PURPOSE: Nerol, a natural monoterpene, is commonly used as a fragrance additive in perfumes and cosmetics due to its pleasant rose-like aromas. Nerol application possesses diverse pharmacological properties, including an...PURPOSE: Nerol, a natural monoterpene, is commonly used as a fragrance additive in perfumes and cosmetics due to its pleasant rose-like aromas. Nerol application possesses diverse pharmacological properties, including anti-microbial, antioxidant, antinociceptive and anti-inflammatory activities, but its effects on sebum production and the consequent skin barrier function remain elusive. Here, we explored the effect of nerol on the lipogenesis of sebocytes. PATIENTS AND METHODS: Immortalized human SZ95 sebocytes were used. The intracellular lipids were quantitatively measured by western blotting or fluorescent Nile Red staining followed by fluorometric analysis, semiquantitative detection or flow cytometry. The cell proliferation and differentiation were detected with CCK8 and flow cytometry, respectively. Moreover, RT-qPCR and immunocytochemistry were used to determine the expression levels of olfactory receptor OR2W3 and cannabinoid receptor-2 (CB2) receptors in SZ95 sebocytes.The mechanism was investigated by RNA interference and Western blotting. RESULTS: Our findings revealed that nerol induced lipid production in SZ95 sebocytes, together with the upregulation of multiple genes related to lipid synthesis, including PPARγ, SREBP-1, and FAS. Nerol also induced sebocyte differentiation, as evidenced by elevated cellular granulation and upregulated differentiation marker genes. Mechanistically, the lipogenic effect of nerol was mediated via CB2, rather than OR2W3 and TRP channels. Moreover, MAPK signaling was involved in neurol's effect. CONCLUSION: Collectively, our findings show that nerol exerts a lipogenic effect on human sebocytes in a CB2-dependent manner through the activation of MAPK pathway, suggesting the therapeutic potential of this monoterpene in controlling cutaneous disorders involving sebaceous gland dysfunction and reduced sebum production, such as atopic dermatitis, skin dryness and aging.
Neuromyelitis optica spectrum disorder (NMOSD) is characterized by the production of autoantibodies against aquaporin 4 (AQP4). Because NMOSD progressively causes irreversible and severe neurological damages, understandi...Neuromyelitis optica spectrum disorder (NMOSD) is characterized by the production of autoantibodies against aquaporin 4 (AQP4). Because NMOSD progressively causes irreversible and severe neurological damages, understanding the initial molecular changes induced by anti-AQP4 antibody binding is crucial for designing early interventions. However, knowledge about the effects of the antibodies before AQP4 loss in brain tissues is limited. Using acutely prepared mouse brain slices, we aimed to investigate the initial molecular impact of NMO model antibodies on AQP4 and its associated proteins. We employed two different types of NMO model antibodies, E5415A and E5415B; E5415A recognizes both M1 and M23 isoforms, whereas E5415B exclusively binds to M23. We found that E5415A but not E5415B disrupted the uniform perivascular localization of AQP4, leading to fragmentation. We further addressed the impact of these changes on AQP4-associated proteins and found that strong colocalizations between AQP4 and dystrophin-glycoprotein complex (DGC) components were preserved, even after AQP4 localization pattern became fragmented. Thus, our study reveals the initial molecular changes in the AQP4 channel at the astrocytic endfeet in response to NMO model antibodies and highlights the early pathological events occurring in NMOSD.
Celecoxib, a non-steroidal anti-inflammatory drug, is widely used in the clinic for its analgesic and anti-inflammatory effects by inhibiting COX-2. Celecoxib also modulates many ion channels including Nav1.5, Kv7 and Kv...Celecoxib, a non-steroidal anti-inflammatory drug, is widely used in the clinic for its analgesic and anti-inflammatory effects by inhibiting COX-2. Celecoxib also modulates many ion channels including Nav1.5, Kv7 and Kv2.1 channels. Here we show a novel role of celecoxib in inhibiting calcium-activated chloride channel ANO1 that is involved in pain sensation. Celecoxib results in a concentration-dependent inhibition of ANO1 current with an IC value of 20.3 ± 1.9 μM, and the residue P701 in the S7 is important for celecoxib-mediated ANO1 inhibition. These results suggest that ANO1 inhibition may contribute to celecoxib's analgesic and anti-inflammatory effects.
Spinal cord injury (SCI) commonly leads to loss of motor and sensory function and results in huge socioeconomic burden, and it triggers numerous secondary pathological events, including oxidative stress and ferroptosis....Spinal cord injury (SCI) commonly leads to loss of motor and sensory function and results in huge socioeconomic burden, and it triggers numerous secondary pathological events, including oxidative stress and ferroptosis. This study investigates the therapeutic potential of Ginkgolide B (GB), a neuroprotective compound derived from Ginkgo biloba, in mitigating SCI by targeting on ferroptosis. By using Erastin-induced ferroptosis in PC12 cells and a rat contusion SCI model, the present study demonstrated that GB significantly improved locomotor recovery, reduced neuronal loss, and attenuated histopathological damage. Mechanistically, GB suppressed ferroptosis markers, including elevated iron content, lipid peroxidation, and ACSL4, while restoring the expression of GPX4 and xCT. Crucially, GB enhanced nuclear translocation of Nrf2, upregulating downstream antioxidants and ferroptosis-related genes (HO-1 and NQO1). Notably, the functions of GB were abolished after utilization of Nrf2 signaling inhibitor ML385 which revealed the role of GB on recovery of SCI was highly related to the activation of Nrf2 signaling. These findings reveal that GB alleviates SCI by inhibiting ferroptosis through Nrf2 activation, positioning it as a promising therapeutic agent. This study elucidates a novel mechanism linking Nrf2 signaling to ferroptosis suppression in SCI and provides a translational framework for repurposing GB in SCI treatment.
Aprepitant, a neurokinin-1 receptor (NK1R) antagonist, has the potential as a novel anticancer agent. This study explored the impact of chronotherapy on the antitumor effect of aprepitant in a mouse model of colorectal c...Aprepitant, a neurokinin-1 receptor (NK1R) antagonist, has the potential as a novel anticancer agent. This study explored the impact of chronotherapy on the antitumor effect of aprepitant in a mouse model of colorectal carcinoma. Aprepitant inhibited the proliferation of Colon-26 cells in vitro in a concentration-dependent manner and reduced the expression of cell cycle-related genes. Diurnal variations in NK1R mRNA and protein levels were observed in Colon-26 tumors, peaking at zeitgeber time (ZT) 2 and ZT 10, respectively. Administration of aprepitant at ZT 6, achieving peak plasma concentration at ZT 10, significantly reduced the tumor volume compared with administration at ZT 18. Despite the lower plasma concentrations and AUC in the ZT 6 group, superior antitumor effect suggests a dosing time-dependent efficacy due to variations in NK1R expression rather than its pharmacokinetics. These findings indicate that the antitumor activity of aprepitant against colorectal cancer can be enhanced by aligning its administration with NK1R expression rhythms, warranting further exploration of aprepitant chronotherapy in cancer chemotherapy.
Rosamultin (Rosa), a natural small-molecule compound, is known for its protective activity against hypoxia-induced injury, but its role in cerebral ischemic stroke injury remains unclear. To assess Rosa's effects on cere...Rosamultin (Rosa), a natural small-molecule compound, is known for its protective activity against hypoxia-induced injury, but its role in cerebral ischemic stroke injury remains unclear. To assess Rosa's effects on cerebral ischemic stroke, the intraluminal filament method was used to construct the middle cerebral artery occlusion and reperfusion (MCAO) in vivo model with 1 h occlusion and 48 h reperfusion. In addition, an oxygen-glucose deprivation and reoxygenation (OGD/R) in vitro model was constructed using HT22 cells. The protective role and underlying mechanism of Rosa on cell injury was also determined in vivo and in vitro. Rosa notably inhibited neurological deficits and diminished infarct volume and neuronal apoptosis in mice exposed to MCAO. Rosa also exerted neuroprotection in the OGD/R model by improving cell viability, decreasing apoptosis, and enhancing the p-Akt and p-mTOR levels. However, LY294002, a PI3K inhibitor, restored the beneficial influences of Rosa after OGD/R. Moreover, Rosa treatment inhibited autophagy levels, and LY294002 partially restored the inhibition of autophagy levels caused by Rosa in the OGD/R model. In addition, Rosa enhanced the p-Akt and p-mTOR levels and inhibited autophagy levels in mice after MCAO. Rosa could attenuate autophagy via activating the PI3K/Akt/mTOR axis, thereby alleviating cerebral ischemia stroke injury.
Ferulic acid (FA) exerts protective effects against cardiovascular-related diseases; however, its role in coronary artery dilation is unclear. Here, we examined the effects and underlying mechanisms of FA in response to...Ferulic acid (FA) exerts protective effects against cardiovascular-related diseases; however, its role in coronary artery dilation is unclear. Here, we examined the effects and underlying mechanisms of FA in response to contractions induced by spasmogenic candidates in porcine coronary arteries (PCAs). FA (3 × 10-3 × 10 M) inhibited high-KCl-induced contractions in a concentration-dependent manner, and FA (3 × 10-10 M) inhibited high-KCl-induced increases in intracellular Ca concentrations in A7r5 cells. FA (3 × 10 M) showed greater inhibition than diltiazem (3 × 10 M) against chemical-induced contractions but weaker inhibition against high-KCl-induced contractions. FA (3 × 10-3 × 10 M) inhibited contractions induced by endothelin-1 (10 M) and NaF (10 M) under Ca-free conditions in a concentration-dependent manner; these contractions were fully suppressed by ML-7 (10 M, a myosin light chain kinase inhibitor). FA (3 × 10 M) also inhibited myosin light chain phosphorylation induced by NaF (10 M) in A7r5 cells regardless of extracellular Ca conditions. These findings indicate that FA inhibits PCA contractions induced by coronary spasmogens by inhibiting L-type Ca channels and intracellular routes responsible for extracellular Ca influx-independent contractions. The latter mechanism may involve the inhibition of myosin light chain phosphorylation-related processes.
Several genetic variants of OATP1B1, a hepatic uptake transporter, increase the blood concentrations of substrate drugs, e.g., ∗15 carriers exhibit higher blood substrate concentrations than ∗1b carriers. It remains uncl...Several genetic variants of OATP1B1, a hepatic uptake transporter, increase the blood concentrations of substrate drugs, e.g., ∗15 carriers exhibit higher blood substrate concentrations than ∗1b carriers. It remains unclear whether these differences are due to changes in expression or intrinsic activity (transport activity per OATP1B1 molecule). This study compared the intrinsic activity of four OATP1B1 variants, ∗1a, ∗1b, ∗5, and ∗15, using HEK293 cell lines that co-expressed large-conductance Ca-activated K (BK) channels and one of the OATP1B1 variants. To estimate the kinetic parameters K and V, 2', 7'-dichlorofluorescein uptake was evaluated. The number of OATP molecules per cell (Q) was calculated from BK channel-mediated whole-cell conductance and the OATP1B1/BK channel expression ratio (ρ) (determined by LC-MS/MS). V (maximum intrinsic transport velocity) was obtained by dividing V by Q, and intrinsic clearance (CL) was calculated as V/K. The K values of ∗1a, ∗1b, ∗5, and ∗15 were 12.5, 9.19, 7.53, and 10.4 μM, and their V values were 3.0, 7.0, 1.5, and 1.2 × 10 mol/OATP molecule/min, respectively. Accordingly, the CL value for OATP1B1∗15 was 15 % lower than that for OATP1B1∗1b, suggesting that the increased blood substrate concentrations observed in OATP1B1∗15 carriers may be due to the decreased intrinsic activity of OATP1B1∗15.
BACKGROUND AND OBJECTIVE: Ischemic stroke is a disease with high incidence. Astaxanthin is a functional foods with protective effects against ischemic stroke. However, the integral mechanism of astaxanthin protect ischem...BACKGROUND AND OBJECTIVE: Ischemic stroke is a disease with high incidence. Astaxanthin is a functional foods with protective effects against ischemic stroke. However, the integral mechanism of astaxanthin protect ischemic stroke is not clear. The aim of this study was to investigate the mechanism of astaxanthin protect ischemic stroke by integrated network analysis. METHODS: Middle cerebral artery occlusion model was used to establish ischemic stroke model, and ischemic stroke models were treated with 25, 45, 65 mg/kg astaxanthin for 7 days. The rats were killed 24 h after successful modeling. Integrated network analysis, molecular docking, molecular dynamics (MD) simulation, and Western blot were used to explore the astaxanthin and potential proteins related to inflammation and cell death. RESULTS: The results of integrated network analysis indicate that astaxanthin may protect ischemic stroke through Toll like receptor signaling pathway and apoptosis pathway. The main targets involved MMP9, IL1B, IL10, Bcl2 and among others. astaxanthin has a low binding score and compact complex with PARP1, AIF, Bax, IL10, MMP9, Bcl2. In addition, astaxanthin has reduced inflammation and cell death-related proteins such as PARP1, AIF, Bax, TLR4, MMP9, IL1β and increased anti-inflammation and anti-cell death-related proteins by Bcl2 and IL10. CONCLUSIONS: Astaxanthin can improve anti-inflammatory, anti-cell death ability after ischemic stroke. Our study provides a theoretical basis for the subsequent experimental and clinical application of astaxanthin in the treatment of ischemic stroke.
Curcumin mitigates memory deficits or improves memory when it is chronically administered to animals. Due to limited bioavailability of curcumin, it remains almost unknown whether acutely treated curcumin influences cogn...Curcumin mitigates memory deficits or improves memory when it is chronically administered to animals. Due to limited bioavailability of curcumin, it remains almost unknown whether acutely treated curcumin influences cognitive function and underlying neural activity. To address this question, we monitored behavior and neural activity in the hippocampus and medial prefrontal cortex of mice treated with vehicle or curcumin while they were engaged in a novel object recognition task. Object recognition memory performance in the novel object recognition task was increased in curcumin-treated mice. Moreover, delta oscillations in the hippocampus were enhanced in the curcumin-administered mice in the test trial. Altogether, acute curcumin treatment boosts delta oscillations for memory recognition possibly by neuromodulation.
Sunagawa Y, Iwashimizu S, Ono M
… +20 more, Mochizuki S, Iwashita K, Sato R, Shimizu S, Funamoto M, Shimizu K, Hamabe-Horiike T, Katanasaka Y, Murakami A, Asakawa T, Inai M, Kan T, Komiyama M, Hawke P, Mori K, Arakawa Y, Hasegawa K, Sakamoto K, Kurokawa J, Morimoto T
BACKGROUND: The anthracycline anticancer drug doxorubicin (DOX) induces myocardial cell death and heart failure. The aim of the present study was to investigate whether nobiletin (NOB), a natural flavonoid isolated from...BACKGROUND: The anthracycline anticancer drug doxorubicin (DOX) induces myocardial cell death and heart failure. The aim of the present study was to investigate whether nobiletin (NOB), a natural flavonoid isolated from citrus peel, has a protective effect against DOX-induced cardiotoxicity. METHODS AND RESULTS: H9C2 cells were pretreated with 100 μM NOB and then treated with 1 μM DOX. An MTT assay revealed that NOB improved the decreased cell viability induced by DOX. A TUNEL assay showed that NOB treatment improved DOX-induced apoptosis in H9C2 cells. Western blotting indicated that DOX-induced increases in cleaved caspase-3 and -9 expression were significantly suppressed by NOB treatment. Motion field imaging of human iPS cell-derived cardiomyocyte sheets showed that NOB significantly suppressed a DOX-induced reduction of their contractile function. Next, to investigate the effect of NOB in vivo, DOX was intraperitoneally administered to mice. Echocardiography showed that oral administration of NOB reduced DOX-induced left ventricular systolic dysfunction, and a TUNEL assay showed that oral administration also inhibited apoptosis in the mouse heart. CONCLUSIONS: These results indicate that NOB treatment suppressed DOX-induced cardiotoxicity by reducing apoptosis. Further study of the mechanism of this effect may lead to the development of a novel therapy for DOX-induced heart failure.
Nociplastic pain represents the third mechanistic descriptor of pain, alongside neuropathic and nociceptive pain, as proposed in 2017 by the International Association for the Study of Pain (IASP). It describes pain occur...Nociplastic pain represents the third mechanistic descriptor of pain, alongside neuropathic and nociceptive pain, as proposed in 2017 by the International Association for the Study of Pain (IASP). It describes pain occurring in the absence of nociceptor activation, tissue damage, or neuropathy. The underlying brain mechanisms of nociplastic pain remain poorly understood. Despite the potentially large patient population with chronic pain of this class, effective pharmacological treatments for nociplastic pain are still limited, highlighting the urgent need for drug development using appropriate preclinical models. In this study, we investigated the anti-sensitization effects of two gabapentinoids-mirogabalin besylate (MGB) and pregabalin (PGB)-using a rodent model of nociplastic pain. This model involves experimental excitation of central amygdala neurons via designer receptors exclusively activated by designer drugs (DREADDs), causing widespread sensitization. Administration of an artificial ligand, deschloroclozapine (DCZ; 0.1 mg/kg, i.p.), significantly reduced the 50 %-paw withdrawal threshold, which was significantly elevated by MGB (10 mg/kg, i.p.) and PGB (30 mg/kg, i.p.), restoring it to levels not significantly different from the pre-DCZ baseline. We conclude that MGB and PGB alleviate widespread sensitization in this nociplastic pain model, likely through their action on αδ-1 subunits within brain circuits that regulate pain sensitivity.
OBJECTIVES: To investigate the therapeutic potential and renal protective mechanisms of hirsutine in diabetic kidney disease (DKD). METHODS: A DKD model was induced in Sprague-Dawley rats using a high-fat diet (HFD) and...OBJECTIVES: To investigate the therapeutic potential and renal protective mechanisms of hirsutine in diabetic kidney disease (DKD). METHODS: A DKD model was induced in Sprague-Dawley rats using a high-fat diet (HFD) and streptozotocin (STZ). High glucose (HG)-stimulated HK-2 cells served as an in vitro model. Reactive oxygen species (ROS) levels in kidney tissues were measured using dihydroethidium (DHE) staining. ELISA was performed to measure MDA, SOD, and GSH in both rat tissues and HK-2 cells. Western blot and immunofluorescence analyses evaluated renal fibrosis, the Nrf2 signaling pathway, and autophagy-related proteins (Beclin 1, LC3I/II, P62). RESULTS: Hirsutine treatment significantly improved metabolic and renal parameters in rats, enhancing renal function and reducing fibrosis, as shown by lower levels of Vimentin, Collagen-IV, and α-SMA. It alleviated oxidative stress, indicated by reduced ROS and MDA levels and increased SOD and GSH activity. Additionally, hirsutine enhanced autophagy, reflected by higher Beclin 1 and LC3I/II levels and decreased P62 expression. By disrupting the Keap1-Nrf2 interaction, hirsutine increased Nrf2 levels and upregulated antioxidative enzymes like NQO1, SOD-2, and HO-1. CONCLUSION: Hirsutine exhibited renoprotective effects in DKD by modulating the Keap1/Nrf2 pathway, mitigating oxidative stress and promoting autophagy, making it a promising candidate for treatment.
Lysophosphatidic acid receptor 1 (LPA) plays a pivotal role in the pathophysiology of various diseases, especially chronic pain. In this study, we assessed the biochemical properties of Compound A, a novel LPA antagonist...Lysophosphatidic acid receptor 1 (LPA) plays a pivotal role in the pathophysiology of various diseases, especially chronic pain. In this study, we assessed the biochemical properties of Compound A, a novel LPA antagonist and its beneficial effects in the fibromyalgia (FM)-like pain model. Compound A was found to be a high-affinity and selective LPA antagonist and have high brain penetrability. Repeated oral administrations of Compound A reversed the hyperalgesia as late as 9 days after the treatments, suggesting this compound has a curative effect in the FM model.
Functional activation of heterotrimeric guanine nucleotide-binding proteins (G-proteins) via G-protein-coupled receptors (GPCRs) has been extensively explored using guanosine-5'-O-(3-[S]thio)triphosphate ([S]GTPγS) bindi...Functional activation of heterotrimeric guanine nucleotide-binding proteins (G-proteins) via G-protein-coupled receptors (GPCRs) has been extensively explored using guanosine-5'-O-(3-[S]thio)triphosphate ([S]GTPγS) binding assay. However, the conventional method is primarily applicable to G family without discrimination among G-protein subtypes. Therefore, this study aims to reestablish a novel method termed "[S]GTPγS binding/immunoprecipitation assay" by identifying a most suitable anti-Gα antibody instead of the previously utilized, now withdrawn antibody. In the initial screening of commercially available anti-Gα antibodies, two were identified and one was selected for further investigations based on efficacy with adenosine-the most potent agonist in our previous research. After optimizing experimental conditions with rat and postmortem human brain membranes, the stimulatory effects of various agonists were evaluated. Some agonists, including nociceptin, exhibited sufficient stimulatory effects for further pharmacological characterization. Nociceptin increased [S]GTPγS binding to Gα in a concentration-dependent manner, response that was insensitive to naloxone but potently inhibited using (±)-J-113397. The method described in this study provides a valuable strategy for determining the intrinsic efficacy of ligands at various GPCRs. This includes nociceptin/orphanin FQ opioid peptide (NOP) receptor selectively coupled to Gα, providing insights into the pharmacological concept of "functional selectivity."
Object recognition memory is an animal's ability to discriminate between novel and familiar items and is supported by neural activities in not only the perirhinal cortex but also the hippocampus and prefrontal cortex. Si...Object recognition memory is an animal's ability to discriminate between novel and familiar items and is supported by neural activities in not only the perirhinal cortex but also the hippocampus and prefrontal cortex. Since we previously demonstrated that ramelteon enhanced object recognition memory in mice, we sought neural correlates of the memory improvement. We recorded neural activity in the hippocampus and prefrontal cortex of mice while they performed a novel object recognition task. We found that theta oscillations in the hippocampus were enhanced when ramelteon-treated mice explored both novel and familiar objects. Moreover, we showed high coherence in phases at low gamma frequencies between the hippocampus and prefrontal cortex. We assume that theta enhancement is indicative of increased cholinergic activity by melatonin receptor activation. High coherence of low gamma oscillations between the hippocampal and prefrontal network in ramelteon-treated mice sampling novel objects suggests better cognitive operations for discrimination between novelty and familiarity. The current study sheds light upon physiological consequences of melatonin receptor activation, further contributing improved cognitive functions.
Nab-paclitaxel (nab-PTX) is transported by organic anion-transporting polypeptide (OATP)1B1 and OATP1B3. Chemotherapy-induced peripheral neuropathy (CIPN) is a representative adverse event associated with gemcitabine plu...Nab-paclitaxel (nab-PTX) is transported by organic anion-transporting polypeptide (OATP)1B1 and OATP1B3. Chemotherapy-induced peripheral neuropathy (CIPN) is a representative adverse event associated with gemcitabine plus nab-PTX (GnP) in patients with pancreatic cancer. Gadoxetic acid is also transported by OATP1B1 and OATP1B3. We aimed to assess whether the enhancement effect of gadoxetic acid-enhanced magnetic resonance (MR) imaging could predict the development of CIPN for GnP. This study evaluated 27 patients with pancreatic cancer who underwent gadoxetic acid-enhanced MR imaging prior to GnP treatment. The contrast enhancement index (CEI), a measure of liver enhancement on hepato-biliary images, was measured. Plasma concentrations of paclitaxel at 0.5, 6, and 24 h after first administration were also determined in 13 patients. Sixteen of the twenty-seven patients (59.3 %) developed ≥ grade 1 CIPN during the first 8 weeks. We found a negative relationship between the CEI and area under the plasma concentration curve of PTX (r = -0.729, p = 0.003). In multivariate analysis, a CEI <1.84 and concomitant diabetes mellitus were independent predictors of CIPN development (hazard ratio, 5.37, p = 0.027; hazard ratio, 3.68, p = 0.012, respectively). Gadoxetic acid-enhanced MR imaging could be useful in predicting the development of CIPN during GnP therapy.
Secreted protein acidic and rich in cysteine (SPARC), a collagen-binding matricellular protein, is reported to facilitate inflammation and fibrosis in various tissues including the kidneys. Ischemia/reperfusion (I/R) is...Secreted protein acidic and rich in cysteine (SPARC), a collagen-binding matricellular protein, is reported to facilitate inflammation and fibrosis in various tissues including the kidneys. Ischemia/reperfusion (I/R) is a major process of acute kidney injury. To investigate whether SPARC inhibition might attenuate renal I/R injury, we injected small interfering RNA (siRNA) targeting SPARC into male BALB/c mice one day before 45 min of renal ischemia followed by 72 h of reperfusion. Serum creatinine concentration, blood urea nitrogen, histological tubular damage, tubulointerstitial fibrosis, and expression of collagen I and transforming growth factor-β were increased after I/R. Expression of 4-hydroxy-2-nonenal, an oxidative stress marker, and the inflammatory cytokines monocyte chemoattractant protein-1 and tumor necrosis factor-α, were also upregulated in I/R kidneys. Overexpression of SPARC mRNA was observed after I/R, and immunohistochemistry revealed that SPARC was localized mainly in damaged tubuloepithelial cells. Additionally, a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1) expression colocalized with SPARC. Injection of siRNA targeting SPARC attenuated renal dysfunction, histological abnormalities, collagen deposition, oxidative stress, and renal inflammation. In addition, SPARC gene knockdown suppressed the I/R-induced increases in ADAMTS1 and matrix metalloproteinase-2/9 expression. In conclusion, I/R-induced SPARC could be a novel therapeutic target against acute kidney injury.
In this study, we aimed to determine the cytotoxic factors involved in ferroptosis induced by nicotine- and tar-free cigarette smoke extract (CSE) from heated tobacco products (HTPs) in vascular smooth muscle cells. CSE...In this study, we aimed to determine the cytotoxic factors involved in ferroptosis induced by nicotine- and tar-free cigarette smoke extract (CSE) from heated tobacco products (HTPs) in vascular smooth muscle cells. CSE decreased mitochondrial metabolic activity and increased lactate dehydrogenase leakage. These cytotoxic effects completely disappeared after removing the carbonyls from the mainstream smoke. α, β-Unsaturated carbonyl compounds (acrolein, methyl vinyl ketone, crotonaldehyde, and methacrolein) in the mainstream smoke of HTPs and CSE caused cell damage, which was inhibited by a ferroptosis inhibitor, UAMC-3203. These results suggest that α, β-unsaturated carbonyl compounds might be involved in CSE-induced ferroptosis.