and DNA detection decreased with PT treatment. CONCLUSIONS: These findings suggest that intraoral administration of PT can prevent PD.
Many studies have reported that adenosine monophosphate-activated protein kinase (AMPK) activators have antidepressant effects. Our previous study suggested that globin digest (GD) activate AMPK in the periphery. However...Many studies have reported that adenosine monophosphate-activated protein kinase (AMPK) activators have antidepressant effects. Our previous study suggested that globin digest (GD) activate AMPK in the periphery. However, the effects of GD on depression remain unclear. Therefore, we examined whether GD has an antidepressant effect in lipopolysaccharide (LPS)-treated mice. LPS-treated mice showed depression-like behavior in the tail-suspension test and reduced hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) expression levels; these changes were prevented by GD. Furthermore, GD enhanced AMPK phosphorylation in the dorsal hippocampus of LPS-treated mice. These findings indicate that GD may produce antidepressant effects via hippocampal AMPK/BDNF signaling.
Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity. ADHD symptoms not only impact patients and their families but also impose soc...Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity. ADHD symptoms not only impact patients and their families but also impose societal costs. Current treatments for ADHD, including environmental adjustments and medication, are symptomatic and require long-term management. Recently, the link between gut microbiota dysbiosis and various psychiatric and neurological disorders has become evident. The effectiveness of fecal microbiota transplantation (FMT) from healthy individuals in treating autism spectrum disorder, a neurodevelopmental disorder related to ADHD, has been demonstrated. However, despite suggestions of a relationship between ADHD and gut microbiota, few studies have explored the efficacy of FMT for ADHD. In the current study, we used 16S rDNA analysis to show that ADHD-like model rats possess a gut microbiota that is distinct from that of healthy rats, and we demonstrated that FMT from healthy rats improved hyperactivity in ADHD-like model rats. Our findings suggest that differences in gut microbiota underlie ADHD-like behaviors and that FMT may be an effective treatment for ADHD.
Depression is a pervasive mental disorder that poses a significant threat to human health globally. Asperuloside (ASP), an iridoid glycoside extracted from Herba Paederiae, exhibits a range of pharmacological activities,...Depression is a pervasive mental disorder that poses a significant threat to human health globally. Asperuloside (ASP), an iridoid glycoside extracted from Herba Paederiae, exhibits a range of pharmacological activities, including anti-tumor and anti-inflammatory effects. This study aims to explore the function and molecular mechanisms of ASP in alleviating depression. Chronic unpredictable mild stress (CUMS) was employed to establish a rat model of depression. Behavioral tests were conducted to evaluate the antidepressant effects of ASP. Apoptosis in hippocampal tissues was assessed using TUNEL assay. Primary hippocampal neuron apoptosis was assessed using Annexin V/PI staining and flow cytometry, while cell death was detected via PI staining. The expression levels of target mRNAs and proteins were analyzed by quantitative PCR (qPCR) and western blotting, respectively. Additionally, the levels of O-GlcNAcylation and ubiquitination were determined by western blot analysis following immunoprecipitation. Molecular docking was performed to elucidate the interaction mode between ASP and its target protein, O-linked β-N-acetylglucosamine transferase (OGT). Our findings revealed that ASP treatment significantly ameliorated depression-like behaviors and cognitive dysfunction, as well as inhibited hippocampus apoptosis in CUMS-induced rats, Moreover, ASP inhibited LPS-induced neuronal cell apoptosis and suppressed the activation of the NF-κB signaling pathway. Mechanistically, we demonstrated that ASP promoted O-GlcNAcylation of IκBα, and suppressed its ubiquitination and phosphorylation, thereby stabilizing IκBα protein. In conclusion, ASP exerts antidepressant effects by enhancing IκBα O-GlcNAcylation, thus inhibiting its ubiquitination and phosphorylation. These findings provide a novel therapeutic target for the treatment of depression.
Stress triggers disorders in accelerated peristalsis, with corticotropin releasing factor receptor 1 (CRF-R1) playing a pivotal role. Enteric glia cells (EGCs) and glial Cx43 are known to influence gastrointestinal motil...Stress triggers disorders in accelerated peristalsis, with corticotropin releasing factor receptor 1 (CRF-R1) playing a pivotal role. Enteric glia cells (EGCs) and glial Cx43 are known to influence gastrointestinal motility, yet their involvement in colonic motor responses to stress remains unclear. Using immunofluorescence and single-cell RNA sequencing data, we identified CRF-R1 expression in EGCs. Male C57BL/6 mice subjected to wrap restraint stress (WRS) revealed stress-induced colonic motility changes. By employing Fluoroacetate, NBI 27914, and Gap26, we elucidated the impact of glial CRF-R1/Cx43 on stress-induced colonic motor responses. Our study demonstrated CRF-R1 expression in EGCs of the small intestine and colon, along with elevated CRF levels and upregulated CRF-R1 in the distal colon under stress. Antagonizing CRF-R1 and disrupting EGC function made mice resistant to colonic stress responses. Mechanistically, increased glial Cx43 expression and activity influenced colonic motor responses in a CRF-R1-dependent manner. Our findings highlight the role of EGC-derived CRF-R1 in stress-induced colonic motor responses via Cx43 activation. Targeting CRF-R1/Cx43 signaling in EGCs may offer a promising approach to mitigate stress-induced colonic transit changes.