Despite the recognized roles of neuroinflammation in mental illnesses, PET imaging on currently available biomarkers has limitations due to the lack of evidence demonstrating their relationship to the molecular and cellu...Despite the recognized roles of neuroinflammation in mental illnesses, PET imaging on currently available biomarkers has limitations due to the lack of evidence demonstrating their relationship to the molecular and cellular events of inflammation associated with the pathology of mental illness. Rodent stress models, such as chronic social defeat stress (SDS), have identified crucial roles for COX-1 and TLR4, which are innate immune molecules, in chronic SDS-induced neuroinflammation and its behavioral consequences. In this study, we performed COX-1 and TLR4 PET imaging at multiple time points during chronic SDS in mice. For COX-1 PET imaging, we used the COX-1 PET probe (S)-[F]KTP-Me. Subchronic SDS transiently increased uptake and slower washout in broad regions of the brain, including the cerebral cortex, hippocampus, striatum, and thalamus. For TLR4 PET imaging, we developed a new BBB-permeable PET probe, [C]1, which detected LPS-induced neuroinflammation. Washout of [C]1 was facilitated in the cerebellum after subchronic and chronic SDS and in the pons-medulla after chronic SDS. Collectively, our findings suggest the potential usefulness of COX-1 and TLR4 PET imaging in visualizing and understanding time-dependent process of neuroinflammation in stress-related mental illnesses.
Vascular endothelial cell-expressing molecules regulate neuronal function. Although cerebrovascular dysregulation is a hallmark of Alzheimer's disease (AD), the effect of changes in molecular expression on neuronal funct...Vascular endothelial cell-expressing molecules regulate neuronal function. Although cerebrovascular dysregulation is a hallmark of Alzheimer's disease (AD), the effect of changes in molecular expression on neuronal function in vascular endothelial cells during disease progression is not clear. In this study, we demonstrated that the cellular communication network factor 1 (CCN1), which is highly expressed in vascular endothelial cells during the chronic stage of AD in mice, is involved in the impairment of cognitive function. Vascular endothelial cells isolated from the brains of App mice show differential expression of genes, including CCN1. CCN1 treatment decreased the synaptic number in cultured hippocampal cells, with changes in the expression of genes associated with morphological changes. In vivo, App mice with CCN1 silencing in vascular endothelial cells demonstrated high spine density and improved spatial learning. No significant change was observed in the number of microglia/macrophages, astrocytes, and amyloid-beta (Aβ) accumulation in the hippocampus of the mice. These results suggest that CCN1 is a key factor modulating neurological dysfunction through neurovascular interactions.
Glutamatergic system dysfunction is associated with the pathophysiology of stress-related psychiatric disorders. However, the role of N-methyl-D-aspartate (NMDA) receptor GluN2C and GluN2D subunits in the pathophysiology...Glutamatergic system dysfunction is associated with the pathophysiology of stress-related psychiatric disorders. However, the role of N-methyl-D-aspartate (NMDA) receptor GluN2C and GluN2D subunits in the pathophysiology of adverse juvenile experiences remain unclear. This study aimed to investigate the involvement of GluN2C and GluN2D subunits in social behavior impairments in mice exposed to social defeat stress as juveniles. Acute administration of PPDA, a GluN2C/GluN2D antagonist, and ketamine, a non-competitive NMDA receptor antagonist, attenuated social behavior impairments in stressed mice. This attenuating effect of ketamine was partially inhibited by the administration of CIQ, a GluN2C/GluN2D-containing NMDA potentiator. The prefrontal cortex of stressed mice exhibited significantly elevated levels of GluN2C and GluN2D proteins compared to control mice. These findings suggest that activation of GluN2C- and/or GluN2D-containing NMDA receptors contributes to the development of social behavioral impairments induced by juvenile social defeat stress. Moreover, these subunits may play a role in the therapeutic effects of ketamine. Targeting GluN2C/GluN2D subunits of NMDA receptors may be novel therapeutic strategies for stress-related psychiatric disorders in adolescents with adverse juvenile experiences.
Erythropoiesis-stimulating agents (ESAs) increase hemoglobin mass and maximal oxygen uptake; however, it remains unclear whether the abuse of ESAs enhances exercise performance. Therefore, we herein investigated the effe...Erythropoiesis-stimulating agents (ESAs) increase hemoglobin mass and maximal oxygen uptake; however, it remains unclear whether the abuse of ESAs enhances exercise performance. Therefore, we herein investigated the effects of darbepoetin alfa (DPO), a long-acting erythropoietin analog, on exercise performance in trained male and female mice. Exercise performance was assessed as the number of arrivals at the halfway line of a flow rate-adjustable swimming pool. The DPO treatment significantly increased hematocrit levels regardless of sex, but only enhanced exercise performance in female mice. The sex-specific effect of DPO on exercise performance was not abolished by ovariectomy; the enhancing effect was more pronounced in ovariectomized (OVX) mice than in female mice. This effect of the DPO treatment was attributed to a significant increase in the gene expression of PGC-1alpha in the gastrocnemius (GASTR) muscle of OVX mice, but not female mice. In addition, myocyte hypertrophy, but not angiogenesis, was observed in the GASTR muscle of DPO-treated OVX mice. These results revealed the sex-specific enhancing effect of DPO on exercise performance in trained mice. Enhanced exercise performance did not appear to require female sex hormones and may not be due to direct effects on skeletal muscles.
Cytotoxic effects of cigarette smoke are thought to be causes of cigarette smoking-related diseases such as respiratory infection, chronic obstructive pulmonary disease, and atherosclerosis. Unsaturated carbonyl compound...Cytotoxic effects of cigarette smoke are thought to be causes of cigarette smoking-related diseases such as respiratory infection, chronic obstructive pulmonary disease, and atherosclerosis. Unsaturated carbonyl compounds are major cytotoxic factors in the gas phase of cigarette smoke. Cell death induced by unsaturated carbonyl compounds in cigarette smoke is PKC-dependent ferroptosis. Although the cell sensitivity to unsaturated carbonyl compounds varies by cell types, the molecular mechanisms underlying this sensitivity remain unclear. In this study, we have examined the factors involved in determining sensitivity to unsaturated carbonyl compounds. We found that two mouse macrophage cell lines exhibited different sensitivities; J774.1 macrophages were sensitive to unsaturated carbonyl compounds, whereas RAW264.7 macrophages were resistant. Glutathione synthesis inhibitor increased the sensitivity of RAW264.7 macrophages to unsaturated carbonyl compounds. Quantitative RT-PCR revealed that the expression level of the cystine transporter SLC7A11 was higher in RAW264.7 macrophages than in J774.1 macrophages. Inhibition of SLC7A11 activity increased sensitivity to unsaturated carbonyl compounds, while overexpression of SLC7A11 enhances resistance to these compounds. The current results suggest that the SLC7A11 level is a key factor in determining the macrophage sensitivity to unsaturated carbonyl compounds.
Shimada T, Iwahashi T, Suzuki K
… +11 more, Kasuya T, Yoshimura Y, Konishi K, Kamata A, Konishi M, Miyamura S, Shiode R, Kazui A, Oka K, Okada S, Tanaka H
Chronic nerve compression disorders, such as carpal tunnel syndrome, are common and can significantly impair daily activities due to motor and sensory dysfunctions. Currently, no systemic pharmacotherapy exists for preve...Chronic nerve compression disorders, such as carpal tunnel syndrome, are common and can significantly impair daily activities due to motor and sensory dysfunctions. Currently, no systemic pharmacotherapy exists for preventing or treating disease progression. This study aims to investigate whether Neurotropin®, an established analgesic, has therapeutic effects. A chronic nerve compression model was created by wrapping a silicone tube around the sciatic nerve in C57BL/6 mice. Nerves were evaluated electrophysiologically and histologically 2 weeks post-surgery. To confirm the preventive effect on disease onset, we administered Neurotropin® subcutaneously. Additionally, continuous subcutaneous administration of Neurotropin® was started 2 weeks post-surgery, and the therapeutic effects were evaluated at 4 and 8 weeks. Furthermore, the therapeutic effects of daily oral administration of Neurotropin®, starting 2 weeks post-surgery, were evaluated at 8 weeks. Significant decreases in nerve conduction velocity and axonal myelination were observed at 2 weeks post-injury. Neurotropin® administration initiated concurrently with model creation did not prevent disease onset at 2 weeks post-surgery. However, starting administration of Neurotropin® 2 weeks post-injury significantly improved outcomes at 8 weeks post-surgery compared to the control group, with continuous subcutaneous and daily oral administration. Neurotropin® may exhibit therapeutic effects for chronic nerve compression disorders.
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease, and neuroprotection is an important approach to improving AD outcomes. Rhizoma of Anemarrhena asphodeloides (RAA) is a commonly used Traditional Chines...BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease, and neuroprotection is an important approach to improving AD outcomes. Rhizoma of Anemarrhena asphodeloides (RAA) is a commonly used Traditional Chinese Medicine (TCM) with demonstrated neuroprotective effects, but its anti-AD mechanism requires further exploration. AIM OF THE STUDY: To elucidate the neuroprotective mechanism of RAA on TMT-induced AD mice. MATERIALS AND METHODS: The AD mice model was established via intraperitoneal injection of TMT. The effect of RAA on ameliorating learning and memory was assessed using the Morris Water Maze (MWM) and Y-maze tests. Haematoxylin-Eosin (HE), Nissl, and TUNEL staining were used to observe the neuroprotective effect of RAA. The components in serum containing RAA (RAA-S) were detected using UPLC-Q-Orbitrap MS. Potential targets were predicted through network pharmacology and molecular docking. Serum levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GPx) were measured with ELISA kits. The HT22 hippocampal neuronal cell line injured by l-glutamate (L-Glu) was used to further elucidate the mechanism of RAA. ROS levels in HT22 cells were detected with the 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe and flow cytometry. Apoptosis in HT22 cells was measured by flow cytometry. The proteins MAP2, GAP-43, Nrf2, Keap1, HO-1, Bax, and Bcl-2 were detected by Western blotting. Immunofluorescence staining was employed to observe Nrf2 nuclear translocation. RESULTS: RAA significantly increased the residence time of mice in the W zone and enhanced the correct alternation rate in TMT-treated mice. RAA preserved the integrity and orderly arrangement of nerve cells. A total of 12 components were detected in RAA-S. AKT1, PPARG, CASP3, STAT3, HSP90AA1, and NFE2L2 (Nrf2) were involved in the RAA-S target pathway network. Molecular docking revealed that Nrf2 exhibited the highest average binding energy with all components in RAA-S. In vivo, RAA elevated MAP2, GAP-43, Nrf2, and HO-1 levels, along with GPx, GSH, and SOD activity, which had been reduced by TMT. Additionally, RAA reduced serum levels of MDA and ROS, which had been elevated by TMT. In vitro, RAA-S reduced HT22 cell apoptosis and ROS accumulation caused by TMT. Furthermore, RAA-S promoted the expression of N-Nrf2 and HO-1 in L-Glu-injured HT22 cells. CONCLUSION: RAA attenuated oxidative stress induced by TMT and L-Glu in AD model mice. The underlying mechanism was associated with the activation of the Nrf2/Keap1-HO-1 pathway.
The purpose of the present study is to investigate changes in the kynurenine pathway after intracerebral hemorrhage (ICH) and its effects on ICH-induced injury. The exposure of a primary rat microglial culture to thrombi...The purpose of the present study is to investigate changes in the kynurenine pathway after intracerebral hemorrhage (ICH) and its effects on ICH-induced injury. The exposure of a primary rat microglial culture to thrombin increased the mRNA level of kynurenine 3-monooxygenase (KMO), and this increase was attenuated by a p38 MAPK inhibitor. Thrombin also increased the protein level of KMO. In the cultured medium, the ratio of quinolinic acid (QUIN), an N-methyl-d-aspartate receptor (NMDAR) agonist, to kynurenic acid (KYNA), its antagonist, increased. The increase in the QUIN/KYNA ratio was blocked by Ro61-8048, a KMO inhibitor. The mRNA expression of KMO increased in an in vivo murine ICH model. Immunohistochemical staining showed that increased KMO co-localized with neurons, microglia, and astrocytes. The QUIN/KYNA ratio increased after ICH but was blocked by Ro61-8048 or clodronate, a microglia toxin. Ro61-8048 ameliorated brain edema; however, this effect was masked by MK-801, an NMDAR antagonist. Ro61-8048 protected against neuron loss in the perihematomal region and repaired neurological deficits assessed using the corner turn and pole tests. In conclusion, thrombin-induced changes in KMO in microglia mainly and intermediary metabolites of the kynurenine pathway appear to play crucial roles in neuronal injury after ICH.
Diabetic retinopathy (DR) is the leading cause of blindness among working-age adults, and inflammation and oxidative stress contribute to DR development. However, no effective treatments are currently approved for DR. Th...Diabetic retinopathy (DR) is the leading cause of blindness among working-age adults, and inflammation and oxidative stress contribute to DR development. However, no effective treatments are currently approved for DR. Therefore, this study aimed to investigate the effects of SMTP-44D-a Stachybotrys microspora-derived compound with anti-inflammatory and antioxidant properties-on DR in in vivo and in vitro models. Diabetes was induced in rats using 60 mg/kg streptozocin, followed by treatment with SMTP-44D every second day. Retinal function was assessed using electroretinography every 2 months for 8 months. SMTP-44D prevented diabetes-induced b-wave amplitude reductions in electroretinogram and decreased retinal ganglion cell apoptosis. SMTP-44D also reduced the accumulation of advanced glycation end-products (AGEs), AGE receptors, and 8-hydroxydeoxyguanosine in the retina. Furthermore, when rat retinal Müller cells were cultured in DMEM medium containing 35 mM glucose (high glucose, HG) and treated with SMTP-44D for 24 h, SMTP-44D mitigated cell death, reactive oxygen species production, and inflammatory cytokine levels in the cells. These findings suggest that SMTP-44D exhibits significant antioxidant and anti-inflammatory effects, highlighting its potential as a therapeutic candidate for DR.
BACKGROUND: Renal tubular injury (RTI) is one of the key characteristics of diabetic nephropathy (DN). Penehyclidine hydrochloride (PHC) was an anticholinergic drug with renoprotective effects, but its specific mechanism...BACKGROUND: Renal tubular injury (RTI) is one of the key characteristics of diabetic nephropathy (DN). Penehyclidine hydrochloride (PHC) was an anticholinergic drug with renoprotective effects, but its specific mechanism in the treatment of DN was still unclear. METHODS: We treated different diabetic mouse models and high glucose-induced RTI models by PHC. Histological analyses were performed using flow cytometry and staining, and ELISA evaluated the ROS, apoptosis, and related markers under different treatments. The molecular interactions were analyzed by ChIP, dual-luciferase reporter, and CoIP. RESULTS: PHC alleviated RTI by activating mitophagy and inhibiting apoptosis, and the protective effect could be rescued by PARK2 knockdown. Nrf2 bound to the promoter region of PARK2 and promoted its expression. PHC reduced the level of apoptosis by reducing the degree of nuclear translocation of AIFM1, which was rescued by PARK2 knockdown. PARK2 knockdown reduced the non-degradative ubiquitination of AIFM1, thus promoting its nuclear translocation and ultimately facilitating renal tubular cells (RTCs) apoptosis. The over-expression of AIFM1 rescued the RTCs apoptosis antagonized by PHC. CONCLUSIONS: PHC activated Nrf2 to up-regulate PARK2 transcription to induce mitophagy and inhibit apoptosis mediated by nuclear translocation of AIFM1 through promoting non-degradative ubiquitination of AIFM1, ultimately rescuing RTI in DN.
Aging affects emotional, cognitive, and social functions, increasing susceptibility to neuropsychiatric conditions. C57BL/6 mice are commonly used to study aging mechanisms, yet differences between C57BL/6J and C57BL/6N...Aging affects emotional, cognitive, and social functions, increasing susceptibility to neuropsychiatric conditions. C57BL/6 mice are commonly used to study aging mechanisms, yet differences between C57BL/6J and C57BL/6N substrains remain underexplored. This study compared aging-related behavioral changes in these substrains. Aging reduced exploratory activity and heightened anxiety in C57BL/6J, but not C57BL/6N, mice. Conversely, aging reduced social novelty preference in C57BL/6N, but not C57BL/6J, mice. Male mice of both substrains exhibited increased female urine sniffing with age. These findings highlight substrain-specific aging effects, underscoring the importance of substrain selection in behavioral studies of aged mice for drug development.
Major depressive disorder (MDD) is among the most common mental disorders worldwide and is characterized by dysregulated reward processing associated with anhedonia. Selective serotonin reuptake inhibitors (SSRIs) are th...Major depressive disorder (MDD) is among the most common mental disorders worldwide and is characterized by dysregulated reward processing associated with anhedonia. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for MDD; however, their onset of action is delayed. Recent reports have shown that serotonin neurons in the dorsal raphe nucleus (DRN) are activated by rewards and play a vital role in reward processing. However, whether antidepressant treatment affects the DRN serotonin neuronal response to rewards in awake animals remains unknown. In this study, we measured the activity of DRN serotonin neurons in awake mice and determined the effects of antidepressants and chronic stress on DRN serotonin neuronal activity. We found that acute treatment with citalopram, an SSRI, significantly decreased sucrose-induced activation of DRN serotonin neurons. The decrease in response to acute citalopram treatment was attenuated by chronic citalopram treatment. Acute treatment with (S)-WAY100135, a 5-HT receptor antagonist, dose-dependently inhibited the response to acute citalopram treatment. These results indicate that autoinhibition by activating 5-HT receptors via acute SSRI treatment may blunt the reward response, which can be recovered after chronic SSRI treatment.
BACKGROUND: The global increase in diabetes, driven by aging populations and lifestyle changes, has led to an increase in the incidence of diabetic cardiomyopathy (DCM). DCM is characterized by metabolic abnormalities, o...BACKGROUND: The global increase in diabetes, driven by aging populations and lifestyle changes, has led to an increase in the incidence of diabetic cardiomyopathy (DCM). DCM is characterized by metabolic abnormalities, oxidative stress, and inflammation, leading to cardiac remodeling and dysfunction. Goreisan (GRS), a traditional Japanese Kampo medicine, is commonly used to treat fluid control such as edema, due to its diuretic effect. In this study, we examined the effects of GRS on DCM. METHODS: We first established a new mouse model of DCM and then evaluated the effects of GRS on DCM using a recently developed model. RESULTS: The DCM mouse model developed cardiac hypertrophy, fibrosis, and dysfunction by nine weeks, which was ameliorated by GRS administration. GRS suppressed apoptosis and protein degradation by inhibiting Akt dephosphorylation and oxidative stress in DCM mice. In contrast, no differences in inflammatory cytokine levels were observed, regardless of GRS administration. CONCLUSION: GRS has potential efficacy in preventing DCM onset and development.
Paclitaxel induces peripheral neuropathy, which is considered a dose-limiting factor. However, appropriate prophylactic agents are currently unavailable. We investigated the prophylactic effects of calmangafodipir, a sup...Paclitaxel induces peripheral neuropathy, which is considered a dose-limiting factor. However, appropriate prophylactic agents are currently unavailable. We investigated the prophylactic effects of calmangafodipir, a superoxide dismutase mimetic, on paclitaxel-induced peripheral neuropathy using a male rat model. Repeated administration of paclitaxel (6 mg/kg, intraperitoneal, once weekly for 4 weeks) resulted in mechanical allodynia in the von Frey test and axonal degeneration in the sciatic nerve. Conversely, calmangafodipir (1-10 mg/kg, intravenous, thrice weekly for 4 weeks) prevented mechanical allodynia and axonal degeneration induced by paclitaxel. These results suggest that calmangafodipir may inhibit paclitaxel-induced peripheral neuropathy.
Pulmonary hypertension (PH) is a progressive disease with a poor prognosis in which high pulmonary artery pressure leads to right heart failure, therefore, there is an urgent need to elucidate pathological mechanisms and...Pulmonary hypertension (PH) is a progressive disease with a poor prognosis in which high pulmonary artery pressure leads to right heart failure, therefore, there is an urgent need to elucidate pathological mechanisms and to develop new treatment for PH. Minocycline has not only antibacterial effects but also anti-inflammatory effects in various tissues. We hypothesize that minocycline could prevent PH development in rats. PH was induced by a single intraperitoneal injection of monocrotaline (MCT, 60 mg/kg), and minocycline (20 mg/kg) was treated daily for 14 days from the day of MCT injection. Minocycline inhibited the rise in mean pulmonary arterial pressure of MCT-induced PH rats and improved the attenuation of acetylcholine-induced relaxation in isolated intrapulmonary artery from MCT-induced PH rats. Minocycline further inhibited vascular wall thickening of pulmonary arterioles and showed a tendency to inhibit the muscularization of pulmonary arterioles in MCT-induced PH rats. PH-preventing effect of minocycline does not seem to be mediated via the actions on matrix metalloproteinase, inflammatory cytokines, and mast cells migration in lung. In summary, we revealed for the first time that minocycline ameliorated the MCT-induced PH in rats, at least partly through preventing pulmonary artery endothelial dysfunction and wall thickening.
We investigated whether an anti-inflammatory lipid metabolite named 5,6-DiHETE reduces vascular permeability by inhibiting TRPV4 channels in vivo. In wild-type (WT) mice, histamine-induced dye extravasation was reduced b...We investigated whether an anti-inflammatory lipid metabolite named 5,6-DiHETE reduces vascular permeability by inhibiting TRPV4 channels in vivo. In wild-type (WT) mice, histamine-induced dye extravasation was reduced by pre-administration of 5,6-DiHETE. In TRPV4-deficient mice, extravasation and histamine-induced edema were already reduced, and 5,6-DiHETE had no additional effect. In isolated WT aortas, 5,6-DiHETE attenuated acetylcholine-induced relaxation, but this effect was absent in TRPV4-deficient aortas. These findings suggest that 5,6-DiHETE reduces vascular permeability by inhibiting TRPV4 activity.
The processes of autophagy, including autophagosome formation, fusion of autophagosomes with lysosomes, and degradation of autophagosomes by lysosomes, are regulated by various mechanisms. We recently found that treatmen...The processes of autophagy, including autophagosome formation, fusion of autophagosomes with lysosomes, and degradation of autophagosomes by lysosomes, are regulated by various mechanisms. We recently found that treatment with resveratrol, an activator of the NAD-dependent protein deacetylase Sirtuin-1 (SIRT1), in a mouse model prevented autophagosome accumulation in the heart with high mTORC1 activity. In this study, we investigated whether SIRT1 mediates the effects of resveratrol on autophagosome elimination using a cardiomyocyte model. In H9c2 cardiomyocytes, treatment with the mTORC1 activator MHY1485 induced autophagosome accumulation accompanied by increases in fragmented mitochondria within the autophagosomes and levels of intracellular reactive oxygen species (ROS), indicative of impaired autophagy-mediated elimination of mitochondria and resultant oxidative stress. MHY1485 suppressed the fusion of autophagosomes with lysosomes. Co-treatment with resveratrol attenuated the MHY1485-induced increases in autophagosomes, mitochondria within autophagosomes, and levels of ROS. Knockdown of Sirt1 reversed the reductions in autophagosomes and ROS levels induced by resveratrol under the condition of MHY1485 treatment. Neither resveratrol treatment nor Sirt1 knockdown modulated the phosphorylation levels of UVRAG, a target of mTORC1 for suppression of autophagosome-lysosome fusion. Our findings suggest that SIRT1 mediates the resveratrol-induced promotion of autophagosome elimination in cells with high mTORC1 activity.
Elevated reactive species and AGEs contribute to deregulation of transcription factors e.g., NF-κB and Nrf2 in diabetic peripheral neuropathy (DPN). Okanin, a bioactive chalcone, is active against redox imbalance, immune...Elevated reactive species and AGEs contribute to deregulation of transcription factors e.g., NF-κB and Nrf2 in diabetic peripheral neuropathy (DPN). Okanin, a bioactive chalcone, is active against redox imbalance, immune response, and pro-inflammatory events. The current investigation assessed effects of okanin in streptozotocin-induced DPN in rats. Wistar rats were divided into 6 groups (n = 6): Control, DPN, Okanin 2.5, Okanin 5, Okanin 10, and Gpn (Gabapentin). After 6 weeks of streptozotocin (55 mg/kg) injection, okanin (2.5, 5, 10 mg/kg), and gabapentin (50 mg/kg), were administered for 4 weeks. The streptozotocin-induced reduction in body weight, and increased feed/water intake, insulin, glucose, and HbA1c levels were mitigated by okanin or gabapentin. In DPN rats, Okanin or gabapentin ameliorated insulin resistance and β-cell function, inflammatory indices, and oxidative stress in the sciatic nerve of rodents thereby culminating in a decrease in hyperalgesia and allodynia. Okanin and streptozotocin-treated rats had significantly declined levels of AGEs, the receptor for AGEs, and NF-κB, and an upsurge in Nrf2 expression. In streptozotocin-induced DPN model, okanin ameliorates nociceptive-like responses by regulating the AGEs/NF-κB/Nrf2 pathway, suggesting that okanin has therapeutic value against DPN which needs further studies involving human subjects.
Nitric oxide (NO)-donor drugs, which stimulate reduced form of soluble guanylate cyclase (sGC), have different efficacy to the arteries and veins. This study examined whether sGC activators, which activate oxidized/apo s...Nitric oxide (NO)-donor drugs, which stimulate reduced form of soluble guanylate cyclase (sGC), have different efficacy to the arteries and veins. This study examined whether sGC activators, which activate oxidized/apo sGC, also have arteriovenous selectivity similar to that of NO-donor drugs. The mechanical responses of the isolated blood vessels were assessed using the organ chamber technique and protein expression was verified using western blotting. BAY 60-2770 (sGC activator) caused concentration-dependent relaxation in both porcine coronary arteries and veins, with the response being slightly more pronounced in the arteries. In contrast, sodium nitroprusside (NO-donor drug)-induced relaxation of the arteries was slightly weaker than that of the veins. Vasorelaxant responses to 8-Br-cGMP (cGMP analog) did not differ between the arteries and veins. In the presence of ODQ (heme oxidant), the heterogeneities in the responses to BAY 60-2770 and sodium nitroprusside between the arteries and veins disappeared. The sGC expression in the arteries did not differ from that in the veins. These findings suggest that sGC activators, in contrast to NO-donor drugs, have greater effects on the arteries than on the veins. This may be due to differences in the balance of sGC forms expressed in the arteries and veins.
Glucocorticoid-induced osteoporosis (GIOP) is a widespread disease characterized by low bone density. There remains a lack of effective means for osteoporosis. Rehmannioside A (ReA), an iridoid glycoside, exhibits variou...Glucocorticoid-induced osteoporosis (GIOP) is a widespread disease characterized by low bone density. There remains a lack of effective means for osteoporosis. Rehmannioside A (ReA), an iridoid glycoside, exhibits various pharmacological activities. This study aimed to explore the role and mechanism of ReA in osteogenic differentiation of osteoblasts. Cell viability, reactive oxygen species (ROS) generation, and cell apoptosis were assessed using corresponding assay kits. Real-time quantitative polymerase chain reaction, Western blotting, and alkaline phosphatase (ALP) staining were performed to evaluate the osteogenic differentiation of MC3T3-E1 cells. Alizarin red S staining was used to assess the mineralization of MC3T3-E1 cells. Protein expression associated with the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway was analyzed using Western blotting. Micro-computed tomography, histopathological, and immunohistochemical analyses were performed to determine the therapeutic effect of ReA on GIOP in vivo.The results showed that ReA promoted the osteogenic differentiation of MC3T3-E1 cells by regulating the PI3K/AKT signaling pathway and protected mice against glucocorticoid-induced bone loss by promoting osteoblast-mediated bone formation in vivo. The findings of the current study revealed that ReA is a potential therapeutic agent for osteoporosis.