bims-hypoxi 2021-06-06 papers

bims-hypoxi

Biomed News

on Hypoxia and HIF1-alpha

Issue of 2021‒06‒06
nineteen papers selected by
Ashish Kaul
University of Tsukuba

Neuroprotective and Angiogenesis Effects of Levetiracetam Following Ischemic Stroke in Rats.
Caffeine Inhibits Growth of Temozolomide-Treated Glioma via Increasing Autophagy and Apoptosis but Not via Modulating Hypoxia, Angiogenesis, or Endoplasmic Reticulum Stress in Rats.
UCA1 Overexpression Promotes Hypoxic Breast Cancer Cell Proliferation and Inhibits Apoptosis via HIF-1α Activation.
Regeneration in Spinal Disease: Therapeutic Role of Hypoxia-Inducible Factor-1 Alpha in Regeneration of Degenerative Intervertebral Disc.
Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target.
Intermittent Hypobaric Hypoxic Preconditioning Provides Neuroprotection by Increasing Antioxidant Activity, Erythropoietin Expression and Preventing Apoptosis and Astrogliosis in the Brain of Adult Rats Exposed to Acute Severe Hypoxia.
Suppression of hypoxia and inflammatory pathways by Phyllanthus niruri extract inhibits angiogenesis in DMBA-induced breast cancer mice.
Characterization of stable hypoxia-preconditioned dental pulp stem cells compared with mobilized dental pulp stem cells for application for pulp regenerative therapy.
BDNF promotes neuronal survival after neonatal hypoxic-ischemic encephalopathy by up-regulating Stx1b and suppressing VDAC1.
Prognostic and clinicopathological implications of expression of Beclin-1 and hypoxia-inducible factor 1α in serous ovarian carcinoma: an immunohistochemical study.
The role of HIF proteins in maintaining the metabolic health of the intervertebral disc.
Lycopene Attenuates Hypoxia-Induced Testicular Injury by Inhibiting PROK2 Expression and Activating PI3K/AKT/mTOR Pathway in a Varicocele Adult Rat.
Role of Hypoxia in the Control of the Cell Cycle.
Hypoxia induces chemoresistance of esophageal cancer cells to cisplatin through regulating the lncRNA-EMS/miR-758-3p/WTAP axis.
Hypoxic microenvironment induced spatial transcriptome changes in pancreatic cancer.
Histone Deacetylase 5 Is an Early Epigenetic Regulator of Intermittent Hypoxia Induced Sympathetic Nerve Activation and Blood Pressure.
Glucose Metabolic Dysfunction in Neurodegenerative Diseases-New Mechanistic Insights and the Potential of Hypoxia as a Prospective Therapy Targeting Metabolic Reprogramming.
Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia.
HIF-1α in the Crosstalk Between Reactive Oxygen Species and Autophagy Process: A Review in Multiple Sclerosis.

Front Pharmacol. 2021 ;12 638209

Neuroprotective and Angiogenesis Effects of Levetiracetam Following Ischemic Stroke in Rats.

Xiang Yao, Wenping Yang, Zhendong Ren, Haoran Zhang, Dafa Shi, Yanfei Li, Ziyang Yu, Qiu Guo, Guangwei Yang, Yingjiang Gu, Hairong Zhao, Ke Ren.

  Objective: The present study explored whether levetiracetam (LEV) could protect against experimental brain ischemia and enhance angiogenesis in rats, and investigated the potential mechanisms in vivo and in vitro. Methods: The middle cerebral artery was occluded for 60 min to induce middle cerebral artery occlusion (MCAO). The Morris water maze was used to measure cognitive ability. The rotation test was used to assess locomotor function. T2-weighted MRI was used to assess infarct volume. The neuronal cells in the cortex area were stained with cresyl purple. The anti-inflammatory effects of LEV on microglia were observed by immunohistochemistry. Enzyme-linked immunosorbent assays (ELISA) were used to measure the production of pro-inflammatory cytokines. Western blotting was used to detect the levels of heat shock protein 70 (HSP70), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1α (HIF-1α) in extracts from the ischemic cortex. Flow cytometry was used to observe the effect of LEV on neuronal cell apoptosis. Results: LEV treatment significantly increased the density of the surviving neurons in the cerebral cortex and reduced the infarct size (17.8 ± 3.3% vs. 12.9 ± 1.4%, p < 0.01) after MCAO. Concurrently, the time required to reach the platform for LEV-treated rats was shorter than that in the saline group on day 11 after MCAO (p < 0.01). LEV treatment prolonged the rotarod retention time on day 14 after MCAO (84.5 ± 6.7 s vs. 59.1 ± 6.2 s on day 14 compared with the saline-treated groups, p < 0.01). It also suppressed the activation of microglia and inhibited TNF-α and Il-1β in the ischemic brain (135.6 ± 5.2 pg/ml vs. 255.3 ± 12.5 pg/ml, 18.5 ± 1.3 pg/ml vs. 38.9 ± 2.3 pg/ml on day 14 compared with the saline-treated groups, p < 0.01). LEV treatment resulted in a significant increase in HIF-1α, VEGF, and HSP70 levels in extracts from the ischemic cerebral cortex. At the same time, LEV reduced neuronal cell cytotoxicity and apoptosis induced by an ischemic stroke (p < 0.01). Conclusion: LEV treatment promoted angiogenesis and functional recovery after cerebral ischemia in rats. These effects seem to be mediated through anti-inflammatory and antiapoptotic activities, as well as inducing the expression of HSP70, VEGF, and HIF-1α.

Keywords:  heat shock protein 70; hypoxia-inducible factor; ischemic stroke; levetiracetam; neuroprotection; vascular endothelial growth factor

DOI:  https://doi.org/10.3389/fphar.2021.638209
Nutr Cancer. 2021 Jun 01. 1-8

Caffeine Inhibits Growth of Temozolomide-Treated Glioma via Increasing Autophagy and Apoptosis but Not via Modulating Hypoxia, Angiogenesis, or Endoplasmic Reticulum Stress in Rats.

Jin-Cherng Chen, Juen-Haur Hwang.

Thirty rats with glioma were divided into control group, temozolomide (TMZ) group (TMZ 30 mg/kg once daily for 5 day), and TMZ plus Caffeine group (TMZ 30 mg/kg once daily for 5 day and caffeine 100 mg/kg once daily for 2 weeks). The relative tumor fold and expression of hypoxia-induced factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), neuropilin-1 (NRP-1), CCAAT/enhancer-binding protein homologous protein (CHOP), LC-3A/B, apoptosis-inducing factor-1 (AIF-1), and cleaved caspase three were compared. The relative tumor fold of TMZ plus Caffeine group was lower significantly than that of TMZ group at day 14. HIF-1α, VEGF, NRP-1, and CHOP expressions were not significantly different in the three groups. The LC-3A/B expression of TMZ plus Caffeine group was higher significantly than that of the control group and TMZ group. The AIF expressions of TMZ group and TMZ plus Caffeine group were higher significantly than that of the control group. The caspase-3 expression of TMZ plus Caffeine group was higher significantly than that of the control group and TMZ group. In conclusions, the inhibitory effect of caffeine on TMZ-treated glioma might be associated with increasing expressions of autophagy- and apoptosis-related genes.

DOI: https://doi.org/10.1080/01635581.2021.1931361
J Oncol. 2021 ;2021 5512156

UCA1 Overexpression Promotes Hypoxic Breast Cancer Cell Proliferation and Inhibits Apoptosis via HIF-1α Activation.

Hani Choudhry.

The noncoding RNA termed urothelial carcinoma-associated 1 (UCA1) is an oncogenic lncRNA involved in promoting the growth of several tumors through various pathways. The aim of this study was to explore the expression of UCA1 in hypoxic breast cancer and its impact on tumorigenesis in low levels of oxygen. Here, we show that UCA1 is upregulated in a number of hypoxic (1% O2) breast cancer cells. In addition, UCA1 expression is significantly overexpressed in breast cancer tissues compared to matched normal cells. UCA1 knockdown in hypoxia inhibits breast cancer proliferation and induces apoptosis. The knockdown of hypoxia-inducible transcription factor 1α (HIF-1α) but not HIF-2α significantly decreases the expression of UCA1 in hypoxia. Overall, these findings indicate that UCA1 is a hallmark of hypoxic breast cancer and its expression is positively regulated by HIF-1α.

DOI: https://doi.org/10.1155/2021/5512156
Int J Mol Sci. 2021 May 17. pii: 5281. [Epub ahead of print]22(10):

Regeneration in Spinal Disease: Therapeutic Role of Hypoxia-Inducible Factor-1 Alpha in Regeneration of Degenerative Intervertebral Disc.

Jin-Woo Kim, Neunghan Jeon, Dong-Eun Shin, So-Young Lee, Myongwhan Kim, Dong Hun Han, Jae Yeon Shin, Soonchul Lee.

  The intervertebral disc (IVD) is a complex joint structure comprising three primary components-namely, nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplate (CEP). The IVD retrieves oxygen from the surrounding vertebral body through CEP by diffusion and likely generates ATP via anaerobic glycolysis. IVD degeneration is characterized by a cascade of cellular, compositional, structural changes. With advanced age, pronounced changes occur in the composition of the disc extracellular matrix (ECM). NP and AF cells in the IVD possess poor regenerative capacity compared with that of other tissues. Hypoxia-inducible factor (HIF) is a master transcription factor that initiates a coordinated cellular cascade in response to a low oxygen tension environment, including the regulation of numerous enzymes in response to hypoxia. HIF-1α is essential for NP development and homeostasis and is involved in various processes of IVD degeneration process, promotes ECM in NP, maintains the metabolic activities of NP, and regulates dystrophic mineralization of NP, as well as angiogenesis, autophagy, and apoptosis during IVD degeneration. HIF-1α may, therefore, represent a diagnostic tool for early IVD degeneration and a therapeutic target for inhibiting IVD degeneration.

Keywords:  disc degeneration; hypoxia-inducible factor-1α; intervertebral disc; nucleus pulposus; regeneration

DOI:  https://doi.org/10.3390/ijms22105281
Int J Mol Sci. 2021 May 27. pii: 5703. [Epub ahead of print]22(11):

Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target.

Vittoria Infantino, Anna Santarsiero, Paolo Convertini, Simona Todisco, Vito Iacobazzi.

  In order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underlies the metabolic and functional changes of cancer cells. Noteworthy, HIF-1 represents a promising target for novel cancer therapeutics. In this review, we summarize the molecular mechanisms underlying the interplay between HIF-1 and energetic metabolism, with a focus on mitochondria, of hypoxic cancer cells.

Keywords:  HIF-1; TCA cycle; cancer metabolism; hypoxia; mitochondria

DOI:  https://doi.org/10.3390/ijms22115703
Int J Mol Sci. 2021 May 17. pii: 5272. [Epub ahead of print]22(10):

Intermittent Hypobaric Hypoxic Preconditioning Provides Neuroprotection by Increasing Antioxidant Activity, Erythropoietin Expression and Preventing Apoptosis and Astrogliosis in the Brain of Adult Rats Exposed to Acute Severe Hypoxia.

Débora Coimbra-Costa, Fernando Garzón, Norma Alva, Tiago C C Pinto, Fernando Aguado, Joan Ramon Torrella, Teresa Carbonell, Ramón Rama.

  BACKGROUND: Exposure to intermittent hypoxia has been demonstrated to be an efficient tool for hypoxic preconditioning, preventing damage to cells and demonstrating therapeutic benefits. We aimed to evaluate the effects of respiratory intermittent hypobaric hypoxia (IHH) to avoid brain injury caused by exposure to acute severe hypoxia (ASH).METHODS: biomarkers of oxidative damage, mitochondrial apoptosis, and transcriptional factors in response to hypoxia were assessed by Western blot and immunohistochemistry in brain tissue. Four groups of rats were used: (1) normoxic (NOR), (2) exposed to ASH (FiO2 7% for 6 h), (3) exposed to IHH for 3 h per day over 8 days at 460 mmHg, and (4) ASH preconditioned after IHH.
RESULTS: ASH animals underwent increased oxidative-stress-related parameters, an upregulation in apoptotic proteins and had astrocytes with phenotype forms compatible with severe diffuse reactive astrogliosis. These effects were attenuated and even prevented when the animals were preconditioned with IHH. These changes paralleled the inhibition of NF-κB expression and the increase of erythropoietin (EPO) levels in the brain.
CONCLUSIONS: IHH exerted neuroprotection against ASH-induced oxidative injury by preventing oxidative stress and inhibiting the apoptotic cascade, which was associated with NF-κB downregulation and EPO upregulation.

Keywords:  HIF; NF-κB; apoptosis-inducing factor; erythropoietin; glial fibrillary acidic protein; glutathione; superoxide dismutase

DOI:  https://doi.org/10.3390/ijms22105272
Res Pharm Sci. 2021 Apr;16(2): 217-226

Suppression of hypoxia and inflammatory pathways by Phyllanthus niruri extract inhibits angiogenesis in DMBA-induced breast cancer mice.

Abu Hanifah Ramadhani, Ahmad Hafidul Ahkam, Aditya Ragil Suharto, Yoga Dwi Jatmiko, Hideo Tsuboi, Muhaimin Rifa'i.

  Background and purpose: Angiogenesis has been one of the hallmarks of cancer. In recent years, Phyllanthus niruri extract (PNE) was reported to inhibit angiogenesis by decreasing the levels of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) in breast cancer. However, the experimental results were confirmed in cancer cell lines only, whereas the anti-angiogenic activity in animal models has not been demonstrated. In this study, we tried to examine the anti-angiogenic activity of PNE on BALB/c strain mice models that were induced for breast cancer using the carcinogenic substance 7,12- dimethylbenz[a]anthracene (DMBA).Experimental approach: Experimental animals were divided into five different groups; vehicle, DMBA, PNE 500 mg/kg, PNE 1000 mg/kg; and PNE 2000 mg/kg. Mammary carcinogenesis was induced using a subcutaneous injection of 15 mg/kg of DMBA for 12 weeks. Afterward, oral PNE treatment was given for the following 5 weeks. VEGFA and HIF-1α were observed using immunohistochemistry. Endothelial cell markers CD31, CD146, and CD34 were observed using the fluorescent immunohistochemistry method. The levels of interleukin-6 (IL-6), IL-17, and C-X-C motif chemokine (CXCL12) were measured using flow cytometry.
Findings/Results: The survival analysis indicated that PNE increased the survival rate of mice (P = 0.043, log-rank test) at all doses. The PNE treatment decreased the immunoreactive score of angiogenic factors (VEGF and HIF-1α), as well as the endothelial cell markers (CD31, CD146, and CD34). The PNE- treated groups also decreased the levels of inflammatory cytokines (IL-6, IL-17, and CXCL12) at all doses.
Conclusion and implications: This finding suggests that PNE may inhibit the progression of angiogenesis in breast cancer mice by targeting the hypoxia and inflammatory pathways.

Keywords:  Angiogenesis; Breast cancer; DMBA; Inflammation; Phyllanthus niruri

DOI:  https://doi.org/10.4103/1735-5362.310528
Stem Cell Res Ther. 2021 May 29. 12(1): 302

Characterization of stable hypoxia-preconditioned dental pulp stem cells compared with mobilized dental pulp stem cells for application for pulp regenerative therapy.

Mohammed Zayed, Koichiro Iohara, Hideto Watanabe, Mami Ishikawa, Michiyo Tominaga, Misako Nakashima.

  BACKGROUND: Dental pulp stem cells (DPSCs) have been developed as a potential source of mesenchymal stem cells (MSCs) for regeneration of dental pulp and other tissues. However, further strategies to isolate highly functional DPSCs beyond the colony-forming methods are required. We have demonstrated the safety and efficacy of DPSCs isolated by G-CSF-induced mobilization and cultured under normoxia (mobilized DPSCs, MDPSCs) for pulp regeneration. The device for isolation of MDPSCs, however, is not cost-effective and requires a prolonged cell culture period. It is well known that MSCs cultured under hypoxic-preconditions improved MSC proliferation activity and stemness. Therefore, in this investigation, we attempted to improve the clinical utility of DPSCs by hypoxia-preconditioned DPSCs (hpDPSCs) compared with MDPSCs to improve the potential clinical utility for pulp regeneration in endodontic dentistry.METHODS: Colony-forming DPSCs were isolated and preconditioned with hypoxia in a stable closed cultured system and compared with MDPSCs isolated from the individual dog teeth. We examined the proliferation rate, migration potential, anti-apoptotic activity, and gene expression of the stem cell markers and angiogenic/neurotrophic factors. Trophic effects of the conditioned medium (CM) were also evaluated. In addition, the expression of immunomodulatory molecules upon stimulation with IFN-γ was investigated. The pulp regenerative potential and transplantation safety of hpDPSCs were further assessed in pulpectomized teeth in dogs by histological and immunohistochemical analyses and by chemistry of the blood and urine tests.
RESULTS: hpDPSCs demonstrated higher proliferation rate and expression of a major regulator of oxygen homeostasis, HIF-1α, and a stem cell marker, CXCR-4. The direct migratory activity of hpDPSCs in response to G-CSF was significantly higher than MDPSCs. The CM of hpDPSCs stimulated neurite extension. However, there were no changes in angiogenic, migration, and anti-apoptotic activities compared with the CM of MDPSCs. The expression of immunomodulatory gene, PTGE was significantly upregulated by IFN gamma in hpDPSCs compared with MDPSCs. However, no difference in nitric oxide was observed. The regenerated pulp tissue was quantitatively and qualitatively similar in hpDPSC transplants compared with MDPSC transplants in dog teeth. There was no evidence of toxicity or adverse events of the hpDPSC transplantation.
CONCLUSIONS: These results demonstrated that the efficacy of hpDPSCs for pulp regeneration was identical, although hpDPSCs improved stem cell properties compared to MDPSCs, suggesting their potential clinical utility for pulp regeneration.

Keywords:  Dental pulp stem cells; Dog teeth; Hypoxia; Prime condition; Pulp regeneration

DOI:  https://doi.org/10.1186/s13287-021-02240-w
Brain Res Bull. 2021 May 28. pii: S0361-9230(21)00144-1. [Epub ahead of print]

BDNF promotes neuronal survival after neonatal hypoxic-ischemic encephalopathy by up-regulating Stx1b and suppressing VDAC1.

Lu-Lu Xue, Ruo-Lan Du, Yue Hu, Liu-Lin Xiong, Zhang-Yu Su, Zheng Ma, Ya-Xin Tan, Jia Liu, Qiao Hu, Zhao-Qiong Zhu, Ting-Hua Wang, Xue-Zheng Liu.

  Neonatal hypoxic-ischemic encephalopathy (HIE), is a major cause of neurologic disorders in terms of neonates, with the unclear underlying mechanisms. In the study, triphenyl tetrazolium chloride (TTC) staining and Zea-longa score were performed to examine the neurologic damage in hypoxia and ischemia (HI) rats. The results showed that HI induced obviously infarct and serious neurologic impairment in neonatal rats. Then, protein chip was applied to detect the differential expression genes in cortex and hippocampus and found the brain-derived neurotrophic factor (BDNF) down-regulated both in cortex and hippocampus. Moreover, low expression of BDNF after HI in right cortex and hippocampus was validate by immunohistochemistry (IHC) and Western Blotting (WB). Afterwards, overexpressing and interfering HSV vector were produced, then verified by immunofluorescent staining and real-time quantitative polymerase chain reaction (qRT-PCR). The results of Tuj1 staining indicated that overexpression of BDNF could promote axonal regeneration and inhibit neuron swelling, whereas BDNF interference take an opposite effect after Oxygen glucose deprivation (OGD) injury. Finally, the interaction network among BDNF and associated proteins as examined by Genemania and confirmed by qRT-PCR. We found that the expression of VDAC1 was decreased and Stx1b was increased when BDNF overexpressing, which indicated that BDNF promoted neurite regrowth after OGD might be related to downregulation of VDAC1 and upregulation of Stx1b. Our results might provide novel strategy for the treatment of neurological defects induced by cerebral ischemia and hypoxia.

Keywords:  BDNF; Neonatal HIE; Stx1b; VDAC1; neurite regeneration

DOI:  https://doi.org/10.1016/j.brainresbull.2021.05.013
Pol J Pathol. 2021 ;pii: 44166. [Epub ahead of print]72(1): 23-38

Prognostic and clinicopathological implications of expression of Beclin-1 and hypoxia-inducible factor 1α in serous ovarian carcinoma: an immunohistochemical study.

Mohamed Alabiad, Ola Harb, Doaa Mandour, Rehab Hemeda, Rham Z Ahmed, Ahmed El-Taher, Gamal Osman, Amany Shalaby, Amr A A Alnemr, Mostafa T Abdelfattah.

  Serous ovarian carcinoma (SOC) is an ovarian cancer with a high fatality rate. Therefore, a lot of researchers have tried to identify novel prognostic biomarkers which might improve the patient prognosis. The aims of the study were to detect the tissue protein expression of Beclin-1 in addition to HIF-1α in SOC patients, to evaluate the relationship between their expression, the clinicopathological parameters, patients' prognosis, and the relation to chemotherapy resistance in SOC. We evaluated the expression of Beclin-1 in addition to HIF-1α in 60 patients with SOC using immunohistochemistry, followed all patients for about 36 months, analyzed associations between both markers' expression, clinicopathological data, and patients' prognosis. Beclin-1 expression was related to low grade (p = 0.002), early SOC stage, absence of peritoneal spread (p = 0.006), and absence of lymph nodes, and distant metastases (p = 0.004 and < 0.001 respectively), while HIF-1α expression was associated with higher grade and stage (p = 0.007), and presence of nodal and distant metastases (p < 0.001 and = 0.012 respectively). High Beclin-1 expression and low HIF-1α expression were positively associated with good response to chemotherapy (p = 0.047 and p = 0.022 respectively), a lower recurrence rate after successful therapy (p = 0.006 and < 0.001 respectively), and increased three-year recurrence-free and overall survival rates (p < 0.001). In SOC patients; Beclin-1 is a good prognostic marker, while HIF-1α is a poor prognostic marker.

Keywords:   Beclin-1; HIF-1α; immunohistochemistry.; survival; serous ovarian carcinoma

DOI:  https://doi.org/10.5114/pjp.2021.106441
Nat Rev Rheumatol. 2021 Jun 03.

The role of HIF proteins in maintaining the metabolic health of the intervertebral disc.

Elizabeth S Silagi, Ernestina Schipani, Irving M Shapiro, Makarand V Risbud.

The physiologically hypoxic intervertebral disc and cartilage rely on the hypoxia-inducible factor (HIF) family of transcription factors to mediate cellular responses to changes in oxygen tension. During homeostatic development, oxygen-dependent prolyl hydroxylases, circadian clock proteins and metabolic intermediates control the activities of HIF1 and HIF2 in these tissues. Mechanistically, HIF1 is the master regulator of glycolytic metabolism and cytosolic lactate levels. In addition, HIF1 regulates mitochondrial metabolism by promoting flux through the tricarboxylic acid cycle, inhibiting downsteam oxidative phosphorylation and controlling mitochondrial health through modulation of the mitophagic pathway. Accumulation of metabolic intermediates from HIF-dependent processes contribute to intracellular pH regulation in the disc and cartilage. Namely, to prevent changes in intracellular pH that could lead to cell death, HIF1 orchestrates a bicarbonate buffering system in the disc, controlled by carbonic anhydrase 9 (CA9) and CA12, sodium bicarbonate cotransporters and an intracellular H+/lactate efflux mechanism. In contrast to HIF1, the role of HIF2 remains elusive; in disorders of the disc and cartilage, its function has been linked to both anabolic and catabolic pathways. The current knowledge of hypoxic cell metabolism and regulation of HIF1 activity provides a strong basis for the development of future therapies designed to repair the degenerative disc.

DOI: https://doi.org/10.1038/s41584-021-00621-2
Evid Based Complement Alternat Med. 2021 ;2021 3471356

Lycopene Attenuates Hypoxia-Induced Testicular Injury by Inhibiting PROK2 Expression and Activating PI3K/AKT/mTOR Pathway in a Varicocele Adult Rat.

Hongqiang Wang, Baojuan Zhu, Lei Yu, Qiang Li, Shenqian Li, Peitao Wang, Tao Jing, Tongyi Men.

Purpose: The aim of this study was to evaluate the effect of lycopene on hypoxia-induced testicular injury in rat model and explore the underlying mechanism.Methods: Six-week-old male Wistar rats (n = 36) were randomly divided into three groups (n = 12/group): a normal group (NG, sham control), a varicocele group (VG), and a varicocele treated by lycopene group (VLG). Bilateral renal veins constriction was performed on rats in VG and VLG. Simultaneously, rats in VLG were treated to lycopene by intragastric administration. Four weeks later, sperm was collected for sperm analysis. Testes and epididymides were harvested for morphological change analysis, histologic analysis, ELISA, qRT-PCR, and western blot.
Results: Our observations were that lycopene improved the hypoxia-induced testicular injury in vivo. Prokineticin 2(PROK2) and prokineticin receptor 2 (PROKR2) were overexpressed in VG (P < 0.01), and lycopene inhibited the PROK2 expression (P < 0.01). Proliferating cell nuclear antigen (PCNA) and sex hormones were increased by lycopene in VLG (P < 0.05). Lycopene restored the quality and activity of sperm by blocking PROK2 expression (P < 0.05). The expression of VEGF was increased, as HIF-1/NF-κB pathway was upregulated in VLG (P < 0.05). Meanwhile, expression of pAKT/AKT in VLG was higher than that in VG (P < 0.05). In addition, lycopene reduced levels of interleukin-1β (IL-1β) and interleukin-2 (IL-2) in VLG (P < 0.05), compared to NG.
Conclusions: Lycopene improved the hypoxia-induced testicular injury by inhibiting the expression of PROK2 and decreasing levels of IL-1β and IL-2, which might show us a novel and promising treatment for varicocele testicular injury.

DOI: https://doi.org/10.1155/2021/3471356
Int J Mol Sci. 2021 May 05. pii: 4874. [Epub ahead of print]22(9):

Role of Hypoxia in the Control of the Cell Cycle.

Jimena Druker, James W Wilson, Fraser Child, Dilem Shakir, Temitope Fasanya, Sonia Rocha.

  The cell cycle is an important cellular process whereby the cell attempts to replicate its genome in an error-free manner. As such, mechanisms must exist for the cell cycle to respond to stress signals such as those elicited by hypoxia or reduced oxygen availability. This review focuses on the role of transcriptional and post-transcriptional mechanisms initiated in hypoxia that interface with cell cycle control. In addition, we discuss how the cell cycle can alter the hypoxia response. Overall, the cellular response to hypoxia and the cell cycle are linked through a variety of mechanisms, allowing cells to respond to hypoxia in a manner that ensures survival and minimal errors throughout cell division.

Keywords:  2-OGDs; HIF; PHDs; cell cycle; hypoxia; mitosis

DOI:  https://doi.org/10.3390/ijms22094874
Aging (Albany NY). 2021 Jun 03. 13

Hypoxia induces chemoresistance of esophageal cancer cells to cisplatin through regulating the lncRNA-EMS/miR-758-3p/WTAP axis.

Zi-Jiang Zhu, Yao Pang, Gang Jin, Hong-Yi Zhang, Wen-Hao Wang, Jia-Wei Liu, Guang-Xin Tuo, Peng Wu, Yi Yang, Ze-Quan Wang, Kui Wang.

  Hypoxia contributes significantly to the development of chemoresistance of many malignancies including esophageal cancer (EC). Accumulating studies have indicated that long non-coding RNAs play important roles in chemotherapy resistance. Here, we identified a novel lncRNA-EMS/miR-758-3p/WTAP axis that was involved in hypoxia-mediated chemoresistance to cisplatin in human EC. Hypoxia induced the expressions of lncRNA EMS and WTAP, and reduced the expression of miR-758-3p in EC cell line ECA-109. In addition, the expressions of EMS and WTAP were required for the hypoxia-induced drug resistance to cisplatin in EC cells, while overexpression of miR-758-3p reversed such chemoresistance. The targeting relationships between EMS and miR-758-3p, as well as miR-758-3p and WTAP, were verified by luciferase-based reporter assays and multiple quantitative assays after gene overexpression/knockdown. Moreover, we found significant correlations between tumor expressions of these molecules. Notably, higher levels of EMS/WTAP, or lower levels of miR-758-3p in tumors predicted worse survivals of EC patients. Furthermore, in a xenograft mouse model, targeted knockdown of EMS and WTAP in ECA-109 cells markedly attenuated the resistance of tumors to cisplatin treatments. Our study uncovers a critical lncRNA-EMS/miR-758-3p/WTAP axis in regulating hypoxia-mediated drug resistance to cisplatin in EC.

Keywords:  EMS; chemoresistance; esophageal cancer; hypoxia; miR-758-3p

DOI:  https://doi.org/10.18632/aging.203062
Cancer Biol Med. 2021 Jun 04. pii: j.issn.2095-3941.2021.0158. [Epub ahead of print]

Hypoxic microenvironment induced spatial transcriptome changes in pancreatic cancer.

Huizhi Sun, Danfang Zhang, Chongbiao Huang, Yuhong Guo, Zhao Yang, Nan Yao, Xueyi Dong, Runfen Cheng, Nan Zhao, Jie Meng, Baocun Sun, Jihui Hao.

  OBJECTIVE: Hypoxia is a significant feature of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). It is associated with tumor invasion, metastasis, and drug resistance. However, the spatial distribution of hypoxia-related heterogeneity in PDAC remains unclear.METHODS: Spatial transcriptomics (STs), a new technique, was used to investigate the ST features of engrafted human PDAC in the ischemic hind limbs of nude mice. Transcriptomes from ST spots in the hypoxic tumor and the control were clustered using differentially-expressed genes. These data were compared to determine the spatial organization of hypoxia-induced heterogeneity in PDAC. Clinical relevance was validated using the Tumor Cancer Genome Atlas and KM-plotter databases. The CMAP website was used to identify molecules that may serve as therapeutic targets for PDAC.
RESULTS: ST showed that the tumor cell subgroups decreased to 7 subgroups in the hypoxia group, compared to 9 subgroups in the control group. Different subgroups showed positional characteristics and different gene signatures. Subgroup 6 located at the invasive front showed a higher proliferative ability under hypoxia. Subgroup 6 had active functions including cell proliferation, invasion, and response to stress. Expressions of hypoxia-related genes, LDHA, TPI1, and ENO1, induced changes. CMAP analysis indicated that ADZ-6482, a PI3K inhibitor, was targeted by the invasive subgroup in hypoxic tumors.
CONCLUSIONS: This study is the first to describe hypoxic microenvironment-induced spatial transcriptome changes in PDAC, and to identify potential treatment targets for PDAC. These data will provide the basis for further investigations of the prognoses and treatments of hypoxic tumors.

Keywords:  Pancreatic cancer; hypoxia; spatial transcriptomic

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2021.0158
Front Physiol. 2021 ;12 688322

Histone Deacetylase 5 Is an Early Epigenetic Regulator of Intermittent Hypoxia Induced Sympathetic Nerve Activation and Blood Pressure.

Ning Wang, Ying-Jie Peng, Xiaoyu Su, Nanduri R Prabhakar, Jayasri Nanduri.

  Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA). Long term IH (LT-IH) triggers epigenetic reprogramming of the redox state involving DNA hypermethylation in the carotid body chemo reflex pathway resulting in persistent sympathetic activation and hypertension. Present study examined whether IH also activates epigenetic mechanism(s) other than DNA methylation. Histone modification by lysine acetylation is another major epigenetic mechanism associated with gene regulation. Equilibrium between the activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs) determine the level of lysine acetylation. Here we report that exposure of rat pheochromocytoma (PC)-12 cells to IH in vitro exhibited reduced HDAC enzyme activity due to proteasomal degradation of HDAC3 and HDAC5 proteins. Mechanistic investigations showed that IH-evoked decrease in HDAC activity increases lysine acetylation of α subunit of hypoxia inducible factor (HIF)-1α as well as Histone (H3) protein resulting in increased HIF-1 transcriptional activity. Trichostatin A (TSA), an inhibitor of HDACs, mimicked the effects of IH. Studies on rats treated with 10 days of IH or TSA showed reduced HDAC activity, HDAC5 protein, and increased HIF-1 dependent NADPH oxidase (NOX)-4 transcription in adrenal medullae (AM) resulting in elevated plasma catecholamines and blood pressure. Likewise, heme oxygenase (HO)-2 null mice, which exhibit IH because of high incidence of spontaneous apneas (apnea index 72 ± 1.2 apnea/h), also showed decreased HDAC activity and HDAC5 protein in the AM along with elevated circulating norepinephrine levels. These findings demonstrate that lysine acetylation of histone and non-histone proteins is an early epigenetic mechanism associated with sympathetic nerve activation and hypertension in rodent models of IH.

Keywords:  HDAC5; HIF-1; histone 3; hypertension; intermittent hypoxia; lysine deacetylase; obstructive sleep apnea

DOI:  https://doi.org/10.3389/fphys.2021.688322
Int J Mol Sci. 2021 May 31. pii: 5887. [Epub ahead of print]22(11):

Glucose Metabolic Dysfunction in Neurodegenerative Diseases-New Mechanistic Insights and the Potential of Hypoxia as a Prospective Therapy Targeting Metabolic Reprogramming.

Rongrong Han, Jing Liang, Bing Zhou.

  Glucose is the main circulating energy substrate for the adult brain. Owing to the high energy demand of nerve cells, glucose is actively oxidized to produce ATP and has a synergistic effect with mitochondria in metabolic pathways. The dysfunction of glucose metabolism inevitably disturbs the normal functioning of neurons, which is widely observed in neurodegenerative disease. Understanding the mechanisms of metabolic adaptation during disease progression has become a major focus of research, and interventions in these processes may relieve the neurons from degenerative stress. In this review, we highlight evidence of mitochondrial dysfunction, decreased glucose uptake, and diminished glucose metabolism in different neurodegeneration models such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). We also discuss how hypoxia, a metabolic reprogramming strategy linked to glucose metabolism in tumor cells and normal brain cells, and summarize the evidence for hypoxia as a putative therapy for general neurodegenerative disease.

Keywords:  brain energy metabolism; glucose; hypoxia; metabolic reprogramming; neurodegenerative disease

DOI:  https://doi.org/10.3390/ijms22115887
Int J Mol Sci. 2021 May 24. pii: 5555. [Epub ahead of print]22(11):

Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia.

Matias Estaras, Manuel R Gonzalez-Portillo, Miguel Fernandez-Bermejo, Jose M Mateos, Daniel Vara, Gerardo Blanco-Fernandez, Diego Lopez-Guerra, Vicente Roncero, Gines M Salido, Antonio González.

  In certain diseases of the pancreas, pancreatic stellate cells form an important part of fibrosis and are critical for the development of cancer cells. A hypoxic condition develops within the tumor, to which pancreatic stellate cells adapt and are able to proliferate. The consequence is the growth of the tumor. Melatonin, the product of the pineal gland, is gaining attention as an agent with therapeutic potential against pancreatic cancers. Its actions on tumor cells lead, in general, to a reduction in cell viability and proliferation. However, its effects on pancreatic stellate cells subjected to hypoxia are less known. In this study, we evaluated the actions of pharmacological concentrations of melatonin (1 mM-1 µM) on pancreatic stellate cells subjected to hypoxia. The results show that melatonin induced a decrease in cell viability at the highest concentrations tested. Similarly, the incorporation of BrdU into DNA was diminished by melatonin. The expression of cyclins A and D also was decreased in the presence of melatonin. Upon treatment of cells with melatonin, increases in the expression of major markers of ER stress, namely BIP, phospho-eIF2α and ATF-4, were detected. Modulation of apoptosis was noticed as an increase in caspase-3 activation. In addition, changes in the phosphorylated state of p44/42, p38 and JNK MAPKs were detected in cells treated with melatonin. A slight decrease in the content of α-smooth muscle actin was detected in cells treated with melatonin. Finally, treatment of cells with melatonin decreased the expression of matrix metalloproteinases 2, 3, 9 and 13. Our observations suggest that melatonin, at pharmacological concentrations, diminishes the proliferation of pancreatic stellate cells subjected to hypoxia through modulation of cell cycle, apoptosis and the activation of crucial MAPKs. Cellular responses might involve certain ER stress regulator proteins. In view of the results, melatonin could be taken into consideration as a potential therapeutic agent for pancreatic fibrosis.

Keywords:  apoptosis; fibrosis; hypoxia; melatonin; mitogen-activated protein kinases; pancreatic stellate cells

DOI:  https://doi.org/10.3390/ijms22115555
Cell Mol Neurobiol. 2021 Jun 05.

HIF-1α in the Crosstalk Between Reactive Oxygen Species and Autophagy Process: A Review in Multiple Sclerosis.

Rezvan Asgari, Reza Yarani, Pantea Mohammadi, Mohammad Sajad Emami Aleagha.

  Cellular stress can lead to the production of reactive oxygen species (ROS) while autophagy, as a catabolic pathway, protects the cells against stress. Autophagy in its turn plays a pivotal role in the pathophysiology of multiple sclerosis (MS). In the current review, we first summarized the contribution of ROS and autophagy to MS pathogenesis. Then probable crosstalk between these two pathways through HIF-1α for the first time has been proposed with the hope of employing a better understanding of MS pathophysiology and probable therapeutic approaches.

Keywords:  Autophagy; HIF-1α; Multiple sclerosis; ROS

DOI:  https://doi.org/10.1007/s10571-021-01111-5