bims-redobi 2024-11-03 papers

bims-redobi

Biomed News

on Redox biology

Issue of 2024–11–03
sixteen papers selected by
Vanesa Cepas López, Candiolo Cancer Institute

Assessing the therapeutic potential of KK14 peptide derived from Cyprinus Carpio in reducing intercellular ROS levels in oxidative Stress-Induced In vivo zebrafish larvae model: An integrated bioinformatics, antioxidant, and neuroprotective analysis.
Self-assembled aldehyde dehydrogenase-activatable nano-prodrug for cancer stem cell-enriched tumor detection and treatment.
Unraveling the redox code to improve physiological research in human health and disease.
Suppression of JNK pathway protects neurons from oxidative injury via attenuating parthanatos in glutamate-treated HT22 neurons.
Multiple variables influence the finely calibrated antioxidant defenses of Clostridioides difficile.
Demystifying the management of cancer through smart nano-biomedicine via regulation of reactive oxygen species.
TNF-ɑ induces mitochondrial dysfunction to drive NLRP3/Caspase-1/GSDMD-mediated pyroptosis in MCF-7 cells.
Nanozymes as Glucose Scavengers and Oxygenerators for Enhancing Tumor Radiotherapy.
Dapagliflozin mitigates cellular stress and inflammation through PI3K/AKT pathway modulation in cardiomyocytes, aortic endothelial cells, and stem cell-derived β cells.
ACSS2 regulates ferroptosis in an E2F1-dependent manner in breast cancer brain metastatic cells.
A cocktail of Cu2+- and Zn2+-peptoid-based chelators can stop ROS formation for Alzheimer's disease therapy.
Functional analysis of TkWRKY33: A key regulator in drought-induced natural rubber synthesis in Taraxacum kok-saghyz.
Biologically logic-gated Trojan-horse strategy for personalized triple-negative breast cancer precise therapy by selective ferroptosis and STING pathway provoking.
UVA Irradiation Promotes Melanoma Cell Proliferation Mediated by OPN3 Independently of ROS Production.
An increase in reactive oxygen species underlies neonatal cerebellum repair.
The ability in managing reactive oxygen species affects Escherichia coli persistence to ampicillin after nutrient shifts.

J Biochem Mol Toxicol. 2024 Nov;38(11): e70027

Assessing the therapeutic potential of KK14 peptide derived from Cyprinus Carpio in reducing intercellular ROS levels in oxidative Stress-Induced In vivo zebrafish larvae model: An integrated bioinformatics, antioxidant, and neuroprotective analysis.

Madhumitha Vijayanand, Ajay Guru, Mohammed Rafi Shaik, Shaik Althaf Hussain, Praveen Kumar Issac.

  H2O2 is a significant reactive oxygen species (ROS) that hinders redox-mediated processes and contributes to oxidative stress and neurodegenerative disorders. Oxidative stress causes impairment of cell macromolecules, which results in cell dysfunction and neurodegeneration. Alzheimer's disease and other neurodegenerative diseases are serious conditions linked to oxidative stress. Antioxidant treatment approaches are a novel and successful strategy for decreasing neurodegeneration and reducing oxidative stress. This study explored the antioxidant and neuroprotective characteristics of KK14 peptide synthesized from LEAP 2B (liver-expressed antimicrobial peptide-2B) derived from Cyprinus carpio L. Molecular docking studies were used to assess the antioxidant properties of KK14. The peptide at concentrations 5-45 μM was examined by using in vitro and in vivo assessment. Analysis was done on the developmental and neuroprotective potential of KK14 peptide treatment in H2O2-exposed zebrafish larvae which showed Nonlethal deformities. KK14 improves antioxidant enzyme activity like catalase and superoxide dismutase. Furthermore, it reduces neuronal damage by lowering lipid peroxidation and nitric oxide generation while increasing acetylcholinesterase activity. It improved the changes in swimming behavior and the cognitive damage produced by exposure to H2O2. To further substantiate the neuroprotective potential of KK14, intracellular ROS levels in zebrafish larvae were assessed. This led to a reduction in ROS levels and diminished lipid peroxidation. The KK14 has upregulated the antioxidant genes against oxidative stress. Overall, this study proved the strong antioxidant activity of KK14, suggesting its potential as a strong therapeutic option for neurological disorders caused by oxidative stress.

Keywords:  KK14; Zebrafish models; antimicrobial peptide; antioxidant; neuroprotection; oxidative stress

DOI:  https://doi.org/10.1002/jbt.70027
Nat Commun. 2024 Oct 31. 15(1): 9417

Self-assembled aldehyde dehydrogenase-activatable nano-prodrug for cancer stem cell-enriched tumor detection and treatment.

Bowen Li, Jianwu Tian, Fu Zhang, Chongzhi Wu, Zhiyao Li, Dandan Wang, Jiahao Zhuang, Siqin Chen, Wentao Song, Yufu Tang, Yuan Ping, Bin Liu.

Cancer stem cells, characterized by high tumorigenicity and drug-resistance, are often responsible for tumor progression and metastasis. Aldehyde dehydrogenases, often overexpressed in cancer stem cells enriched tumors, present a potential target for specific anti-cancer stem cells treatment. In this study, we report a self-assembled nano-prodrug composed of aldehyde dehydrogenases activatable photosensitizer and disulfide-linked all-trans retinoic acid for diagnosis and targeted treatment of cancer stem cells enriched tumors. The disulfide-linked all-trans retinoic acid can load with photosensitizer and self-assemble into a stable nano-prodrug, which can be disassembled into all-trans retinoic acid and photosensitizer in cancer stem cells by high level of glutathione. As for the released photosensitizer, overexpressed aldehyde dehydrogenase catalyzes the oxidation of aldehydes to carboxyl under cancer stem cells enriched microenvironment, activating the generation of reactive oxygen species and fluorescence emission. This generation of reactive oxygen species leads to direct killing of cancer stem cells and is accompanied by a noticeable fluorescence enhancement for real-time monitoring of the cancer stem cells enriched microenvironment. Moreover, the released all-trans retinoic acid, as a differentiation agent, reduce the cancer stem cells stemness and improve the cancer stem cells enriched microenvironment, offering a synergistic effect for enhanced anti-cancer stem cells treatment of photosensitizer in inhibition of in vivo tumor growth and metastasis.

DOI: https://doi.org/10.1038/s41467-024-53771-8
Physiol Rep. 2024 Nov;12(21): e70105

Unraveling the redox code to improve physiological research in human health and disease.

Josh Thorley.

  Redox reactions, involving electron transfer, are critical to human physiology. However, progress in understanding redox metabolism is hindered by flawed analytical methods. This review highlights emerging techniques that promise to revolutionize redox research, enhancing our comprehension of human health and disease. Oxygen, vital for aerobic metabolism, also produces reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. While historically seen as harmful, ROS at low concentrations are now recognized as key regulators of cell signaling. A balance between ROS and antioxidants, known as redox balance, is crucial, and deviations can lead to oxidative stress. Recent studies have distinguished beneficial "oxidative eustress" from harmful "oxidative distress." New techniques, such as advanced mass spectrometry and high-throughput immunoassays, offer improved accuracy in measuring redox states and oxidative damage. These advancements are pivotal for understanding redox signaling, cysteine oxidation, and their implications for disease. Looking ahead, the development of precision redox medicine could lead to better treatments for oxidative stress-related diseases and foster interventions promoting health.

Keywords:  ROS; cysteine; hydrogen peroxide; redox signaling

DOI:  https://doi.org/10.14814/phy2.70105
Sci Rep. 2024 10 28. 14(1): 25793

Suppression of JNK pathway protects neurons from oxidative injury via attenuating parthanatos in glutamate-treated HT22 neurons.

Wuqiong Zhang, Huaiyu Sun, Weixuan Zhao, Jiaai Li, Hongmei Meng.

  Oxidative stress causes diverse neurological disorders. Parthanatos is a type of programmed cell death, characterised by strong activation of poly (ADP-ribose) (PAR) polymerase-1 (PARP-1), PAR polymer accumulation, and nuclear translocation of apoptosis-inducing factor (AIF), and is involved in cellular oxidative injury. Signalling by c-Jun-N-terminal protein kinase (JNK) is activated by reactive oxygen species (ROS), and this also contributes to ROS production. However, the exact relationship between JNK signalling and parthanatos in neurological disorders triggered by oxidative stress is unclear. In this study, glutamate-treated HT22 neurons were used to investigate whether the signalling by JNK contributes a regulatory role to parthanatos in oxidative stress-related neurological disease. JNK signalling was activated in glutamate-treated HT22 neurons, demonstrated via upregulation of p-JNK levels. Pre-treatment with SP600125 markedly inhibited JNK signalling, increased cell viability, and significantly reversed PARP-1 overproduction, PAR polymer accumulation, and nuclear AIF translocation. In addition, inhibition of JNK signalling severely reduced the production of both intracellular ROS and mitochondria superoxide. This study indicated that parthanatos in glutamate-treated HT22 neurons could be suppressed by JNK signalling inhibition. JNK activation participated in parthanatos via an increase in intracellular ROS levels.

Keywords:  Cell death; JNK; Neurons; Parthanatos; ROS

DOI:  https://doi.org/10.1038/s41598-024-76640-2
mBio. 2024 Oct 30. e0254424

Multiple variables influence the finely calibrated antioxidant defenses of Clostridioides difficile.

Erin B Purcell.

  The obligate anaerobe Clostridioides difficile encodes multiple reductases to detoxify molecular oxygen and reactive oxygen species. Caulat and colleagues have characterized the activity and regulation of four such reductases (L. C. Caulat, A. Lotoux, M. C. Martins, N. Kint, et al., mBio 15:e01591-24, 2024, https://doi.org/10.1128/mbio.01591-24). Each proved critical for clostridial survival in a different range of oxygen concentrations; together, they ameliorate a broad range of oxidative stress levels. Moreover, two previously uncharacterized regulators were found to control reductase gene expression in response to oxidative stress. The genetic repressor Rex and the reductase FdpF are both sensitive to the NAP+:NADH ratio, which is affected by a cell's metabolic state as well as redox activity. While oxygen is known to influence the expression of metabolism genes in C. difficile, the mechanisms for cross-talk between the pathways that respond to oxidative and metabolic stress are not well known. The NADH dependence of Rex and FdpF may represent a newly mapped junction between these pathways.

Keywords:  Clostridioides difficile; antioxidant; oxidative stress; oxygen reductase

DOI:  https://doi.org/10.1128/mbio.02544-24
Naunyn Schmiedebergs Arch Pharmacol. 2024 Oct 31.

Demystifying the management of cancer through smart nano-biomedicine via regulation of reactive oxygen species.

Abhay Prakash Mishra, Rajesh Kumar, Seetha Harilal, Manisha Nigam, Deepanjan Datta, Sudarshan Singh, Neti Waranuch, Chuda Chittasupho.

  Advancements in therapeutic strategies and combinatorial approaches for cancer management have led to the majority of cancers in the initial stages to be regarded as treatable and curable. However, certain high-grade cancers in the initial stages are still regarded as chronic and difficult to manage, requiring novel therapeutic strategies. In this era of targeted and precision therapy, novel strategies for targeted delivery of drug and synergistic therapies, integrating nanotherapeutics, polymeric materials, and modulation of the tumor microenvironment are being developed. One such strategy is the study and utilization of smart-nano biomedicine, which refers to stimuli-responsive polymeric materials integrated with the anti-cancer drug that can modulate the reactive oxygen species (ROS) in the tumor microenvironment or can be ROS responsive for the mitigation as well as management of various cancers. The article explores in detail the ROS, its types, and sources; the antioxidant system, including scavengers and their role in cancer; the ROS-responsive targeted polymeric materials, including synergistic therapies for the treatment of cancer via modulating the ROS in the tumor microenvironment, involving therapeutic strategies promoting cancer cell death; and the current landscape and future prospects.

Keywords:  Cancer; Cancer theranostics; Free radicals; Metallic nanomaterials; Nano-biomedicine; Reactive oxygen species

DOI:  https://doi.org/10.1007/s00210-024-03469-x
Sci Rep. 2024 10 29. 14(1): 25880

TNF-ɑ induces mitochondrial dysfunction to drive NLRP3/Caspase-1/GSDMD-mediated pyroptosis in MCF-7 cells.

Kexin Gao, Yancui Liu, Cheng Sun, Ying Wang, Hongrong Bao, Guoyang Liu, Jinrui Ou, Ping Sun.

  Pyroptosis is a gasdermin-mediated pro-inflammatory form of programmed cell death (PCD). Tumor necrosis factor-ɑ (TNF-ɑ) is an inflammatory cytokine, and some studies have shown that TNF-ɑ can cause pyroptosis of cells and exert anti-tumor effects. However, whether TNF-ɑ exerts anti-tumor effects on breast cancer cells by inducing pyroptosis has not been reported. In this study, to explore the impact of TNF-ɑ on pyroptosis in breast cancer cells, we treated MCF-7 cells with TNF-ɑ and found that TNF-ɑ induced cell death. Moreover, we observed that the dead cells were swollen with obvious balloon-like bubbles, which was a typical sign of pyroptosis. Further studies have found that the anti-tumor effect of TNF-ɑ on breast cancer cells in vitro was achieved through the canonical pyroptosis pathway. In addition, TNF-ɑ-induced pyroptosis in MCF-7 cells was associated with mitochondrial dysfunction, in which mitochondrial membrane potential was decreased and mitochondrial ROS production was increased. After inhibiting ROS production, the activation effect of TNF-ɑ on NLRP3/Caspase-1/GSDMD pathway was weakened, and the inhibitory effect of TNF-ɑ on the growth of MCF-7 cells in vitro was also decreased, further confirming the involvement of ROS in TNF-ɑ-induced pyroptosis. Overall, our study revealed a new mechanism by which TNF-ɑ exerts an anti-tumor effect by inducing pyroptosis in MCF-7 cells through the ROS/NLRP3/Caspase-1/GSDMD pathway, which may provide new therapeutic ideas for the treatment of breast cancer.

Keywords:  Breast cancer; Pyroptosis; ROS; TNF-ɑ

DOI:  https://doi.org/10.1038/s41598-024-76997-4
ACS Appl Mater Interfaces. 2024 Oct 31.

Nanozymes as Glucose Scavengers and Oxygenerators for Enhancing Tumor Radiotherapy.

Yuxuan Zhang, Xingchen Li, Xiaojun Ren, Dongzhou Wang, Yuechen Zhao, Yuan Wang, Shunzi Jin, Quan Lin, Kun Zou, Tiejun Wang.

  Insufficient accumulation of reactive oxygen species (ROS) due to tumor hypoxia significantly contributes to increased radiation resistance and the failure of radiotherapy (RT). Therefore, developing methods to alleviate hypoxia and boost ROS levels represents a promising strategy for enhanced radiosensitivity. This study introduced a self-cascade catalytic Pt@Au nanozymes as a radiosensitizer, using glucose oxidase (GOx)-, catalase (CAT)-, and peroxidase (POD)-like activities to improve hypoxia and increase ROS accumulation, thereby affecting glucose metabolism and enhancing the effects of RT. Pt@Au nanozymes exhibit GOx-like activity, which not only depletes glucose to induce starvation therapy, but also generates hydrogen peroxide (H2O2) for cascade reactions. Moreover, Pt@Au nanozymes demonstrate CAT-like activity, catalyzing the conversion of H2O2 to O2. This conversion effectively alleviates hypoxia, stabilizes ROS, increases DNA damage, significantly enhancing RT efficacy and sustaining the effects of starvation therapy. As high-Z materials, Pt@Au nanozymes can deposit more X-ray energy. Furthermore, the POD-like activity catalyzes the conversion of H2O2 into highly reactive hydroxyl radicals (·OH), which increases ROS levels and enhances RT. Pt@Au nanozymes serve as X-ray computed tomography (CT) imaging agents, allowing for clear differentiation between tumor and normal tissue boundaries and enhancing the precision of RT. In summary, Pt@Au nanozymes serve as effective radiosensitizers by depleting glucose to induce starvation therapy, enhancing cascade reactions, and inhibiting tumor proliferation. Through their self-cascade reactions, these nanozymes dramatically increase oxygen levels within tumors, reduce hypoxia, and enhance ROS levels. This advancement addresses the radioresistance associated with hypoxic tumors, paving the way for innovative strategies in RT.

Keywords:  Cascade catalytic reaction; Nanozyme; Radiosensitization; Starvation therapy; Tumor hypoxia

DOI:  https://doi.org/10.1021/acsami.4c18066
Cardiovasc Diabetol. 2024 Oct 29. 23(1): 388

Dapagliflozin mitigates cellular stress and inflammation through PI3K/AKT pathway modulation in cardiomyocytes, aortic endothelial cells, and stem cell-derived β cells.

Fatmah R Alsereidi, Zenith Khashim, Hezlin Marzook, Ahmed M Al-Rawi, Tiana Salomon, Mahra K Almansoori, Moustafa M Madkour, Ahmed Mohamed Hamam, Mahmoud M Ramadan, Quinn P Peterson, Mohamed A Saleh.

  Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is well-recognized for its therapeutic benefits in type 2 diabetes (T2D) and cardiovascular diseases. In this comprehensive in vitro study, we investigated DAPA's effects on cardiomyocytes, aortic endothelial cells (AECs), and stem cell-derived beta cells (SC-β), focusing on its impact on hypertrophy, inflammation, and cellular stress. Our results demonstrate that DAPA effectively attenuates isoproterenol (ISO)-induced hypertrophy in cardiomyocytes, reducing cell size and improving cellular structure. Mechanistically, DAPA mitigates reactive oxygen species (ROS) production and inflammation by activating the AKT pathway, which influences downstream markers of fibrosis, hypertrophy, and inflammation. Additionally, DAPA's modulation of SGLT2, the Na+/H + exchanger 1 (NHE1), and glucose transporter (GLUT 1) type 1 highlights its critical role in maintaining cellular ion balance and glucose metabolism, providing insights into its cardioprotective mechanisms. In aortic endothelial cells (AECs), DAPA exhibited notable anti-inflammatory properties by restoring AKT and phosphoinositide 3-kinase (PI3K) expression, enhancing mitogen-activated protein kinase (MAPK) activation, and downregulating inflammatory cytokines at both the gene and protein levels. Furthermore, DAPA alleviated tumor necrosis factor (TNFα)-induced inflammation and stress responses while enhancing endothelial nitric oxide synthase (eNOS) expression, suggesting its potential to preserve vascular function and improve endothelial health. Investigating SC-β cells, we found that DAPA enhances insulin functionality without altering cell identity, indicating potential benefits for diabetes management. DAPA also upregulated MAFA, PI3K, and NRF2 expression, positively influencing β-cell function and stress response. Additionally, it attenuated NLRP3 activation in inflammation and reduced NHE1 and glucose-regulated protein GRP78 expression, offering novel insights into its anti-inflammatory and stress-modulating effects. Overall, our findings elucidate the multifaceted therapeutic potential of DAPA across various cellular models, emphasizing its role in mitigating hypertrophy, inflammation, and cellular stress through the activation of the AKT pathway and other signaling cascades. These mechanisms may not only contribute to enhanced cardiac and endothelial function but also underscore DAPA's potential to address metabolic dysregulation in T2D.

Keywords:  AKT signaling; Beta cells; Cardiomyocyte; Dapagliflozin; Endothelial cells; Inflammation; Sodium-glucose cotransporter

DOI:  https://doi.org/10.1186/s12933-024-02481-y
bioRxiv. 2024 Oct 21. pii: 2024.10.18.619082. [Epub ahead of print]

ACSS2 regulates ferroptosis in an E2F1-dependent manner in breast cancer brain metastatic cells.

Emily M Esquea, Riley G Young, Lorela Ciraku, Jessica Merzy, Nusaiba N Ahmed, Alexandra N Talarico, Mangalam Karuppiah, Wiktoria Gocal, Nicole L Simone, Alexej Dick, Mauricio J Reginato.

Brain metastasis diagnosis in breast cancer patients is considered an end-stage event. The median survival after diagnosis is measured in months, thus there is an urgent need to develop novel treatment strategies. Breast cancers that metastasize to the brain must adapt to the unique brain environment and are highly dependent on acetate metabolism for growth and survival. However, the signaling pathways that regulate survival in breast cancer brain metastatic (BCBM) tumors are not known. Primary brain tumor cells can convert acetate to acetyl-CoA via phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by the cyclin-dependent kinase-5 (CDK5) regulated by the nutrient sensor O-GlcNAc transferase (OGT). Here, we show that breast cancer cells selected to metastasize to the brain contain increased levels of O-GlcNAc, OGT and ACSS2-Ser267 phosphorylation compared to parental breast cancer cells. Moreover, OGT and CDK5 are required for breast cancer cell growth in the brain parenchyma in vivo. Importantly, ACSS2 and ACSS2-S267D phospho-mimetic mutant are critical for in vivo breast cancer growth in the brain but not in the mammary fat pad. Mechanistically, we show that ACSS2 regulates BCBM cell survival by suppressing ferroptosis via regulation of E2F1-mediated expression of anti-ferroptotic proteins SLC7A11 and GPX4. Lastly, we show treatment with a novel brain-permeable small molecule ACSS2 inhibitor induced ferroptosis and reduced BCBM growth ex vivo and in vivo . These results suggest a crucial role for ACSS2 in protecting from ferroptosis in breast cancer brain metastatic cells and suggests that breast cancer brain metastatic cells may be susceptible to ferroptotic inducers.

DOI: https://doi.org/10.1101/2024.10.18.619082
Chem Sci. 2024 Oct 24.

A cocktail of Cu2+- and Zn2+-peptoid-based chelators can stop ROS formation for Alzheimer's disease therapy.

Anastasia E Behar, Galia Maayan.

The formation of reactive oxygen species (ROS) in the brain is a major cause of neuropathologic degradation associated with Alzheimer's Disease (AD). It has been suggested that the copper (Cu)-amyloid-β (Aβ) peptide complex can lead to ROS formation in the brain. An external chelator for Cu that can extract Cu from the CuAβ complex should inhibit the formation of ROS, making Cu chelation an excellent therapeutic approach for AD. Such a chelator should possess high selectivity for Cu over zinc (Zn), which is also present within the synaptic cleft. However, such selectivity is generally hard to achieve in one molecule due to the similarities in the binding preferences of these two metal ions. As an alternative to monotherapy (where Cu extraction is performed using a single chelator), herein we describe a variation of combination therapy - a novel cocktail approach, which is based on the co-administration of two structurally different peptidomimetic chelators, aiming to target both Cu2+ and Zn2+ ions simultaneously but independently from each other. Based on rigorous spectroscopic experiments, we demonstrate that our peptidomimetic cocktail allows, for the first time, the complete and immediate inhibition of ROS production by the CuAβ complex in the presence of Zn2+. In addition, we further demonstrate the high stability of the cocktail under simulated physiological conditions and its resistance to proteolytic degradation by trypsin and report the water/n-octanol partition coefficient, initially assessing the blood-brain barrier (BBB) permeability potential of the chelators.

DOI: https://doi.org/10.1039/d4sc04313h
Plant Physiol Biochem. 2024 Oct 25. pii: S0981-9428(24)00900-8. [Epub ahead of print]217 109232

Functional analysis of TkWRKY33: A key regulator in drought-induced natural rubber synthesis in Taraxacum kok-saghyz.

Yulin Wu, Yaxin Liu, Yunchuan Zhang, Gaoquan Dong, Jie Yan, Hao Zhang.

  WRKY proteins, which form a transcription factor superfamily that responds to jasmonic acid (JA) signals, regulate various developmental processes and stress responses in plants, including Taraxacum kok-saghyz (TKS). TKS serves as an ideal model plant for studying rubber production and lays the foundation for a comprehensive understanding of JA-mediated regulation of natural rubber synthesis. In the present study, we screened and identified a valuable transcription factor, TkWRKY33, based on transcriptome data from TKS in response to JA. We investigated its role in the regulation of natural rubber synthesis within the JA signaling pathway and its function in response to drought stress. Through protein-protein interactions and transcriptional regulation analysis, we found that TkWRKY33 may regulate natural rubber synthesis through the JA-TkMPK3-TkWRKY33-(TkGGPS5/TkACAT8) cascade pathway, possibly by participating in JA-activated mitogen-activated protein kinase (MAPK) signaling. Overexpression of TkWRKY33 in tobacco, along with functional analysis of drought resistance and comparative analysis of natural rubber content after drought stress, revealed that TkWRKY33 not only enhances plant drought resistance by regulating the expression of genes related to reactive oxygen species (ROS) scavenging through the JA signaling pathway, but also has a close relationship with the signal transduction pathway mediated by the JA hormone in regulating natural rubber synthesis. The TkWRKY33 is recognized as a valuable transcription factor, which likely plays a role in regulating natural rubber biosynthesis through the JA-activated MAPK cascade signaling pathway JA-TkMPK3-TkWRKY33-(TkGGPS5/TkACAT8).

Keywords:  Drought resistance; Jasmonic acid signaling pathway; Natural rubber synthesis; Taraxacum kok-saghyz (TKS); WRKY

DOI:  https://doi.org/10.1016/j.plaphy.2024.109232
Biomaterials. 2024 Oct 21. pii: S0142-9612(24)00439-3. [Epub ahead of print]315 122905

Biologically logic-gated Trojan-horse strategy for personalized triple-negative breast cancer precise therapy by selective ferroptosis and STING pathway provoking.

Shuai Guo, Tianwang Guan, Yushen Ke, Yuping Lin, Rundong Tai, Jujian Ye, Zhilin Deng, Shaohui Deng, Caiwen Ou.

  Amidst the therapeutic quandaries associated with triple-negative breast cancer (TNBC), an aggressive malignancy distinguished by its immune resistance and limited treatment avenues, the urgent need for innovative solutions is underscored. To conquer the dilemma, we present a groundbreaking approach that ingeniously employs DNA-fragments-containing exosomes (DNA-Exo) and the concept of "biological logic-gates" to achieve precise homing and controlled selective activation of ferroptosis and stimulator interferon genes (STING) pathways. Leveraging insights from our previous research, a nano-Trojan-horse, Fe0@HMON@DNA-Exo, is engineered via in situ Fe0 synthesis within the glutathione (GSH)-responsiveness degradable hollow mesoporous organosilica nanoparticles (HMON) and subsequently enveloped in DNA-Exo derived from 7-ethyl-10-hydroxycamptothecin (SN38)-treated 4T1 cells. Emphasizing the precision of our approach, the DNA-Exo ensures specific 'homing' to TNBC cells, rendering a targeted delivery mechanism. Concurrently, the concept of "biological logic-gates" is employed to dictate a meticulous and selective activation of STING in antigen-presenting cells (APCs) under OR logic-gating with robust immune response and Fe0-based ferroptosis in TNBC cells under AND logic-gating with reactive oxygen species (ROS) storm generation. In essence, our strategy exhibits great potential in transforming the "immunologically cold" nature of TNBC, enabling precise control over cellular responses, illuminating a promising therapeutic paradigm that is comprehensive and productive in pursuing precision oncology and paving the way for personalized TNBC therapies.

Keywords:  Biological logic-gate; Ferroptosis; Stimulator interferon genes (STING) pathway; Triple-negative breast cancer (TNBC); Trojan-horse strategy

DOI:  https://doi.org/10.1016/j.biomaterials.2024.122905
Pigment Cell Melanoma Res. 2024 Oct 30.

UVA Irradiation Promotes Melanoma Cell Proliferation Mediated by OPN3 Independently of ROS Production.

Yulei Zhang, Wen Zeng, Wei Zhang, Yu Wang, Shuqi Jin, Ting Liu, Huanhuan Luo, Hongguang Lu.

  UVA radiation, a primary risk factor in melanoma progression, partly acts through the mediation of reactive oxygen species (ROS). The role of ROS in driving cutaneous melanoma toward an invasive phenotype and whether it occurs through opsins (OPNs), which are photosensitive G protein-coupled receptors, is not fully understood. This study focuses on the impact of UVA radiation on melanoma cell proliferation, with a special emphasis on OPN3. Investigating the biphasic response to various UVA doses (0.75-9 J/cm2) in A375 and MV3 cell lines, and using EdU and CCK-8 assays, we observed dose-dependent changes in cell proliferation. Interestingly, UVA irradiation at these doses of 0.75, 1.5 and 3 J/cm2 did not significantly induce ROS production. Our study further delves into the role of OPN3, a photosensitive receptor, in melanoma progression. Following UVA exposure, an increase in OPN3 expression was observed in melanoma cells lines A375 and MV3, indicating its role as a UVA-sensitive sensor and its influence on cell proliferation. Additionally, UVA-induced calcium flux in two melanoma cells lines pointed to a calcium-dependent G protein-coupled pathway in melanoma proliferation, mediated by OPN3 and not reliant on ROS. This research sheds light on the mechanism of UVA-induced melanoma progression, underscoring OPN3 as a pivotal regulator and advancing our understanding of UVA's interaction with opsins in melanoma progression.

Keywords:  OPN3; ROS (reactive oxygen species); UVA; melanoma; proliferation

DOI:  https://doi.org/10.1111/pcmr.13206
bioRxiv. 2024 Oct 17. pii: 2024.10.14.618368. [Epub ahead of print]

An increase in reactive oxygen species underlies neonatal cerebellum repair.

Anna Pakula, Salsabiel El Nagar, N Sumru Bayin, Jens Bager Christensen, Daniel N Stephen, Adam James Reid, Richard Koche, Alexandra L Joyner.

The neonatal mouse cerebellum shows remarkable regenerative potential upon injury at birth, wherein a subset of Nestin-expressing progenitors (NEPs) undergoes adaptive reprogramming to replenish granule cell progenitors that die. Here, we investigate how the microenvironment of the injured cerebellum changes upon injury and contributes to the regenerative potential of normally gliogenic-NEPs and their adaptive reprogramming. Single cell transcriptomic and bulk chromatin accessibility analyses of the NEPs from injured neonatal cerebella compared to controls show a temporary increase in cellular processes involved in responding to reactive oxygen species (ROS), a known damage-associated molecular pattern. Analysis of ROS levels in cerebellar tissue confirm a transient increased one day after injury at postanal day 1, overlapping with the peak cell death in the cerebellum. In a transgenic mouse line that ubiquitously overexpresses human mitochondrial catalase (mCAT), ROS is reduced 1 day after injury to the granule cell progenitors, and we demonstrate that several steps in the regenerative process of NEPs are curtailed leading to reduced cerebellar growth. We also provide evidence that microglia are involved in one step of adaptive reprogramming by regulating NEP replenishment of the granule cell precursors. Collectively, our results highlight that changes in the tissue microenvironment regulate multiple steps in adaptative reprogramming of NEPs upon death of cerebellar granule cell progenitors at birth, highlighting the instructive roles of microenvironmental signals during regeneration of the neonatal brain.

DOI: https://doi.org/10.1101/2024.10.14.618368
mSystems. 2024 Oct 29. e0129524

The ability in managing reactive oxygen species affects Escherichia coli persistence to ampicillin after nutrient shifts.

Ruixue Zhang, Christopher Hartline, Fuzhong Zhang.

  Bacterial persistence profoundly impacts biofilms, infections, and antibiotic effectiveness. Persister formation can be substantially promoted by nutrient shift, which commonly exists in natural environments. However, mechanisms that promote persister formation remain poorly understood. Here, we investigated the persistence frequency of Escherichia coli after switching from various carbon sources to fatty acid and observed drastically different survival rates. While more than 99.9% of cells died during a 24-hour ampicillin (AMP) treatment after the glycerol to oleic acid (GLY → OA + AMP) shift, a surprising 56% of cells survived the same antibiotic treatment after the glucose to oleic acid (GLU → OOA + AMP) shift. Using a combination of single-cell imaging and time-lapse microscopy, we discovered that the induction of high levels of reactive oxygen species (ROS) by AMP is the primary mechanism of cell killing after switching from gluconeogenic carbons to OA + AMP. Moreover, the timing of the ROS burst is highly correlated (R2 = 0.91) with the start of the rapid killing phase in the time-kill curves for all gluconeogenic carbons. However, ROS did not accumulate to lethal levels after the GLU → OA + AMP shift. We also found that the overexpression of the oxidative stress regulator and ROS detoxification enzymes strongly affects the amounts of ROS and the persistence frequency following the nutritional shift. These findings elucidate the different persister frequencies resulting from various nutrient shifts and underscore the pivotal role of ROS. Our study provides insights into bacterial persistence mechanisms, holding promise for targeted therapeutic interventions combating bacterial resistance effectively.
IMPORTANCE: This research delves into the intriguing realm of bacterial persistence and its profound implications for biofilms, infections, and antibiotic efficacy. The study focuses on Escherichia coli and how the switch from different carbon sources to fatty acids influences the formation of persister-resilient bacterial cells resistant to antibiotics. The findings reveal a striking variation in survival rates, with a significant number of cells surviving ampicillin treatment after transitioning from glucose to oleic acid. The key revelation is the role of reactive oxygen species (ROS) in cell killing, particularly after switching from gluconeogenic carbons. The timing of ROS bursts aligns with the rapid killing phase, highlighting the critical impact of oxidative stress regulation on persistence frequency. This research provides valuable insights into bacterial persistence mechanisms, offering potential avenues for targeted therapeutic interventions to combat bacterial resistance effectively.

Keywords:  antibiotic persistence; nutrient shift; reactive oxygen species; stress response

DOI:  https://doi.org/10.1128/msystems.01295-24