Curcuminoid PBPD induces cuproptosis and endoplasmic reticulum stress in cervical cancer via the Notch1/RBP-J/NRF2/FDX1 pathway.

Curcumin has been shown to have antitumor properties, but its low potency and bioavailability has limited its clinical application. We designed a novel curcuminoid, [1-propyl-3,5-bis(2-bromobenzylidene)-4-piperidinone] (PBPD), which has higher antitumor strength and improves bioavailability. Cell counting kit-8 was used to detect cell activity. Transwell assay was used to detect cell invasion and migration ability. Western blot and quantitative polymerase chain reaction were used to detect protein levels and their messenger RNA expression. Immunofluorescence was used to detect the protein location. PBPD significantly inhibited the proliferation of cervical cancer cells, with an IC50 value of 4.16 µM for Hela cells and 3.78 µM for SiHa cells, leading to the induction of cuproptosis. Transcriptome sequencing analysis revealed that PBPD significantly inhibited the Notch1/Recombination Signal Binding Protein for Immunoglobulin kappa J Region (RBP-J) and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathways while upregulating ferredoxin 1 (FDX1) expression. Knockdown of Notch1 or RBP-J significantly inhibited NRF2 expression and upregulated FDX1 expression, leading to the inhibition of nicotinamide adenine dinucleotide phosphate activity and the induction of oxidative stress, which in turn activated endoplasmic reticulum stress and induced cell death. The overexpression of Notch1 or RBP-J resulted in the enrichment of RBP-J within the NRF2 promoter region, thereby stimulating NRF2 transcription. NRF2 knockdown resulted in increase in FDX1 expression, leading to cuproptosis. In addition, PBPD inhibited the acidification of tumor niche and reduced cell metabolism to inhibit cervical cancer cell invasion and migration. In conclusion, PBPD significantly inhibits the proliferation, invasion, and migration of cervical cancer cells and may be a novel potential drug candidate for treatment of cervical cancer.

Vitamin C as Scavenger of Reactive Oxygen Species during Healing after Myocardial Infarction.

Currently, coronary artery bypass and reperfusion therapies are considered the gold standard in long-term treatments to restore heart function after acute myocardial infarction. As a drawback of these restoring strategies, reperfusion after an ischemic insult and sudden oxygen exposure lead to the exacerbated synthesis of additional reactive oxidative species and the persistence of increased oxidation levels. Attempts based on antioxidant treatment have failed to achieve an effective therapy for cardiovascular disease patients. The controversial use of vitamin C as an antioxidant in clinical practice is comprehensively systematized and discussed in this review. The dose-dependent adsorption and release kinetics mechanism of vitamin C is complex; however, this review may provide a holistic perspective on its potential as a preventive supplement and/or for combined precise and targeted therapeutics in cardiovascular management therapy.

The Vitamin C Enantiomers Possess a Comparable Potency in the Induction of Oxidative Stress in Cancer Cells but Differ in Their Toxicity.

The use of vitamin C (VC) in high doses demonstrates a potent tumor suppressive effect by mediating a glucose-dependent oxidative stress in Kirsten rat sarcoma (KRAS) mutant cancer cells. VC with arsenic trioxide (ATO) is a promising drug combination that might lead to the development of effective cancer therapeutics. Considering that a tumor suppressive effect of VC requires its high-dose administration, it is of interest to examine the toxicity of two enantiomers of VC (enantiomer d-optical isomer D-VC and natural l-optical isomer L-VC) in vitro and in vivo. We show that the combinations of L-VC with ATO and D-VC with ATO induced a similar cytotoxic oxidative stress in KrasG12D-expressing mutant cancer cells as indicated by a substantial increase in reactive oxidative species (ROS) production and depolarization of mitochondria. To examine the L-VC and D-VC toxicity effects, we administered high doses of D-VC and L-VC to CD1 mice and carried out an evaluation of their toxic effects. The daily injections of L-VC at a dose of 9.2 g/kg for 18 days were lethal to mice, while 80% of mice remained alive following the similar high-dose administration of D-VC. Following the drug injection courses and histopathological studies, we determined that a natural form of VC (L-VC) is more harmful and toxic to mice when compared to the effects caused by the similar doses of D-VC. Thus, our study indicates that the two enantiomers of VC have a similar potency in the induction of oxidative stress in cancer cells, but D-VC has a distinctive lower toxicity in mice compared to L-VC. While the mechanism of a distinctive toxicity between D-VC and L-VC is yet to be defined, our finding marks D-VC as a more preferable option compared to its natural enantiomer L-VC in clinical settings.

The Contribution of Type 2 Diabetes to Parkinson's Disease Aetiology.

Type 2 diabetes (T2D) and Parkinson's disease (PD) are chronic disorders that have a significant health impact on a global scale. Epidemiological, preclinical, and clinical research underpins the assumption that insulin resistance and chronic inflammation contribute to the overlapping aetiologies of T2D and PD. This narrative review summarises the recent evidence on the contribution of T2D to the initiation and progression of PD brain pathology. It also briefly discusses the rationale and potential of alternative pharmacological interventions for PD treatment.

A missense mutant of ocrl1 promotes apoptosis of tubular epithelial cells and disrupts endocytosis and the cell cycle of podocytes in Dent-2 Disease.

BACKGROUND: This study aimed to identify an orcl1 mutation in a patient with Dent-2 Disease and investigate the underlying mechanisms. METHODS: The ocrl1 mutation was identified through exome sequencing. Knockdown of orcl1 and overexpression of the orcl1 mutant were performed in HK-2 and MPC5 cells to study its function, while flow cytometry measured reactive oxygen species (ROS), phosphatidylserine levels, and cell apoptosis. Scanning electron microscopy observed crystal adhesion, while transmission electron microscopy examined kidney tissue pathology. Laser scanning confocal microscopy was used to examine endocytosis, and immunohistochemical and immunofluorescence assays detected protein expression. Additionally, podocyte-specific orcl1 knockout mice were generated to investigate the role of orcl1 in vivo. RESULTS: We identified a mutation resulting in the replacement of Histidine with Arginine at position 318 (R318H) in ocrl1 in the proband. orcl1 was widely expressed in the kidney. In vitro experiments showed that knockdown of orcl1 and overexpression of ocrl1 mutant increased ROS, phosphatidylserine exocytosis, crystal adhesion, and cell apoptosis in HK-2 cells. Knockdown of orcl1 in podocytes reduced endocytosis and disrupted the cell cycle while increasing cell migration. In vivo studies in mice showed that conditional deletion of orcl1 in podocytes caused glomerular dysfunction, including proteinuria and fibrosis. CONCLUSION: This study identified an R318H mutation in orcl1 in a patient with Dent-2 Disease. This mutation may contribute to renal injury by promoting ROS production and inducing cell apoptosis in tubular cells, while disrupting endocytosis and the cell cycle, and promoting cell migration of podocytes. Video Abstract.

Effects of static magnetic field on the sulfate metabolic pathway involved in Magnetospirillum magneticum AMB-1 cell growth and magnetosome formation.

AIMS: Magnetotactic bacteria (MTB) can use their unique intracellular magnetosome organelles to swim along the Earth's magnetic field. They play important roles in the biogeochemical cycles of iron and sulfur. Previous studies have shown that the applied magnetic fields could affect the magnetosome formation and antioxidant defense systems in MTB. However, the molecular mechanisms by which magnetic fields affect MTB cells remain unclear. We aim to better understand the dark at 28°C-29°C for 20 h, as shownthe interactions between magnetic fields and cells, and the mechanism of MTB adaptation to magnetic field at molecular levels. METHODS AND RESULTS: We performed microbiological, transcriptomic, and genetic experiments to analyze the effects of a weak static magnetic field (SMF) exposure on the cell growth and magnetosome formation in the MTB strain Magnetospirillum magneticum AMB-1. The results showed that a 1.5 mT SMF significantly promoted the cell growth but reduced magnetosome formation in AMB-1, compared to the geomagnetic field. Transcriptomic analysis revealed decreased expression of genes primarily involved in the sulfate reduction pathway. Consistently, knockout mutant lacking adenylyl-sulfate kinase CysC did no more react to the SMF and the differences in growth and Cmag disappeared. Together with experimental findings of increased reactive oxidative species in the SMF-treated wild-type strain, we proposed that cysC, as a key gene, can participate in the cell growth and mineralization in AMB-1 by SMF regulation. CONCLUSIONS: This study suggests that the magnetic field exposure can trigger a bacterial oxidative stress response involved in AMB-1 growth and magnetosome mineralization by regulating the sulfur metabolism pathway. CysC may serve as a pivotal enzyme in mediating sulfur metabolism to synchronize the impact of SMF on both growth and magnetization of AMB-1.

Surfactin induces autophagy, apoptosis, and cell cycle arrest in human oral squamous cell carcinoma.

OBJECTIVES: To investigate the anticancer effects and underlying mechanisms of surfactin on human oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The capacity of surfactin to induce apoptosis, autophagy, and cell cycle arrest of two different human OSCC cell lines was investigated by cell viability, acridine orange staining, and cell cycle regulatory protein expression, respectively. The signaling network underlying these processes were determined by the analysis of reactive oxygen species (ROS) generation, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, endoplasmic reticulum (ER) stress-related protein levels, calcium release, mitogen-activated protein kinases activation, and cell cycle regulatory protein expression through corresponding reagents and experiments under various experimental conditions using specific pharmaceutical inhibitors or small interfering RNAs. RESULTS: Surfactin was able to induce apoptosis through NADPH oxidase/ROS/ER stress/calcium-downregulated extracellular signal-regulated kinases 1/2 pathway. Surfactin could also lead to autophagy that shared the common regulatory signals with apoptosis pathway until calcium node. Cell cycle arrest at G2 /M phase caused by surfactin was demonstrated through p53 and p21 accumulation combined p34cdc2 , phosphorylated p34cdc2 , and cyclin B1 inhibition, which was regulated by NADPH oxidase-derived ROS. CONCLUSION: Surfactin could induce apoptosis, autophagy, and cell cycle arrest in ROS-dependent manner, suggesting a multifaced anticancer agent for OSCC.

Diabetic oxidative stress-induced telomere damage aggravates periodontal bone loss in periodontitis.

Periodontitis, one of the most common oral complications of diabetes mellitus (DM), causes a reduction in alveolar bone height and loss of alveolar bone mass. It has been shown that DM aggravates the progression of periodontitis, but the mechanism remains inconclusive. The hyperglycemic environment of DM has been proven to generate reactive oxygen species (ROS). Since telomeres, guanine-rich repeats, are highly susceptible to oxidative attack, we speculate that the excessive accumulation of ROS in DM could induce telomere damage resulting in dysfunction of periodontal ligament cells, especially periodontal ligament stem cells (PDLSCs), which reduces the ability of tissue repair and reconstruction in diabetic periodontitis. In this study, our current data revealed that oxidative telomere damage occurred in the periodontal ligaments of diabetic mice. And Micro-CT scans showed reduced alveolar bone height and impaired alveolar bone mass in a diabetic periodontitis model. Next, cultured mouse PDLSCs (mPDLSCs) were treated with the oxidant tert-butyl hydroperoxide (t-BHP) in vitro, as we expected telomere damage was observed and resulted in cellular senescence and dysfunction. Taken together, oxidative stress in DM causes telomere dysfunction and PDLSCs senescence, which influences periodontal bone tissue regeneration and reconstruction and ultimately exacerbates bone loss in periodontitis.

An Overview of Oxidative Stress, Neuroinflammation, and Neurodegenerative Diseases.

Oxidative stress has been linked with a variety of diseases, being involved in the debut and/or progress of several neurodegenerative disorders. This review intends to summarize some of the findings that correlate the overproduction of reactive oxygen species with the pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Oxidative stress was also noted to modify the inflammatory response. Even though oxidative stress and neuroinflammation are two totally different pathological events, they are linked and affect one another. Nonetheless, there are still several mechanisms that need to be understood regarding the onset and the progress of neurodegenerative diseases in order to develop efficient therapies. As antioxidants are a means to alter oxidative stress and slow down the symptoms of these neurodegenerative diseases, the most common antioxidants, enzymatic as well as non-enzymatic, have been mentioned in this paper as therapeutic options for the discussed disorders.

Exposure to perfluorooctane sulfonate reduced cell viability and insulin release capacity of ß cells.

Per- and polyfluoroalkyl substances (PFAS) are found to have multiple adverse outcomes on human health. Recently, epidemiological and toxicological studies showed that exposure to PFAS had adverse impacts on pancreas and showed association with insulin abnormalities. To explore how PFAS may contribute to diabetes, we studied impacts of perfluorooctane sulfonate (PFOS) on cell viability and insulin release capacity of pancreatic ß cells by using in vivo and in vitro methods. We found that 28-day administration with PFOS (10 mg/(kg body weight•day)) caused reductions of pancreas weight and islet size in male mice. PFOS administration also led to lower serum insulin level both in fasting state and after glucose infusion among male mice. For cell-based in vitro bioassay, we used mouse ß-TC-6 cancer cells and found 48-hr exposure to PFOS decreased the cell viability at 50 µmol/L. By measuring insulin content in supernatant, 48-hr pretreatment of PFOS (100 µmol/L) decreased the insulin release capacity of ß-TC-6 cells after glucose stimulation. Although these concentrations were higher than the environmental concentration of PFOS, it might be reasonable for high concentration of PFOS to exert observable toxic effects in mice considering mice had a faster removal efficiency of PFOS than human. PFOS exposure (50 µmol/L) to ß-TC-6 cells induced intracellular accumulation of reactive oxidative specie (ROS). Excessive ROS induced the reactive toxicity of cells, which eventually invoke apoptosis and necrosis. Results in this study provide evidence for the possible causal link of exposure to PFOS and diabetes risk.

Mutant p53 Mediates Sensitivity to Cancer Treatment Agents in Oesophageal Adenocarcinoma Associated with MicroRNA and SLC7A11 Expression.

TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio- and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53.

Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function.

Multiple clinical studies have shown that bardoxolone methyl, a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2), is effective in increasing glomerular filtration rate in patients with chronic kidney disease. However, whether an Nrf2 activator can protect tubules from proteinuria-induced tubular damage via anti-inflammatory and antioxidative stress mechanisms is unknown. Using an Institute of Cancer Research-derived glomerulonephritis (ICGN) mouse model of nephrosis, we examined the effects of dihydro-CDDO-trifluoroethyl amide (dh404), a rodent-tolerable bardoxolone methyl analog, in protecting the tubulointerstitium; dh404 markedly suppressed tubular epithelial cell damage in the renal interstitium of ICGN mice. The tubular epithelial cells of ICGN mice showed a decrease in the size and number of mitochondria, as well as the breakdown of the crista structure, whereas the number and ultrastructure of mitochondria were maintained by the dh404 treatment. To further determine the effect of dh404 on mitochondrial function, we used human proximal tubular cells in vitro. Stimulation with albumin and free fatty acid increased mitochondrial reactive oxygen species (ROS). However, dh404 administration diminished mitochondrial ROS. Our data show that dh404 significantly reduced proteinuria-induced tubular cell mitochondrial damage, suggesting that improved redox balance and mitochondrial function and suppression of inflammation underlie the cytoprotective mechanism of Nrf2 activators, including bardoxolone methyl, in diabetic kidney disease.-Nagasu, H., Sogawa, Y., Kidokoro, K., Itano, S., Yamamoto, T., Satoh, M., Sasaki, T., Suzuki, T., Yamamoto, M., Wigley, W. C., Proksch, J. W., Meyer, C. J., Kashihara, N. Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function.

[Role of mitochondrial damage in cadmium-induced cell apoptosis and DNA damage of hepatocytes].

OBJECTIVE: To investigate the role of mitochondrial damage mediated by reactive oxidative species(ROS) in cadmium-induced cell apoptosis and DNA damage of L02 hepatocytes, so as to provide experimental basis for the subsequent study and protection of people exposed to Cd. METHODS: The L02 hepatocytes were cultured in vitro treated with 0-90 µmol/L Cd for 24 h, and the methylthiazolyldiphenyltetrazoliumbromide assay was used to detect the cell viability. The colony formation assay, flow cytometry, comet assay, 2', 7'-dichlorofluorescein diacetate, MitoTracker Red CMXRos and 10-N-nonyl-acridine-orange, mitochondrial membrane potential detection kit(JC-1) and adenosine triphosphate(ATP) assay kits and Western Blot were used to investigate cell growth and proliferation, cell apoptosis, DNA damage, ROS levels, mitochondrial morphology, mitochondrial membrane potential, mitochondrial mass, ATP content and related proteins after the cells exposed to 0, 20, 40 µmol/L Cd for 24 h. The cells were pretreated with vitamin C before adding Cd exposure, and ROS levels, mitochondrial function, cell apoptosis, DNA damage and proteins were measured. RESULTS: The cell viability was significantly inhibited with the increase of Cd concentration and treatment time. The cells were treated with Cd for 24 h for further study according to the result of MTT assay. Compared with control group, the colony formation rate were 8. 23% and 6. 17% respectively in 20 and 40 µmol/L Cd treatment and the apoptosis rate were 15. 85% and 26. 26%, respectively. We also found that the B cell lymphoma/leukemia(Bcl-2) gene protein was significantly reduced, while the levels of Bcl-2 associated X protein(Bax) and cleaved cysteine aspastic acid-specific protease 3(cleaved-caspase-3) were increased in a dose-dependent manner. Cd treatment also induced DNA damage and accumulation of intracellular ROS, accompanied by a mitochondrial morphological change, significant decrease in Δψm, mitochondrial mass, ATP content, mitochondrial cytochrome C(cyt c) and an increase in cytoplasmic cyt c expression(P<0. 05). In addition, pretreatment with antioxidant vitamin C not only significantly increased cyt c, mitochondrial mass, ATP content and mitochondrial cyt c, but also reduced the expression of cytoplasmic cyt c(P<0. 05), cell apoptosis and DNA damage induced by Cd. CONCLUSION: Cd exposure could induce ROS accumulation in L02 hepatocytes, which can lead to mitochondrial damage, and ultimately lead to cell apoptosis and DNA damage.

Upconverting Carbon Nanodots from Ethylenediaminetetraacetic Acid (EDTA) as Near-Infrared Activated Phototheranostic Agents.

This work describes the synthesis of nitrogen-doped carbon nanodots (CNDs) synthesized from ethylenediaminetetraacetic acid (EDTA) as a precursor and their application as luminescent agents with a dual-mode theranostic role as near-infrared (NIR) triggered imaging and photodynamic therapy agents. Interestingly, these fluorescent CNDs are more rapidly and selectively internalized by tumor cells and exhibit very limited cytotoxicity until remotely activated with a NIR illumination source. These CNDs are excellent candidates for phototheranostic purposes, for example, simultaneous imaging and therapy can be carried out on cancer cells by using their luminescent properties and the in situ generation of reactive oxidative species (ROS) upon excitation in the NIR range. In the presence of CNDs, NIR remote activation induces the in vitro killing of U251MG cells. Through the use of flow imaging cytometry, we have been able to successfully map and quantify the different types of cell deaths induced by the presence of intracellular superoxide anions (. O2 - ) and hydrogen peroxide (H2 O2 ) ROS generated in situ upon NIR irradiation.

Unsaturated Squalene Content in Emulsion Vaccine Adjuvants Plays a Crucial Role in ROS-Mediated Antigen Uptake and Cellular Immunity.

Emulsion-based adjuvants have been demonstrated to be an effective tool in increasing vaccine efficacy. Here, we aimed to launch a mechanistic study on how emulsion adjuvants interact with immune cells and to elucidate the roles of the core oil in vaccine immunogenicity. Our results showed that treatment of dendritic cells (DCs) and splenocytes with a squalene-based emulsion (referred as SqE) induced reactive oxidative species (ROS) production and resulted in an increase in apoptotic and necrotic cells in a concentration- and time-dependent manner. Furthermore, DCs cocultured with cellular debris of SqE-pretreated splenocytes resulted in a higher level of ovalbumin (OVA) antigen uptake by DCs than those cocultured with untreated splenocytes. Interestingly, the potency was rather attenuated when splenocytes were pretreated with N-acetyl-cysteine, an antioxidant. Notably, SqE possesses a high impact on eliciting ROS-mediated antigen uptake compared with a squalane-based emulsion (SqA). Concordantly, immunogenicity studies have shown that SqE is better able than SqA to activate antigen-presenting cells, and to enhance antigen-specific T-cell immunity. Taken together, our results show that unsaturated squalene oil cored within emulsions plays a crucial role in ROS-mediated antigen uptake and cellular immunity, providing a basis for the design and development of vaccine adjuvant.

Tubal origin of ovarian cancer - the double-edged sword of haemoglobin.

Ovarian high-grade serous carcinoma (HGSC) is the most malignant neoplasm of the gynaecological tract. While the origins of many human malignant neoplasms are clear, the origin of HGSC remains poorly understood. This lack of knowledge limits our understanding of its pathogenesis and compromises efforts devoted to developing better early detection tools and effective preventative interventions. The paradigm of the tubal origin of HGSC has been advanced since the initial report of dysplastic lesions (now known as serous tubal intraepithelial carcinomas or STICs) that morphologically resemble HGSC in the Fallopian tube. These were observed in a group of patients with a genetic predisposition to ovarian cancer who were undergoing risk-reducing salpingo-oophorectomy. Since then, a series of clinico-pathological and molecular studies have characterized STICs and their concurrent HGSCs, and the results support the new paradigm of a tubal origin of many 'ovarian' HGSCs. Reactive oxygen species-containing ovulatory follicular fluid has been thought to be the major culprit behind DNA damage in tubal epithelial cells, leading to either cell death or, if the cells survive, mutagenesis. A recent report from this journal demonstrates that ferryl haemoglobin (Hb) in peritoneal fluid could prevent cell death from DNA-damaged fimbrial epithelial cells, facilitating ovulation-induced carcinogenesis of tubal epithelium. This timely study provides new insight into the tumour initiation event in HGSC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mitochondrial NADP+-Dependent Isocitrate Dehydrogenase Deficiency Exacerbates Mitochondrial and Cell Damage after Kidney Ischemia-Reperfusion Injury.

Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, synthesizing NADPH, which is essential for mitochondrial redox balance. Ischemia-reperfusion (I/R) is one of most common causes of AKI. I/R disrupts the mitochondrial redox balance, resulting in oxidative damage to mitochondria and cells. Here, we investigated the role of IDH2 in I/R-induced AKI. I/R injury in mice led to the inactivation of IDH2 in kidney tubule cells. Idh2 gene deletion exacerbated the I/R-induced increase in plasma creatinine and BUN levels and the histologic evidence of tubule injury, and augmented the reduction of NADPH levels and the increase in oxidative stress observed in the kidney after I/R. Furthermore, Idh2 gene deletion exacerbated I/R-induced mitochondrial dysfunction and morphologic fragmentation, resulting in severe apoptosis in kidney tubule cells. In cultured mouse kidney proximal tubule cells, Idh2 gene downregulation enhanced the mitochondrial damage and apoptosis induced by treatment with hydrogen peroxide. This study demonstrates that Idh2 gene deletion exacerbates mitochondrial damage and tubular cell death via increased oxidative stress, suggesting that IDH2 is an important mitochondrial antioxidant enzyme that protects cells from I/R insult.

Hepatic ischemia/reperfusion injury disrupts the homeostasis of kidney primary cilia via oxidative stress.

Acute kidney injury (AKI) is a major complication of hepatic surgeries. The primary cilium protrudes to the lumen of kidney tubules and plays an important role in renal functions. Disruption of primary cilia homeostasis is highly associated with human diseases including AKI. Here, we investigated whether transient hepatic ischemia induces length change and deciliation of kidney primary cilia, and if so, whether reactive oxygen species (ROS)/oxidative stress regulates those. HIR induced damages to the liver and kidney with increases in ROS/oxidative stress. HIR shortened the cilia of kidney epithelial cells and caused them to shed into the urine. This shortening and shedding of cilia was prevented by Mn(III) tetrakis(1-methyl-4-pyridyl) porphyrin (MnTMPyP, an antioxidant). The urine of patient undergone liver resection contained ciliary proteins. These findings indicate that HIR induces shortening and deciliation of kidney primary cilia into the urine via ROS/oxidative stress, suggesting that primary cilia is associated with HIR-induced AKI and that the presence of ciliary proteins in the urine could be a potential indication of kidney injury.

Neuroimmunomodulatory properties of DPSCs in an in vitro model of Parkinson's disease.

In neurodegenerative diseases, such as Alzheimer's and Parkinson's, microglial cell activation is thought to contribute to their degeneration by producing neurotoxic compounds. While dental pulp stem cells (DPSCs) have been regarded as the next possible cell source for cell replacement therapy (CRT), their actual role when exposed in such harsh environment remains elusive. In this study, the immunomodulatory behavior of DPSCs from human subjects was investigated in a coculture system consisting of neuron and microglia which were treated with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine, which mimics the inflammatory conditions and contribute to degeneration of dopaminergic (DA-ergic) neurons. Assessments were performed on their proliferation, extent of DNA damage, productions of reactive oxygen species (ROS) and nitric oxide (NO), as well as secretion of inflammatory mediators. Notably, DPSCs were shown to attenuate their proliferation, production of ROS, and NO significantly (P < 0.05). Additionally, their immunomodulatory properties were distinct although insignificant changes were observed in DNA damage. Despite DPSCs were exposed to such harsh environment, they were still able to express neuronal markers such as Nestin, Pax 6, and Nurr1, at least by twofold thereby indicating their applicability for CRT especially in PD conditions. To conclude, DPSCs were shown to have immunomodulatory capacities which could probably serve as secondary effects upon transplantation in a CRT regime. © 2017 IUBMB Life, 69(9):689-699, 2017.

Rapid repeatable in vivo detection of retinal reactive oxygen species.

Oxidative injuries, such as those related to reactive oxygen species (ROS), have been implicated in various retinal and optic nerve disorders. Many ROS detection methods have been developed. Although widely utilized, many of these methods are useful only in post mortem tissues, or require relatively expensive equipment, or involve intraocular injection. In the present study, we demonstrated and characterized a chemiluminescent probe L-012 as a noninvasive, in vivo ROS detection agent in the mouse retina. Using optic nerve crush (ONC) and retinal ischemia/reperfusion (I/R) as injury models, we show that L-012 produced intensive luminescent signals specifically in the injured eyes. Histological examination showed that L-012 administration was safe to the retina. Additionally, compounds that reduce tissue superoxide levels, apocynin and TEMPOL, decreased injury-induced L-012 chemiluminescence. The decrease in L-012 signals correlated with their protective effects against retinal I/R-induced morphological and functional changes in the retina. Together, these data demonstrate the feasibility of a fast, simple, reproducible, and non-invasive detection method to monitor in vivo ROS in the retina. Furthermore, the results also show that reduction of ROS is a potential therapeutic approach for protection from these retinal injuries.