bims-nurfan 2023-11-05 papers

bims-nurfan

Biomed News

on NRF2 and Neurological Diseases

Issue of 2023–11–05
eightteen papers selected by
Arif Kamil Salihoğlu, Karadeniz Technical University

miR-196a provides antioxidative neuroprotection via USP15/Nrf2 regulation in Huntington's disease.
NRF2 signaling pathway and telomere length in aging and age-related diseases.
ATF5 attenuates low-magnesium-induced apoptosis by inhibiting endoplasmic reticulum stress via the regulation of mitochondrial reactive oxygen species.
Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production.
Kaempferol exerts antioxidant effects in age-related diminished ovarian reserve by regulating the HSP90/NRF2 pathway.
[TRPA1 channel mediates oxidative stress defense in cancer].
AM1638, a GPR40-Full Agonist, Inhibited Palmitate- Induced ROS Production and Endoplasmic Reticulum Stress, Enhancing HUVEC Viability in an NRF2-Dependent Manner.
Cinnamaldehyde Alleviates Bone Loss by Targeting Oxidative Stress and Mitochondrial Damage via the Nrf2/HO-1 Pathway in BMSCs and Ovariectomized Mice.
Environmental chemicals-induced ROS generation and immunotoxicity: A comprehensive review.
Targeting the Main Sources of Reactive Oxygen Species Production: Possible Therapeutic Implications in Chronic Pain.
Targeting the ferroptosis crosstalk: novel alternative strategies for the treatment of major depressive disorder.
Neuroprotective effects of polyacrylic acid (PAA) conjugated cerium oxide against hydrogen peroxide- and 6-OHDA-induced SH-SY5Y cell damage.
Recent advances and future directions in etiopathogenesis and mechanisms of reactive oxygen species in cancer treatment.
Synthesis and biological evaluation of capsaicin analogues as antioxidant and neuroprotective agents.
Immunity impacts cognitive deficits across neurological disorders.
Gentisic acid ameliorates cisplatin-induced reprotoxicity through suppressing endoplasmic reticulum stress and upregulating Nrf2 pathway.
Nrf2 Regulates the Expression of CYP2D6 by Inhibiting the Activity of Krüppel-Like Factor 9 (KLF9).
In Vivo Intracerebral Administration of α-Ketoisocaproic Acid to Neonate Rats Disrupts Brain Redox Homeostasis and Promotes Neuronal Death, Glial Reactivity, and Myelination Injury.

Free Radic Biol Med. 2023 Oct 29. pii: S0891-5849(23)01085-7. [Epub ahead of print]

miR-196a provides antioxidative neuroprotection via USP15/Nrf2 regulation in Huntington's disease.

Siew Chin Chan, Chih-Wei Tung, Chia-Wei Lin, Yun-Shiuan Tung, Po-Min Wu, Pei-Hsun Cheng, Chuan-Mu Chen, Shang-Hsun Yang.

  Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by the accumulation of mutant Huntingtin protein (mHTT) and oxidative stress-induced neuronal damage. Based on previous reports, microRNA-196a (miR-196a) has emerged as a potential therapeutic target due to its neuroprotective effects in various neurodegenerative diseases. However, whether miR-196a functions through antioxidative effects is still unknown. In this study, we demonstrated that HD models, both in vitro and in vivo, exhibit elevated levels of reactive oxygen species (ROS) and increased neuronal death, and miR-196a mitigates ROS levels and reduces cell death in HD cells. Moreover, we elucidated that miR-196a facilitates the translocation of nuclear factor erythroid 2 (Nrf2) into the nucleus, enhancing the transcription of antioxidant genes, including heme oxygenase-1 (HO-1). We further identified ubiquitin-specific peptidase 15 (USP15), a direct target of miR-196a related to the Nrf2 pathway, and USP15 exacerbates mHTT aggregate formation while partially counteracting miR-196a-induced reductions in mHTT levels. Taken together, these findings shed light on the multifaceted role of miR-196a in HD, highlighting its potential as a therapeutic avenue for ameliorating oxidative stress and neurodegeneration in this debilitating disease.

Keywords:  Antioxidative effect; Huntington's disease; Nrf2; Reactive oxygen species; USP15; miR-196a

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.10.407
Mol Cell Biochem. 2023 Nov 02.

NRF2 signaling pathway and telomere length in aging and age-related diseases.

Alessandro Medoro, Luciano Saso, Giovanni Scapagnini, Sergio Davinelli.

  The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is well recognized as a critical regulator of redox, metabolic, and protein homeostasis, as well as the regulation of inflammation. An age-associated decline in NRF2 activity may allow oxidative stress to remain unmitigated and affect key features associated with the aging phenotype, including telomere shortening. Telomeres, the protective caps of eukaryotic chromosomes, are highly susceptible to oxidative DNA damage, which can accelerate telomere shortening and, consequently, lead to premature senescence and genomic instability. In this review, we explore how the dysregulation of NRF2, coupled with an increase in oxidative stress, might be a major determinant of telomere shortening and age-related diseases. We discuss the relevance of the connection between NRF2 deficiency in aging and telomere attrition, emphasizing the importance of studying this functional link to enhance our understanding of aging pathologies. Finally, we present a number of compounds that possess the ability to restore NRF2 function, maintain a proper redox balance, and preserve telomere length during aging.

Keywords:  Aging; NRF2; Oxidative stress; Telomere length

DOI:  https://doi.org/10.1007/s11010-023-04878-x
Neuroscience. 2023 Oct 30. pii: S0306-4522(23)00476-1. [Epub ahead of print]

ATF5 attenuates low-magnesium-induced apoptosis by inhibiting endoplasmic reticulum stress via the regulation of mitochondrial reactive oxygen species.

Cui Wang, Xiaoyi Wang, Yinyin Xie, Tingting Peng, Yongfeng Wang, Nan Li, Xiangbo Huang, Xiaomei Hu, Nanchang Xie.

  Mitochondrial stress and endoplasmic reticulum stress (ERS) are known to be closely linked. ATF5 is a key regulator of mitochondrial stress and is involved in ERS regulation. Previously, we used a seizure model to demonstrate that ATF5 regulates mitochondrial stress. However, whether ATF5 affects ERS in epilepsy models has yet to be elucidated. In the present study, we investigated the effects of ATF5 on low-magnesium-induced ERS and the potential mechanisms that underlie these effects. We found that lentiviral overexpression of ATF5 significantly improved low-magnesium-induced ERS, as confirmed by the reduced expression levels of GRP78, PERK, ATF4, and CHOP. In addition, ATF5 overexpression reduced reactive oxygen species (ROS) production and elevated superoxide dismutase (SOD) activity, thus demonstrating that ATF5 plays a key role in maintaining redox homeostasis. Furthermore, ATF5 overexpression rescued low-magnesium-induced neuronal apoptosis, as evidenced by the reduced expression levels of Cleaved-caspase-3 and Bax, and the restored levels of Bcl2. However, these effects were significantly eliminated by lentiviral transduction with ATF5 interference. In addition, treatment of neurons with the mitochondrial antioxidant mitoquinone attenuated the onset of oxidative stress caused by ATF5 interference, partially restored the effect on ERS, and rescued cells from apoptosis. Collectively, these data show that ATF5 attenuates low-magnesium-induced neuronal apoptosis by inhibiting ERS through preventing the accumulation of mitochondrial ROS.

Keywords:  ATF5; apoptosis; endoplasmic reticulum stress; reactive oxygen species; seizure

DOI:  https://doi.org/10.1016/j.neuroscience.2023.10.020
bioRxiv. 2023 Oct 18. pii: 2023.10.14.562276. [Epub ahead of print]

Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production.

Neal K Bennett, Megan Lee, Adam L Orr, Ken Nakamura.

Respiratory chain dysfunction can decrease ATP and increase reactive oxygen species (ROS) levels. Despite the importance of these metabolic parameters to a wide range of cellular functions and disease, we lack an integrated understanding of how they are differentially regulated. To address this question, we adapted a CRISPRi- and FACS-based platform to compare the effects of respiratory gene knockdown on ROS to their effects on ATP. Focusing on genes whose knockdown is known to decrease mitochondria-derived ATP, we showed that knockdown of genes in specific respiratory chain complexes (I, III and CoQ10 biosynthesis) increased ROS, whereas knockdown of other low ATP hits either had no impact (mitochondrial ribosomal proteins) or actually decreased ROS (complex IV). Moreover, although shifting metabolic conditions profoundly altered mitochondria-derived ATP levels, it had little impact on mitochondrial or cytosolic ROS. In addition, knockdown of a subset of complex I subunits-including NDUFA8, NDUFB4, and NDUFS8-decreased complex I activity, mitochondria-derived ATP and supercomplex level, but knockdown of these genes had differential effects on ROS. Conversely, we found an essential role for ether lipids in the dynamic regulation of mitochondrial ROS levels independent of ATP. Thus, our results identify specific metabolic regulators of cellular ATP and ROS balance that may help dissect the roles of these processes in disease and identify therapeutic strategies to independently target energy failure and oxidative stress.
Significance: Mitochondrial respiration generates both energy (ATP) and reactive oxygen species (ROS). Insufficient energy and increased ROS from respiratory chain dysfunction may be central to the pathophysiology of neurodegenerative diseases and aging. We established a screening platform using CRISPR and fluorescent-cell sorting to compare the impact of decreasing respiratory chain proteins on ROS and ATP levels. The results provide the first systems-level analysis of how ROS and ATP are differentially regulated, and identify genes and respiratory chain complexes that can manipulate each independently. These findings advance our understanding of the relative contributions of ATP and ROS to disease pathophysiology, and guide the development of therapies to preserve energy while minimizing ROS.

DOI: https://doi.org/10.1101/2023.10.14.562276
Chem Biol Drug Des. 2023 Nov 01.

Kaempferol exerts antioxidant effects in age-related diminished ovarian reserve by regulating the HSP90/NRF2 pathway.

Zhoujia Hua, Wei Zhang, Lin Han, Yuwei Zhang, Xuejuan Jiang, Caifei Ding.

  Kaempferol is the active ingredient of Er-Xian decoction (EXD), a traditional Chinese medicine formula used clinically to treat ovarian dysfunction, but the mechanism of kaempferol relieving age-related diminished ovarian reserve (AR-DOR) is still unclear. In this study, 36 volunteers and 78 DOR patients (37 patients with EXD treatment) were enrolled in the clinical research. Meanwhile, 32-week-old female mice were used to establish the AR-DOR model, and these model mice were intragastrically administered with 100 mg/kg kaempferol in the presence or absence of 200 mg/kg geranylgeranylacetone (GGA) or 1 mg/kg geldanamycin (GDA). The effects of kaempferol on serum hormone levels and oxidative stress-related indexes were detected by enzyme-linked immunosorbent assay. Antral follicle count (AFC) was determined by hematoxylin-eosin staining. The protein levels of HSP90 and nuclear factor erythroid 2-related factor 2 (NRF2) were assayed by Western blot. This study displayed that the serum anti-Mullerian hormone (AMH) level in DOR patients with EXD treatment was higher than that in DOR patients without EXD treatment. Kaempferol treatment reversed the low levels of AMH, estradiol (E2), AFC, superoxide dismutase (SOD), and catalase (CAT), as well as the high levels of follicle-stimulating hormone (FSH), reactive oxygen species (ROS), and malonaldehyde (MDA). The results showed that HSP90 was predicted to have high affinity with kaempferol, and its expression was inhibited by kaempferol, while the expression of NRF2, the target of HSP90, was up-regulated by kaempferol. However, the above effects of kaempferol were reversed by GGA. On the contrary, GDA enhanced the therapeutic effects of kaempferol on AR-DOR mice. Moreover, the treatment of kaempferol resulted in a reduction in the phosphorylation level of heat shock factor 1 (HSF1), the transcription factor associated with HSP90, and an increase in the phosphorylation level of Src, a client protein of HSP90. In summary, kaempferol exerts an antioxidant effect on AR-DOR by inhibiting HSP90 expression to up-regulate NRF2 expression. This study provides a theoretical basis for the clinical application of kaempferol in AR-DOR.

Keywords:  Er-Xian decoction; age-related diminished ovarian reserve; heat shock protein 90; kaempferol; nuclear factor erythroid 2-related factor 2

DOI:  https://doi.org/10.1111/cbdd.14385
Nihon Yakurigaku Zasshi. 2023 ;158(6): 475-477

[TRPA1 channel mediates oxidative stress defense in cancer].

Nobuaki Takahashi.

The unscheduled proliferation of cancer cells outside their natural niches subjects the cells to multiple insults, such as metabolic aberrations, detachment from the extracellular matrix (ECM), hypoxia, and immune cell attacks. Oxidative stress is a hallmark of cancer because these insults can all lead to the accumulation of reactive oxygen species (ROS). However, it remained largely elusive how cancer cells are able to adapt to harsh oxidative environments. Here, we provide evidence that cancer cells co-opt the neuronal ROS-sensing channel TRPA1 to tolerate highly oxidative environments. While TRPA1 is usually expressed at sensory neurons, we found that the channel is also overexpressed in various types of human cancer. TRPA1 does not affect canonical ROS-neutralizing programs but senses ROS and upregulates Ca2＋-dependent anti-apoptotic programs that promotes oxidative-stress tolerance. These findings offer a significant advance in our understanding of adaptation mechanisms to oxidative stress, which represents a substantial hurdle that impedes tumor initiation and progression.

DOI: https://doi.org/10.1254/fpj.23056
Endocrinol Metab (Seoul). 2023 Nov 02.

AM1638, a GPR40-Full Agonist, Inhibited Palmitate- Induced ROS Production and Endoplasmic Reticulum Stress, Enhancing HUVEC Viability in an NRF2-Dependent Manner.

Hwan-Jin Hwang, Joo Won Kim, SukHwan Yun, Min Jeong Park, Eyun Song, Sooyeon Jang, Ahreum Jang, Kyung Mook Choi, Sei Hyun Baik, Hye Jin Yoo.

   Background: G protein-coupled receptor 40 (GPR40) is a key molecule in diabetes and fatty liver, but its role in endothelial dysfunction remains unclear. Our objective in this study was to determine whether GPR40 agonists protect endothelial cells against palmitatemediated oxidative stress.
Methods: Human umbilical vein endothelial cells (HUVECs) were used to investigate effects of various GPR40 agonists on vascular endothelium.
Results: In HUVECs, AM1638, a GPR40-full agonist, enhanced nuclear factor erythroid 2-related factor 2 (NRF2) translocation to the nucleus and heme oxygenase-1 (HO-1) expression, which blocked palmitate-induced superoxide production. Those antioxidant effects were not detected after treatment with LY2922470 or TAK875, GPR40-partial agonists, suggesting that GPR40 regulates reactive oxygen species (ROS) removal in a ligand-dependent manner. We also found that palmitate-induced CCAAT/enhancer-binding protein homologous protein expression; X-box binding protein-1 splicing, nuclear condensation, and fragmentation; and caspase-3 cleavage were all blocked in an NRF2-dependent manner after AM1638 treatment. Both LY2922470 and TAK875 also improved cell viability independent of the NRF2/ROS pathway by reducing palmitate-mediated endoplasmic reticulum stress and nuclear damage. GPR40 agonists thus have beneficial effects against palmitate in HUVECs. In particular, AM1638 reduced palmitate-induced superoxide production and cytotoxicity in an NRF2/HO-1 dependent manner.
Conclusion: GPR40 could be developed as a good therapeutic target to prevent or treat cardiovascular diseases such as atherosclerosis.

Keywords:  Cytotoxicity; Endoplasmic reticulum stress; GPR40 agonist; Human umbilical vein endothelial cell; NRF2; Palmitates

DOI:  https://doi.org/10.3803/EnM.2023.1774
J Agric Food Chem. 2023 Nov 02.

Cinnamaldehyde Alleviates Bone Loss by Targeting Oxidative Stress and Mitochondrial Damage via the Nrf2/HO-1 Pathway in BMSCs and Ovariectomized Mice.

Bing-Hao Lin, Run-Xun Ma, Jing-Tao Wu, Shi-Qi Du, Yi-Yun Lv, Hao-Nan Yu, Wei Zhang, Shu-Ming Mao, Guang-Yao Liu, Yi-Tian Bu, Zi-Hao Chen, Chen Jin, Zong-Yi Wu, Lei Yang.

  Osteoporosis (OP) is typically brought on by disruption of bone homeostasis. Excessive oxidative stress and mitochondrial dysfunction are believed to be the primary mechanisms underlying this disorder. Therefore, in order to restore bone homeostasis effectively, targeted treatment of oxidative stress and mitochondrial dysfunction is necessary. Cinnamaldehyde (CIN), a small molecule that acts as an agonist for the nuclear factor erythroid 2-related factor (Nrf2), has been found to possess antiapoptotic, anti-inflammatory, and antioxidant properties. We found that CIN, while rescuing apoptosis, can also reduce the accumulation of reactive oxygen species (ROS) to improve mitochondrial dysfunction and thus restore the osteogenic differentiation potential of BMSCs disrupted by hydrogen peroxide (H2O2) exposure. The role of CIN was preliminarily considered to be a consequence of Nrf2/HO-1 axis activation. The ovariectomized mice model further demonstrated that CIN treatment ameliorated oxidative stress in vivo, partially reversing OVX-induced bone loss. This improvement was seen in the trabecular microarchitecture and bone biochemical indices. However, when ML385 was concurrently injected with CIN, the positive effects of CIN were largely blocked. In conclusion, this study sheds light on the intrinsic mechanisms by which CIN regulates BMSCs and highlights the potential therapeutic applications of these findings in the treatment of osteoporosis.

Keywords:  Nrf2/HO-1 pathway; bone marrow mesenchymal stem cells; cinnamaldehyde; mitochondrial dysfunction; reactive oxygen species

DOI:  https://doi.org/10.1021/acs.jafc.3c03501
Antioxid Redox Signal. 2023 Nov 02.

Environmental chemicals-induced ROS generation and immunotoxicity: A comprehensive review.

Leonard Clinton D'Souza, Jagdish Paithankar, Helga Stopper, Ashutosh Pandey, Anurag Sharma.

SIGNIFICANCE: Reactive oxygen species (ROS), the reactive oxygen-carrying chemicals moieties, act as pleiotropic signal transducers to maintain various biological processes/functions, including immune response. Increased ROS production leads to oxidative stress, which is implicated in xenobiotics-induced adverse effects. Understanding the immunoregulatory mechanisms and immunotoxicity is of interest to developing therapeutics against xenobiotic insults.
RECENT ADVANCES: While developmental studies have established the essential roles of ROS in the establishment and proper functioning of the immune system, toxicological studies have demonstrated high ROS generation as one of the potential mechanisms of immunotoxicity induced by environmental chemicals, including heavy metals, pesticides, aromatic hydrocarbons (benzene and derivatives), plastics, and nanoparticles. Mitochondrial electron transport and various signaling components, including NADH oxidase, TLRs, NF-κB, JNK, NRF2, p53, and STAT3, are involved in xenobiotic-induced ROS generation and immunotoxicity.
CRITICAL ISSUES: With many studies demonstrating the role of ROS and oxidative stress in xenobiotic-induced immunotoxicity, rigorous and orthogonal approaches are needed to achieve in-depth and precise understanding. The association of xenobiotics-induced immunotoxicity with disease susceptibility to and progression needs more data acquisition. Furthermore, the general methodology needs to be possibly replaced with high throughput precise techniques.
FUTURE DIRECTIONS: The progression of xenobiotic-induced immunotoxicity into disease manifestation is not well documented. Immunotoxicological studies about the combination of xenobiotics, age-related sensitivity, and their involvement in human disease incidence and pathogenesis are warranted.

DOI: https://doi.org/10.1089/ars.2022.0117
Curr Neuropharmacol. 2023 Oct 25.

Targeting the Main Sources of Reactive Oxygen Species Production: Possible Therapeutic Implications in Chronic Pain.

Peng-Fei Cheng, Yuan-He, Meng-Meng Ge, Da-Wei Ye, Jian-Ping Chen, Jin-Xi Wang.

  Humans have long been combating chronic pain. In clinical practice, opioids are first- choice analgesics, but long-term use of these drugs can lead to serious adverse reactions. Finding new, safe and effective pain relievers that are useful treatments for chronic pain is an urgent medical need. Based on accumulating evidence from numerous studies, excess reactive oxygen species (ROS) contribute to the development and maintenance of chronic pain. Some antioxidants are potentially beneficial analgesics in the clinic, but ROS-dependent pathways are completely inhibited only by scavenging ROS directly targeting cellular or subcellular sites. Unfortunately, current antioxidant treatments donot achieve this effect. Furthermore, some antioxidants interfere with physiological redox signaling pathways and fail to reverse oxidative damage. Therefore, the key upstream processes and mechanisms of ROS production that lead to chronic pain in vivo must be identified to discover potential therapeutic targets related to the pathways that control ROS production in vivo. In this review, we summarize the sites and pathways involved in analgesia based on the three main mechanisms by which ROS are generated in vivo, discuss the preclinical evidence for the therapeutic potential of targeting these pathways in chronic pain, note the shortcomings of current research and highlight possible future research directions to provide new targets and evidence for the development of clinical analgesics.

Keywords:  NADPH oxidase; Reactive oxygen species; analgesics.; chronic pain; mitochondria; peroxisome

DOI:  https://doi.org/10.2174/1570159X22999231024140544
Gen Psychiatr. 2023 ;36(5): e101072

Targeting the ferroptosis crosstalk: novel alternative strategies for the treatment of major depressive disorder.

Luyao Wang, Rongyang Xu, Chengying Huang, Guozhong Yi, Zhiyong Li, Huayang Zhang, Rongxu Ye, Songtao Qi, Guanglong Huang, Shanqiang Qu.

  Depression is a major contributor to poor global health and disability, with a recently increasing incidence. Although drug therapy is commonly used to treat depression, conventional antidepressant drugs have several disadvantages, including slow onset, low response rates and severe adverse effects. Therefore, developing effective therapies for depression remains challenging. Although various aetiological theories of depression exist, the underlying mechanisms of depression are complex, and further research is crucial. Moreover, oxidative stress (OS)-induced lipid peroxidation has been demonstrated to trigger ferroptosis. Both OS and ferroptosis are pivotal mechanisms implicated in the pathogenesis of neurological disorders, and investigation of the mediators involved in these processes has emerged as a prominent and active research direction. One previous study revealed that regulatory proteins involved in ferroptosis are implicated in the pathogenesis of depression, and antidepressant drugs could reverse depressive symptoms by inhibiting ferroptosis in vivo, suggesting an important role of ferroptosis in the pathogenesis of depression. Hence, our current comprehensive review offers an up-to-date perspective on the intricate mechanisms involved, specifically concerning ferroptosis and OS in the context of depression, along with promising prospects for using molecular mediators to target ferroptosis. We delineate the key targets of molecular mediators involved in OS and ferroptosis implicated in depression, most notably reactive oxygen species and iron overload. Considering the pivotal role of OS-induced ferroptosis in the pathogenesis of neurological disorders, delving deeper into the underlying subsequent mechanisms will contribute significantly to the identification of novel therapeutic targets for depression.

Keywords:  depression

DOI:  https://doi.org/10.1136/gpsych-2023-101072
Sci Rep. 2023 10 28. 13(1): 18534

Neuroprotective effects of polyacrylic acid (PAA) conjugated cerium oxide against hydrogen peroxide- and 6-OHDA-induced SH-SY5Y cell damage.

Rugmani Meenambal, Tomasz Kruk, Jacek Gurgul, Piotr Warszyński, Danuta Jantas.

Cerium oxide nanoparticles have been widely investigated against neurodegenerative diseases due to their antioxidant properties that aid in quenching reactive oxygen species. In this study, polyacrylic acid conjugated cerium oxide (PAA-CeO) nanoparticles were synthesized in a 50-60 nm size range with a zeta potential of - 35 mV. X-ray photoelectron spectroscopy analysis revealed a mixed valence state of Ce4+ and Ce3+. PAA-CeO nanoparticles were safe for undifferentiated (UN-) and retinoic acid-differentiated (RA-) human neuroblastoma SH-SY5Y cells and reduced the extent of cell damage evoked by hydrogen peroxide (H2O2) and 6-hydroxydopamine (6-OHDA). In the H2O2 model of cell damage PAA-CeO did not affect the caspase-3 activity (apoptosis marker) but attenuated the number of propidium iodide-positive cells (necrosis marker). In the 6-OHDA model, nanoparticles profoundly reduced necrotic changes and partially attenuated caspase-3 activity. However, we did not observe any impact of PAA-CeO on intracellular ROS formation induced by H2O2. Further, the flow cytometry analysis of fluorescein isothiocyanate-labeled PAA-CeO revealed a time- and concentration-dependent cellular uptake of nanoparticles. The results point to the neuroprotective potential of PAA-CeO nanoparticles against neuronal cell damage induced by H2O2 and 6-OHDA, which are in both models associated with the inhibition of necrotic processes and the model-dependent attenuation of activity of executor apoptotic protease, caspase-3 (6-OHDA model) but not with the direct inhibition of ROS (H2O2 model).

DOI: https://doi.org/10.1038/s41598-023-45318-6
Pathol Oncol Res. 2023 ;29 1611415

Recent advances and future directions in etiopathogenesis and mechanisms of reactive oxygen species in cancer treatment.

Priyanka Verma, Bhavika Rishi, Noreen Grace George, Neetu Kushwaha, Himanshu Dhandha, Manpreet Kaur, Ankur Jain, Aditi Jain, Sumita Chaudhry, Amitabh Singh, Fouzia Siraj, Aroonima Misra.

  A class of exceptionally bioactive molecules known as reactive oxygen species (ROS) have been widely studied in the context of cancer. They play a significant role in the etiopathogenesis for cancer. Implication of ROS in cancer biology is an evolving area, considering the recent advances; insights into their generation, role of genomic and epigenetic regulators for ROS, earlier thought to be a chemical process, with interrelations with cell death pathways- Apoptosis, ferroptosis, necroptosis and autophagy has been explored for newer targets that shift the balance of ROS towards cancer cell death. ROS are signal transducers that induce angiogenesis, invasion, cell migration, and proliferation at low to moderate concentrations and are considered normal by-products of a range of biological activities. Although ROS is known to exist in the oncology domain since time immemorial, its excessive quantities are known to damage organelles, membranes, lipids, proteins, and nucleic acids, resulting in cell death. In the last two decades, numerous studies have demonstrated immunotherapies and other anticancer treatments that modulate ROS levels have promising in vitro and in vivo effects. This review also explores recent targets for therapeutic interventions in cancer that are based on ROS generation or inhibition to disrupt the cell oxidative stress balance. Examples include-metabolic targets, targeted therapy with biomarkers, natural extracts and nutraceuticals and targets developed in the area of nano medicine. In this review, we present the molecular pathways which can be used to create therapy plans that target cancer by regulating ROS levels, particularly current developments and potential prospects for the effective implementation of ROS-mediated therapies in clinical settings. The recent advances in complex interaction with apoptosis especially ferroptosis and its role in epigenomics and modifications are a new paradigm, to just mechanical action of ROS, as highlighted in this review. Their inhibition by nutraceuticals and natural extracts has been a scientific challenging avenue that is explored. Also, the inhibition of generation of ROS by inhibitors, immune modulators and inhibitors of apoptosis and ferroptosis is explored in this review.

Keywords:  cancer therapy; ferroptosis; future directions; reactive oxygen species (ROS); recent advances

DOI:  https://doi.org/10.3389/pore.2023.1611415
RSC Adv. 2023 Oct 31. 13(46): 32150-32159

Synthesis and biological evaluation of capsaicin analogues as antioxidant and neuroprotective agents.

Mao Xie, Huixian Wu, Jing Bian, Shutong Huang, Yuanzheng Xia, Yujun Qin, Zhiming Yan.

Capsaicin and its analogues 3a-3q were designed and synthesized as potential new antioxidant and neuroprotective agents. Many analogues exhibited good antioxidant effects, and some showed more potent free radical scavenging activities than the positive drug quercetin (IC50 = 8.70 ± 1.75 μM for DPPH assay and 13.85 ± 2.87 μM for ABTS assay, respectively). The phenolic hydroxyl of capsaicin analogues was critical in determining antioxidant activity. Among these compounds, 3k displayed the most potent antioxidant activity. Cell vitality tests revealed that the representative compound 3k was good at protecting cells from H2O2-induced oxidative damage at low concentrations (cell viability increased to 90.0 ± 5.5% at 10 μM). In addition, the study demonstrated that 3k could reduce intracellular ROS accumulation and increase GSH levels to prevent H2O2-induced oxidative stress in SY5Y cells. In the mitochondrial membrane potential assay, 3k significantly increased the MMP level of SY5Y cells treated with H2O2 and played an anti-neuronal cell death role. These results provide a promising strategy to develop novel capsaicin analogues as potential antioxidant and neuroprotective agents.

DOI: https://doi.org/10.1039/d3ra05107b
J Neurochem. 2023 Oct 29.

Immunity impacts cognitive deficits across neurological disorders.

Benjamin C Shaw, Victoria R Anders, Rachel A Tinkey, Maria L Habean, Orion D Brock, Benjamin J Frostino, Jessica L Williams.

  Cognitive deficits are a common comorbidity with neurological disorders and normal aging. Inflammation is associated with multiple diseases including classical neurodegenerative dementias such as Alzheimer's disease (AD) and autoimmune disorders such as multiple sclerosis (MS), in which over half of all patients experience some form of cognitive deficits. Other degenerative diseases of the central nervous system (CNS) including frontotemporal lobe dementia (FTLD), and Parkinson's disease (PD) as well as traumatic brain injury (TBI) and psychological disorders like major depressive disorder (MDD), and even normal aging all have cytokine-associated reductions in cognitive function. Thus, there is likely commonality between these secondary cognitive deficits and inflammation. Neurological disorders are increasingly associated with substantial neuroinflammation, in which CNS-resident cells secrete cytokines and chemokines such as tumor necrosis factor (TNF)α and interleukins (ILs) including IL-1β and IL-6. CNS-resident cells also respond to a wide variety of cytokines and chemokines, which can have both direct effects on neurons by changing the expression of ion channels and perturbing electrical properties, as well as indirect effects through glia-glia and immune-glia cross-talk. There is significant overlap in these cytokine and chemokine expression profiles across diseases, with TNFα and IL-6 strongly associated with cognitive deficits in multiple disorders. Here, we review the involvement of various cytokines and chemokines in AD, MS, FTLD, PD, TBI, MDD, and normal aging in the absence of dementia. We propose that the neuropsychiatric phenotypes observed in these disorders may be at least partially attributable to a dysregulation of immunity resulting in pathological cytokine and chemokine expression from both CNS-resident and non-resident cells.

Keywords:  Neuroimmunology; cognition; cytokine; glia

DOI:  https://doi.org/10.1111/jnc.15999
Tissue Cell. 2023 Oct 24. pii: S0040-8166(23)00244-6. [Epub ahead of print]85 102256

Gentisic acid ameliorates cisplatin-induced reprotoxicity through suppressing endoplasmic reticulum stress and upregulating Nrf2 pathway.

Ahmet Mentese, Selim Demir, Sevdegul Aydin Mungan, Nihal Turkmen Alemdar, Elif Ayazoglu Demir, Yuksel Aliyazicioglu.

  Reproductive toxicity is a serious side effect of cisplatin (CP) chemotherapy. Gentisic acid (GTA) is a phenolic acid with strong antioxidant properties. Here, we aimed to determine therapeutic effect of GTA against CP-induced testicular toxicity in rats for the first time. Male Sprague-Dawley rats received a single dose of CP (5 mg/kg; intraperitoneal) and treated with GTA (1.5 and 3 mg/kg; intraperitoneal; 3 consecutive days). The levels of oxidative stress (OS), inflammation, endoplasmic reticulum stress (ERS) and apoptosis biomarkers were assessed in the testicular tissue of rats. In addition, how CP affects the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway and the effect of GTA on this situation were also addressed in the testicular tissue. CP administration induced histopathological changes in testicular tissue of rats with a significant increase in OS, inflammation, ERS and apoptosis biomarkers and a decrease in antioxidant capacity and Nrf2 expression levels. Administrations of GTA resulted in an amelioration of these altered parameters. These data suggest that GTA may be a potential therapeutic agent against CP-induced testicular toxicity. Activation of the Nrf2 pathway plays a key role of this therapeutic effect of GTA.

Keywords:  Cisplatin; Endoplasmic reticulum stress; Gentisic acid; Inflammation; Nrf2; Oxidative stress; Testicular toxicity

DOI:  https://doi.org/10.1016/j.tice.2023.102256
Curr Drug Metab. 2023 Oct 24.

Nrf2 Regulates the Expression of CYP2D6 by Inhibiting the Activity of Krüppel-Like Factor 9 (KLF9).

Ferbian Milas Siswanto, Rita Dewi Firmasyah, Maria Dara Novi Handayani, Ami Oguro, Susumu Imaoka.

   AIMS: The aim of the present study is to gain insight into the biology of Parkinson's disease (PD) and cancer to drive translational advances enabling more effective prevention and/or potential treatments.
BACKGROUND: The expression of Cytochrome P450 2D6 (CYP2D6) is correlated with various diseases such as PD and cancer; therefore, exploring its regulatory mechanism at transcriptional levels is of interest. NF-E2-related factor 2 (Nrf2) has been known to be responsible for regulating phase II and phase III drug-metabolizing genes.
OBJECTIVES: The objectives of this study are to investigate the transcriptional regulation of CYP2D6 by Nrf2 and to analyze its role in PD and cancer.
METHODS: Nrf2 was transiently expressed in human hepatoma Hep3B cells, and the expression of CYP2D6 was examined by RT-qPCR. The promoter activity of CYP2D6 and the DNA binding of Nrf2 were examined by luciferase and ChIP assay, respectively. We then investigated the expression and correlation of Nrf2 and CYP2D6 in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets.
RESULTS: In the present study, we demonstrated that Nrf2 down-regulated CYP2D6 mRNA expression in hepatoma Hep3B cells. Mechanistically, Nrf2 binds to the antioxidant responsive element (ARE) in the proximity of krüppel- like factor 9 (KLF9)-binding site within the -550/+51 of CYP2D6 promoter. The inhibition and activation of Nrf2 enhanced and suppressed KLF9 effects on CYP2D6 expression, respectively. The expression levels of Nrf2 and CYP2D6 were upregulated and downregulated in the PD patient GEO datasets compared to the healthy control tissues, and Nrf2 was negatively correlated with CYP2D6. In liver cancer patients, decreased CYP2D6 levels were apparent and associated with a lower probability of survival.
CONCLUSION: Our work revealed the inhibitory role of Nrf2 in regulating CYP2D6 expression. Moreover, Nrf2- dependent regulation of CYP2D6 can be used as a prognostic factor and therapeutic strategy in PD and liver cancer.

Keywords:  CYP2D6; KLF9; Nrf2; Parkinson’s disease; liver cancer; transcriptional regulation

DOI:  https://doi.org/10.2174/0113892002271342231013095255
Mol Neurobiol. 2023 Nov 01.

In Vivo Intracerebral Administration of α-Ketoisocaproic Acid to Neonate Rats Disrupts Brain Redox Homeostasis and Promotes Neuronal Death, Glial Reactivity, and Myelination Injury.

Ângela Beatris Zemniaçak, Rafael Teixeira Ribeiro, Camila Vieira Pinheiro, Sâmela de Azevedo Cunha, Tailine Quevedo Tavares, Ediandra Tissot Castro, Guilhian Leipnitz, Moacir Wajner, Alexandre Umpierrez Amaral.

  Maple syrup urine disease (MSUD) is caused by severe deficiency of branched-chain α-keto acid dehydrogenase complex activity, resulting in tissue accumulation of branched-chain α-keto acids and amino acids, particularly α-ketoisocaproic acid (KIC) and leucine. Affected patients regularly manifest with acute episodes of encephalopathy including seizures, coma, and potentially fatal brain edema during the newborn period. The present work investigated the ex vivo effects of a single intracerebroventricular injection of KIC to neonate rats on redox homeostasis and neurochemical markers of neuronal viability (neuronal nuclear protein (NeuN)), astrogliosis (glial fibrillary acidic protein (GFAP)), and myelination (myelin basic protein (MBP) and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase)) in the cerebral cortex and striatum. KIC significantly disturbed redox homeostasis in these brain structures 6 h after injection, as observed by increased 2',7'-dichlorofluorescein oxidation (reactive oxygen species generation), malondialdehyde levels (lipid oxidative damage), and carbonyl formation (protein oxidative damage), besides impairing the antioxidant defenses (diminished levels of reduced glutathione and altered glutathione peroxidase, glutathione reductase, and superoxide dismutase activities) in both cerebral structures. Noteworthy, the antioxidants N-acetylcysteine and melatonin attenuated or normalized most of the KIC-induced effects on redox homeostasis. Furthermore, a reduction of NeuN, MBP, and CNPase, and an increase of GFAP levels were observed at postnatal day 15, suggesting neuronal loss, myelination injury, and astrocyte reactivity, respectively. Our data indicate that disruption of redox homeostasis, associated with neural damage caused by acute intracerebral accumulation of KIC in the neonatal period may contribute to the neuropathology characteristic of MSUD patients.

Keywords:  Cerebral cortex; Maple syrup urine disease; Neurochemical markers; Redox homeostasis; Striatum; α-Ketoisocaproic acid

DOI:  https://doi.org/10.1007/s12035-023-03718-9