Microenvironmental Stress Research Articles

Heat stress and hypoxia inhibit the secretion of androgens and induce epithelial-to-mesenchymal transition associated with activated TGF-β/Smad signalling in canine cryptorchidism.

Cryptorchidism, as a common congenital disease of canine testes, is mainly caused by factors leading to endocrine abnormalities in testes and infertility in a heat stress and hypoxia microenvironment. Moreover, heat stress and hypoxia, as critical microenvironmental factors, promote epithelial-mesenchymal transition (EMT), which occurs during adult tissue remodelling responses including carcinogenesis and fibrosis and is the main cause of testicular tumours. In this study, we found by haematoxylin-eosin staining that the canine cryptorchid tissue produced a lot of collagen fibres. Also, the quantitative PCR and Western blot results showed that the mRNA and protein levels of the heat stress makers HSP70 and HO-1 and the hypoxia maker HIF-1α are significant higher compared with normal testes. Moreover, we found the expression levels of TGF-βs and its two receptors TGF-βRI and TGF-βRII increased in case of cryptorchidism. From the study in vitro, we found both heat stress and COCl2 mimic hypoxia inhibited the secretion of testosterone (T) and androstenedione (A4) and promoted the expression of the EMT maker α-SMA and vimentin in Leydig cells, and also that heat stress and COCl2 stimulated with the TGF-β signalling promoted the expression of TGF-βs and its two type receptors and also the active phosphorylation of Smad2 and Smad3. The use of LY2109761, a receptor inhibitor of TGF-βs/Smad signalling pathway, was associated with heat stress and COCl2 suppression of androgens' secretion and stimulated EMT in Leydig cells. These findings characterized a novel pathogenesis of cryptorchidism and provided a new idea for therapeutics.

Cancer Is A Survival Process under Persistent Microenvironmental and Cellular Stresses

Cancer Is A Survival Process under Persistent Microenvironmental and Cellular Stresses

Abstract 6197: The role of the integrated stress response in pancreatic cancer adaptation to tumor microenvironmental nutrient stress

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a five-year survival rate ~10%1. PDAC is characterized by an altered/abnormal nutrient tumormicroenvironment (TME)2, and cancer cells must adapt metabolically, which exposes potentialtherapeutic targetable vulnerabilities. Therefore, we seek to identify metabolic pathways thatallow PDAC adaptation to such abnormal TME. The integrated stress response (ISR) is anintracellular stress response pathway that senses diverse stressors, and subsequently initiatesdownstream stress adaptations3. We find both murine and human PDAC have elevatedexpression of ATF4, the most well-characterized ISR effector, compared to paired healthypancreas by immunohistochemistry staining. Further, I find the ISR is activated and critical forPDAC survival/proliferation upon physiological PDAC TME nutrient stress. What is triggering theISR activation in PDAC? Through a variety of studies, I determined that it was the amino acidstress, specifically the depletion of arginine and asparagine, that activated the ISR upstreamkinase GCN2, which is responsible for ATF4 upregulation upon PDAC TME nutritional stress.Through CRISPR-based competition assays, I determined that ATF4 activity was critical forPDAC cells to cope with the depletion of arginine and asparagine, and ATF4 activity wasdispensable when these two amino acids were supplied even though cultured in PDACphysiological TME conditions. Currently, I am seeking to validate these findings in murine PDACmodels, and to determine if ATF4 or GCN2 could be relevant therapeutic targets, using an invivo tumor competition assay that I am developing. Altogether, I find the ISR is active in PDACboth ex vivo and in vivo, and suggest that the ISR is critical for PDAC survival/proliferation byallowing adaptation to abnormal PDAC amino acid TME. This work suggests that the ISR is anovel therapeutic target for PDAC treatment, which ultimately can benefit PDAC patients.

Abstract 126: Defining how oxidative stress drives the evolution of aggressive breast cancers

Abstract Breast cancer is the most commonly diagnosed malignancy in women worldwide. It is a molecularly heterogeneous disease, which poses difficulties in the treatment of more advanced cancers. Despite this fact, the mechanisms contributing to the emergence of aggressive breast cancers remains poorly understood. We focus on reactive oxygen species (ROS), which are induced by a variety of stimuli in breast cancer cells. Moderately elevated ROS levels are tumor-promoting and facilitate the emergence of more aggressive tumours. Our laboratory has developed a unique model of HER2+ breast cancer that evolved to acquire more aggressive properties under conditions of chronic oxidative stress. We identified 20 transcription factors/co-regulators that were specifically overexpressed in these aggressive breast cancers, compared to their parental counterparts. We hypothesize that these transcription factors are central to the ability of breast tumors to adapt to chronic oxidative stress and acquire more aggressive properties. To test this, I have performed an in vivo functional shRNA screen to identify those transcriptional regulators that drive an aggressive phenotype. This will be followed by functional validation studies to interrogate whether and how these unique transcription factors overexpressed in aggressive breast cancers impact tumour growth, metastasis, and drug resistance. Mechanistically, we will explore whether and how these transcriptional responses mediate adaptive responses to tumor microenvironmental stressors, including altered metabolism, hypoxia, and tumor immune responses. This research will broaden our understanding of how breast cancers adapt to oxidative stress responses and represents a necessary first step in the development of novel therapeutics against these invulnerable malignancies. Citation Format: Caitlynn N. Mirabelli, Rachel La Selva, John Heath, Steven Hébert, Jutta Steinberger, Jialin Jiang, Claudia Kleinman, Sidong Huang, Josie Ursini-Siegel. Defining how oxidative stress drives the evolution of aggressive breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 126.

Abstract 17: Enhanced lipid metabolism in brain tumors: An exploitable metabolic vulnerability through diet-induced ketosis

Abstract Altered metabolism displayed by cancer cells helps circumvent a plethora of microenvironmental stressors. We and others have identified enhanced lipid metabolism as an important metabolic pathway in tumors of different etiologies. This “gain of function” contributes to malignant transformation in various malignancies, including brain tumors. Paradoxical to these findings, a high-fat/low carbohydrate ketogenic diet (KD) has demonstrated anti-tumor activity, both alone and in combination with radiation therapy (RT). Therefore, using our novel patient-derived GBM stem cell models, we sought to define mechanistic underpinnings contributing to this disconnect from a metabolic perspective. As an initial investigation, we fed ad libitum standard diet (SD) or KD alone or in combination with hypofractionated RT (hfRT; 6 Gy x 3) to mice injected orthotopically with aggressive GBM tumor cells. Consistent with previous reports, mice fed a KD demonstrated independent anti-tumor activity and potent synergy with RT compared to mice fed a SD. To provide a window into the metabolic consequences of KD in GBM, we performed global metabolomic profiling on tumors and serum from mice fed a SD and KD. Although ketosis was confirmed, no change in glucose was observed in serum of KD mice, suggesting carbohydrates might not be contributing to the observed anti-tumor activity. Interestingly, profound intra-tumoral metabolic changes were observed in tumors from mice fed a KD, with an accumulation of unsaturated fatty acids emerging as a central metabolic node differentiating KD and SD, which was consistent with serum studies. To begin to understand the biologic consequence of these findings, we recapitulated these findings in culture conditions in vitro. Intriguingly, culturing GBM cells with the polyunsaturated fatty acid (PUFA) linoleic acid demonstrated anti-proliferative activity, decreased clonogenic capacity, and synergy with RT in, recapitulating in vivo findings. This was not observed when cultured with the monounsaturated fatty acid oleic acid. Through a series of investigations, we went on to identify lipid storage homeostasis played a contributory role in the differential activity of these different classes of fatty acids. Specifically, we discovered that long-term storage within lipid droplets was less efficient for PUFA, leading to an increase free fatty acid accumulation in cells and lipotoxicity. The anti-tumor activity of PUFAs were rescued following inhibition of lipolysis. These studies collectively reaffirm and provide mechanistic underpinnings of the antitumor activity of KD, suggesting enhanced FA metabolism in brain tumors may serve as an exploitable metabolic vulnerability through diet modification. In addition, it provides a framework to potentially modify this diet to both enhance its antitumor activity and improve tolerability to allow for clinical implementation. Citation Format: Shiva Kant, Pravin Kesarwani, Yi Zhao, Prakash Chinnaiyan. Enhanced lipid metabolism in brain tumors: An exploitable metabolic vulnerability through diet-induced ketosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 17.

Abstract 2180: Deciphering the Warburg effect: Redox is the key to tumor differentiation

Abstract It was proposed by Warburg that the cause and consequence of the Warburg effect were the injury of respiration and cell dedifferentiation, respectively. However, the underlying mechanism was unclear due to limited understanding of metabolic control of epigenetics. Inhibition of mitochondrial electron transport chain (ETC) causes reduction of NAD+/NADH ratio. Recently it was discovered that this redox stress not only drives lactate production from pyruvate to enhance the Warburg effect, but also promotes the conversion of α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), turning the substrate of DNA demethylase TET into an inhibitor of TET, suggesting a potential link between ETC inhibition and dysregulated DNA methylation in cancer. In this study we use a mitochondrial uncoupler niclosamide ethanolamine (NEN) to block the Warburg effect and remodel cancer epigenome. NEN treatment activates ETC and accelerates glutaminolysis to produce αKG, which promotes promoter CpG island demethylation. This epigenomic reprograming not only upregulates tumor suppressor genes such as p53, inhibits N-Myc expression, but also activates neuron differentiation markers to promote differentiation in neuroblastoma cells. Hypoxia is one common microenvironmental stress existing in all solid tumor. NEN treatment reduces 2HG generation from αKG under hypoxia, highlighting its application potential in preventing DNA hypermethylation in vivo. Associated with 2HG reduction, NEN treatment also represses HIF signaling under hypoxia. In addition, NEN treatment inhibits reductive carboxylation flux. Moreover, dietary supplementation with NEN reduces orthotopic neuroblastoma growth and N-Myc expression in vivo. Together, these results validated Warburg’s hypothesis that mitochondrial respiration is the key to maintain normal differentiation. Restoring ETC activity with mitochondrial uncoupler is an effective metabolic/epigenetic therapy against neuroblastoma (Jiang et al., BioRxiv 2021). Citation Format: Jiang Haowen, Rachel L. Greathouse, Bo He, Yang Li, Albert M. LI, Balint Forgo, Selene Banuelos, Joshua Gruber, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye. Deciphering the Warburg effect: Redox is the key to tumor differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2180.

Abstract SY39-02: Accessing evolutionary programs to enable therapeutic resistance

Abstract Twenty million people around the world are diagnosed with cancer every year and over ten million people die because their cancer has metastasized and is incurable using current systemic therapies. Metastatic disease remains incurable because tumors evade all forms of programmed cell death. How is this possible? Unicellular and multicellular organisms have evolved multiple strategies to avoid death from internal and external stresses. While the nature of these catastrophes may be varied, their common property is to doom the organism unless it can access a survival mechanism and/or evolve a resistance mechanism rapidly. One such stress survival mechanism that is present across the tree of life in both unicellular and multicellular organisms is the utilization of a program that enables whole genome doubling (polyploidization) and cell cycle arrest. This evolutionary program allows the organism to avoid environmental stresses and protect the integrity of its genomic material by adopting a quiescent phenotype. In addition, by doubling DNA and increasing RNA and protein material, organisms have increased capacity to evolve further resistance mechanisms to stressors. To date, no common genomic signature has been defined that can explain or identify which patients will develop therapeutically resistant and lethal metastatic cancer. In all these incurable patients, therefore, lethal cancer independently evolves capacities for metastasis, avoidance of all cellular death pathways, and resistance. This convergent outcome across all patients demands an explanation beyond the accrual of stochastic mutations. Since the tumor ecosystem is exposed to constantly changing chemical and biologic conditions, it is generally assumed that cancer cell populations must have the ability to evolve rapidly to acquire mutations to adapt and survive. An alternative and complementary theory to explain cancer cell fitness is that a subset of cancer cells access evolutionary stress survival programs that are inherited as development programs. These development programs enable whole genome doubling (polyploidization) and cell cycle arrest and are seen in multiple cell types, including regenerating liver cells, myocytes under physical strain, and megakaryocytes under metabolic stress. In cancer, access to these stress programs result in cancer cell survival though a state of cell cycle arrest that is simultaneously polyploid and aneuploid. Entering the polyaneuploid cancer cell (PACC) state, cancer cells pause their cell cycle and protect the integrity of their DNA from tumor microenvironmental stresses as well as have increased potential to develop further resistance mechanisms to environmental stressors and toxic therapies. After stress is removed, cells in the PACC state undergo depolyploidization and generate resistant progeny. This enables the generation of heritable variation that can be dispensed to their 2N+ aneuploid progeny, providing population rescue in response to therapeutic stress. Targeting cells in the PACC state opens a new avenue for cancer therapy. Citation Format: Kenneth J. Pienta. Accessing evolutionary programs to enable therapeutic resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY39-02.

Acetyl-CoA Synthetase 2 as a Therapeutic Target in Tumor Metabolism.

Simple SummaryAcetyl-CoA Synthetase 2 (ACSS2) is highly expressed in a variety of tumors, which is very important for tumor growth, proliferation, invasion, and metastasis in the nutritional stress microenvironment. Studies have proven that ACSS2 inhibitors can be effective in halting cancer growth and can be combined with other antineoplastic drugs to reduce drug resistance. This article mainly reviews the mechanism of ACSS2-promoting tumor growth from many aspects and the prospect of clinical application of targeted inhibitors.Acetyl-CoA Synthetase 2 (ACSS2) belongs to a member of the acyl-CoA short-chain synthase family, which can convert acetate in the cytoplasm and nucleus into acetyl-CoA. It has been proven that ACSS2 is highly expressed in glioblastoma, breast cancer, liver cancer, prostate cancer, bladder cancer, renal cancer, and other tumors, and is closely related to tumor stage and the overall survival rate of patients. Accumulating studies show that hypoxia and a low serum level induce ACSS2 expression to help tumor cells cope with this nutrient-poor environment. The potential mechanisms are associated with the ability of ACSS2 to promote the synthesis of lipids in the cytoplasm, induce the acetylation of histones in the nucleus, and facilitate the expression of autophagy genes. Novel-specific inhibitors of ACSS2 are developed and confirmed to the effectiveness in pre-clinical tumor models. Targeting ACSS2 may provide novel approaches for tumor treatment. This review summarizes the biological function of ACSS2, its relation to survival and prognosis in different tumors, and how ACSS2 mediates different pathways to promote tumor metastasis, invasion, and drug resistance.

The Functional Roles and Regulation of Circular RNAs during Cellular Stresses.

Circular RNAs (circRNAs) are a novel class of regulatory RNA involved in many biological, physiological and pathological processes by functioning as a molecular sponge, transcriptional/epigenetic/splicing regulator, modulator of protein–protein interactions, and a template for encoding proteins. Cells are constantly dealing with stimuli from the microenvironment, and proper responses rely on both the precise control of gene expression networks and protein–protein interactions at the molecular level. The critical roles of circRNAs in the regulation of these processes have been heavily studied in the past decades. However, how the microenvironmental stimulation controls the circRNA biogenesis, cellular shuttling, translation efficiency and degradation globally and/or individually remains largely uncharacterized. In this review, how the impact of major microenvironmental stresses on the known transcription factors, splicing modulators and epitranscriptomic regulators, and thereby how they may contribute to the regulation of circRNAs, is discussed. These lines of evidence will provide new insight into how the biogenesis and functions of circRNA can be precisely controlled and targeted for treating human diseases.

The role of PFKFB3 in maintaining colorectal cancer cell proliferation and stemness.

Since generally confronting with the hypoxic and stressful microenvironment, cancer cells alter their glucose metabolism pattern to glycolysis to sustain the continuous proliferation and vigorous biological activities. Bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) isoform 3 (PFKFB3) functions as an effectively modulator of glycolysis and also participates in regulating angiogenesis, cell death and cell stemness. Meanwhile, PFKFB3 is highly expressed in a variety of cancer cells, and can be activated by several regulatory factors, such as hypoxia, inflammation and cellular signals. In colorectal cancer (CRC) cells, PFKFB3 not only has the property of high expression, but also probably relate to inflammation-cancer transformation. Recent studies indicate that PFKFB3 is involved in chemoradiotherapy resistance as well, such as breast cancer, endometrial cancer and CRC. Cancer stem cells (CSCs) are self-renewable cell types that contribute to oncogenesis, metastasis and relapse. Several studies indicate that CSCs utilize glycolysis to fulfill their energetic and biosynthetic demands in order to maintain rapid proliferation and adapt to the tumor microenvironment changes. In addition, elevated PFKFB3 has been reported to correlate with self-renewal and metastatic outgrowth in numerous kinds of CSCs. This review summarizes our current understanding of PFKFB3 roles in modulating cancer metabolism to maintain cell proliferation and stemness, and discusses its feasibility as a potential target for the discovery of antineoplastic agents, especially in CRC.

Interference With Redox Homeostasis Through a G6PD-Targeting Self-Assembled Hydrogel for the Enhancement of Sonodynamic Therapy in Breast Cancer.

Sonodynamics has emerged as a new potential therapy for breast cancer in recent years. However, GSH-mediated redox systems in cancer cells make them tolerable to oxidative stress-related therapy. Herein, in this study, with G6PD, the gatekeeper enzyme of the pentose phosphate pathway, as the regulative target, a self-assembled thermosensitive chitosan-pluronic hydrogel coloaded with ICG (sono-sensitive agent) and RRx-001 (IR@CPGel) was successfully prepared to enhance SDT through interference with redox homeostasis. Both in vitro and in vivo antitumor investigations verified that when integrated with sonodynamic therapy applied in breast cancer treatment, local administration of IR@CPgel could enhance ROS generation under LIFU irradiation and trigger the intrinsic apoptotic pathway of cancer cells, thus effectively inhibiting tumor growth in a safe manner. Moreover, RRx-001 may interfere with redox homeostasis in cancer cells by downregulating G6PD expression. Due to this redox imbalance, proapoptotic signals, such as P21 and P53, were enhanced, and metastasis-related signals, including MMP-2, ZEB1 and HIF-1α, were effectively reduced. Taken together, this work aimed to enhance the efficacy of sonodynamic therapy through local administration of self-assembled IR@CPGel to interfere with redox homeostasis and thus amplify the oxidative stress microenvironment in tumor tissues. In a word, this work provides a new strategy for the SDT enhancement in breast cancer therapy.

Carrier-Free Deferoxamine Nanoparticles against Iron Overload in Brain

Carrier-Free Deferoxamine Nanoparticles against Iron Overload in Brain

Multifunctional Baicalin-Modified Contact Lens for Preventing Infection, Regulating the Ocular Surface Microenvironment and Promoting Corneal Repair.

Corneal injury inevitably leads to disruption of the ocular surface microenvironment, which is closely associated with delayed epithelial cell repair and the development of infection. Recently, drug-loaded therapeutic contact lenses have emerged as a new approach to treating corneal injury due to their advantages of relieving pain, promoting corneal repair, and preventing infection. However, few therapeutic contact lenses could modulate the ocular surface’s inflammation and oxidative stress microenvironment. To address this, in this study, we covalently immobilized multifunctional baicalin (BCL), a flavon molecular with anti-inflammatory, anti-oxidative stress, and antibacterial capabilities, onto the surface of the contact lens. The BCL-modified contact lens showed excellent optical properties, powerful antibacterial properties, and non-toxicity to endothelial cells. Furthermore, the BCL-modified contact lens could significantly modulate the ocular surface microenvironment, including inhibition of macrophage aggregation and resistance to epithelium damage caused by oxidative stress. In animal models, BCL-modified corneal contact lens effectively promoted corneal epithelial cells repair. These excellent properties suggested that multifunctional BCL molecules had great application potential in the surface engineering of ophthalmic medical materials.

Light amplified oxidative stress in tumor microenvironment by carbonized hemin nanoparticles for boosting photodynamic anticancer therapy

Photodynamic therapy (PDT), which utilizes light excite photosensitizers (PSs) to generate reactive oxygen species (ROS) and consequently ablate cancer cells or diseased tissue, has attracted a great deal of attention in the last decades due to its unique advantages. However, the advancement of PDT is restricted by the inherent characteristics of PS and tumor microenvironment (TME). It is urgent to explore high-performance PSs with TME regulation capability and subsequently improve the therapeutic outcomes. Herein, we reported a newly engineered PS of polymer encapsulated carbonized hemin nanoparticles (P-CHNPs) via a facile synthesis procedure for boosting photodynamic anticancer therapy. Solvothermal treatment of hemin enabled the synthesized P-CHNPs to enhance oxidative stress in TME, which could be further amplified under light irradiation. Excellent in vitro and in vivo PDT effects were achieved due to the improved ROS (hydroxyl radicals and singlet oxygen) generation efficiency, hypoxia relief, and glutathione depletion. Moreover, the superior in vitro and in vivo biocompatibility and boosted PDT effect make the P-CHNPs a potential therapeutic agent for future translational research.

Effects of Epiphytes on the Seagrass Phyllosphere

The seagrass phyllosphere consists of a dynamic mosaic of physico-chemical microgradients that modulate light harvesting, gas and nutrient exchange between the photosynthetic leaves and the surrounding water-column. The phyllosphere is thus of vital importance for seagrass growth and fitness. However, unfavorable environmental conditions such as water-column hypoxia, increasing temperature and high nutrient inputs that are predicted to increase in frequency and severity in the Anthropocene, can render the leaf microenvironment into a hostile microhabitat that is challenging or even harmful for the plants—especially if leaves are covered by epiphytic biofilms. Here we summarize effects of epiphytic biofilms on seagrass leaves and discuss how they change and affect the biogeochemical processes and chemical conditions in the seagrass phyllosphere. During night-time, water-column hypoxia can lead to anoxic conditions at the leaf/epiphyte interface, reducing diffusive O2supply and thus O2availability for plant respiration and transport to below-ground tissues. Furthermore, anoxia in epiphytic biofilms can also enable anaerobic microbial processes that can lead to harmful nitric oxide productionviadenitrification. Such microenvironmental stress conditions at night-time are exacerbated by increasing temperatures. In the light, the leaf epiphytic biofilm community often results in lower leaf photosynthetic activity and efficiency due to epiphyte-induced shading and a combination of O2build-up and CO2reduction in the phyllosphere owing to thicker total diffusional pathways, phyllosphere basification and epiphytic carbon fixation. Furthermore, absorbed light energy in the epiphytic biofilm can also drive an increase in the leaf surface temperature relative to the surrounding seawater potentially aggravating heating events in the surrounding seawater. In combination, all these above-mentioned diurnal effects of epiphytes result in higher compensation photon irradiance of epiphyte-covered leaves and thus higher light requirements of seagrasses.

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance.

The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.

Red blood cell biomimetic nanoparticle with anti-inflammatory, anti-oxidative and hypolipidemia effect ameliorated atherosclerosis therapy

A main pathogenic factor of atherosclerosis is the local oxidative stress microenvironment. Probucol (PU) has anti-inflammatory, antioxidative and hypolipidemic effects, showing great potential to treat atherosclerosis. However, its low bioavailability limits its development. Herein, PU was encapsulated to form RP-PU with star-shaped polymers and red blood cell membranes. Star-shaped polymers show lower solution viscosity, a smaller hydrodynamic radius and a higher drug loading content than linear polymers. RP-PU had a good sustained-release effect and excellent biocompatibility. RP-PU can be efficiently internalized by cells to improve biodistribution. ApoE−/− mice were treated with RP-PU, and the contents of lipids and related metabolic enzymes were effectively reduced. The collagen fibers in the aortic root sections were reduced by RP-PU compared with control and PU. Moreover, RP-PU inhibited foam cell formation, decreased ICAM-1 and MCP-1 expression and delayed lesion formation. Consequently, RP-PU biomimetic nanoparticles can be developed as an anti-atherosclerotic nanotherapeutic.

Thioredoxin 1 supports colorectal cancer cell survival and promotes migration and invasion under glucose deprivation through interaction with G6PD.

Overcoming energy stress is a critical step for cells in solid tumors. Under this stress microenvironment, cancer cells significantly alter their energy metabolism to maintain cell survival and even metastasis. Our previous studies have shown that thioredoxin-1 (Trx-1) expression is increased in colorectal cancer (CRC) and promotes cell proliferation. However, the exact role and mechanism of how Trx-1 is involved in energy stress are still unknown. Here, we observed that glucose deprivation of CRC cells led to cell death and promoted the migration and invasion, accompanied by upregulation of Trx-1. Increased Trx-1 supported CRC cell survival under glucose deprivation. Whereas knockdown of Trx-1 sensitized CRC cells to glucose deprivation-induced cell death and reversed glucose deprivation-induced migration, invasion, and epithelial-mesenchymal transition (EMT). Furthermore, we identified glucose-6-phosphate dehydrogenase (G6PD) interacting with Trx-1 by HuPortTM human protein chip, co-IP and co-localization. Trx-1 promoted G6PD protein expression and activity under glucose deprivation, thereby increasing nicotinamide adenine dinucleotide phosphate (NADPH) generation. Moreover, G6PD knockdown sensitized CRC cells to glucose deprivation-induced cell death and suppressed glucose deprivation-induced migration, invasion, and EMT. Inhibition of Trx-1 and G6PD, together with inhibition of glycolysis using 2-deoxy-D-glucose (2DG), resulted in significant anti-tumor effects in CRC xenografts in vivo. These findings demonstrate a novel mechanism and may represent a new effective therapeutic regimen for CRC.

Study on the Local Anti-Osteoporosis Effect of Polaprezinc-Loaded Antioxidant Electrospun Membrane.

BackgroundCompared with the healthy condition, osteoporotic bone defects are often accompanied by poor osteogenesis and excessive reactive oxygen species (ROS), which pose serious challenges to bone augmentation and repair by normal resorbable guided bone regeneration (GBR) membrane.PurposePolaprezinc (PZ) was loaded into polycaprolactone/gelatin (PG) hybrid electrospun nanofibers to fabricate a GBR membrane with antioxidant and osteogenesis ability.MethodsA series of physicochemical characterization were performed by scanning electron microscopy, Fourier-transform infrared spectroscopy, and water contact angle measurement. In addition to membrane degradation and PZ release detection, membranes were tested for cell viability, differentiation, and protein expression in MC3T3-E1 cells by CCK8, alkaline phosphatase activity, mineralization, and Western blotting assays. The membrane osteogenic capacity in cranial bone defects was studied by micro-CT in vivo.ResultsPZ was successfully doped into the PCL/GEL nanofibers to form a hydrophilic GBR membrane. The cumulative release of PZ was closely related to the membrane degradation behavior. PG/0.4%PZ membranes produced the best protective effect on cell proliferation/differentiation under oxidative stress microenvironment; however, the PG/0.8%PZ membrane was cytotoxic. Western blotting demonstrated that the PZ-loaded membrane upregulated the Nrf2/HO-1/SOD1 signaling molecules in a concentration-dependent manner. In addition, micro-CT results showed an abundant formation of new bones in the PG/0.4%PZ group compared to the PG group.ConclusionPZ-loaded degradable PG membranes (especially PG/0.4%PZ) have great potential to accelerate bone regeneration in oxidative stress-related diseases.

An Antioxidative Sophora Exosomes Encapsulated Hydrogel Promotes Spinal Cord Repair by Regulating Oxidative Stress Microenvironment

An Antioxidative Sophora Exosomes Encapsulated Hydrogel Promotes Spinal Cord Repair by Regulating Oxidative Stress Microenvironment