REVIEW | doi:10.20944/preprints202012.0553.v1
Online: 22 December 2020 (10:46:28 CET)
Solid tumors are typically associated with unbridled proliferation of malignant cells, accompanied by an immature and dysfunctional tumor-associated vascular network. Consequent impairment in transport of nutrients and oxygen eventually leads to a hypoxic environment wherein cells must adapt to survive and overcome these stresses. Hypoxia inducible factors (HIFs) are central transcription factors in the hypoxia response and drive the expression of a vast number of survival genes in cancer cells and in cells in the tumor microenvironment. HIFs are tightly controlled by a class of oxygen sensors, the HIF-prolyl hydroxylase domain proteins (PHDs), which hydroxylate HIFs, thereby marking them for proteasomal degradation. Remarkable and intense research during the past decade has revealed that, contrary to expectations, PHDs are often overexpressed in many tumor types and that inhibition of PHDs can lead to decreased tumor growth, impaired metastasis and diminished tumor-associated immune-tolerance. Therefore, PHDs represent an attractive therapeutic target in cancer research. Multiple PHD inhibitors have been developed that have either been recently accepted in China as erythropoiesis stimulating agents (ESA) or are currently in phase III trials. We review here the function of HIFs and PHDs in cancer and related therapeutic opportunities.
Subject: Biology, Anatomy & Morphology Keywords: Hypoxia Inducible Factor; HIF; Ischemia; Hypoxia; Adaptation; Alzheimer’s Disease; Parkinson Disease; Neurodegeneration
Online: 26 February 2021 (15:34:31 CET)
Hypoxia is one of the most common pathological conditions which results from ischemic injury, trauma, inflammatory conditions, tumors, The adaptation of the body to hypoxia is a phenomenon that is of great importance both in normal conditions and in Most of the cellular response’ reactions to hypoxia is associated with a family of transcription factors called hypoxia-inducible factors (HIF). They induce the expression of a wide range of genes that help cells adapt to a hypoxic HIF functions are currently being extensively studied. In 2019, William G. Kaelin and Gregg Semenza from the USA and Sir Peter J. Ratcliffe from the UK received the Nobel Prize in Physiology or Medicine for the discovery of the basic mechanisms of adaptation to hypoxia and investigation of the role of HIF factor in the regulation of the hormone erythropoietin Based on its pivotal physiological importance, the HIF factor attracts more and more attention as a new potential target for treating a large number of diseases associated with Most of the experimental work dealing with the HIF factor is focused on its role in liver and However, increasing amount of experimental results clearly demonstrates that the HIF factor-based response represents an universal adaptation mechanism for all kinds of tissues, including the nervous system where HIF is critical for regulating neurogenesis, nerve cell differentiation, and neuronal This review provides actual overview about the complex role of HIF-1 in the adaptation of nerve cells to hypoxia with the focus on its potential role by various neuronal
REVIEW | doi:10.20944/preprints202010.0136.v1
Online: 6 October 2020 (15:41:14 CEST)
Erythropoiesis is a complex process driving the production of red blood cells. During homeostasis, adult erythropoiesis takes place in the bone marrow and is tightly controlled by erythropoietin (EPO), a central hormone mainly produced in renal EPO-producing cells. The expression of EPO is strictly regulated by local changes in oxygen partial pressure (pO2) as under deprived oxygen (hypoxia) the transcription factor Hypoxia Inducible Factor-2 induces EPO. However, erythropoiesis regulation extends beyond the well-established HIF-EPO axis, and involves processes modulated by other hypoxia pathway proteins (HPPs), including proteins involved in iron metabolism. The importance of a number of these factors is evident as their altered expression has been associated with various anemia-related disorders, including chronic kidney disease. Eventually, our emerging understanding of HPPs and their regulatory feedback will be instrumental in developing specific therapies for anemic patients and beyond.
CASE REPORT | doi:10.20944/preprints202110.0386.v1
Subject: Medicine & Pharmacology, Anesthesiology Keywords: Atelectasis; Hypoxia; Old age; Spontaneous respiration
Online: 26 October 2021 (12:36:47 CEST)
There are several causes of hypoxia during and after surgery, and atelectasis is a common symptom that occurs during surgery. In particular, elderly patients are more vulnerable to hypoxia due to their existing lung diseases or respiratory muscle weakness. This study presents the cases of two elderly patients who developed hypoxia during total hip arthroplasty under general anesthesia. Positive end expiratory pressure, recruitment maneuver, and increased fraction of inspired oxygen improved hypoxia only temporarily, and patients’ oxygen saturation level again dropped to 79%–80%. We suspected that hypoxia was caused by atelectasis and, therefore, re-sumed spontaneous respiration. Thereafter, both the patients showed an improvement in hypoxia. Intraopera-tive hypoxia that is suspected to be caused by atelectasis can be improved by securing sufficient lung volume for respiration through increased muscle tone with spontaneous respiration
ARTICLE | doi:10.20944/preprints202208.0462.v1
Subject: Life Sciences, Molecular Biology Keywords: Hypoxia; Extracellular vesicles; Breast Cancer; Cell Invasion
Online: 26 August 2022 (14:08:23 CEST)
Hypoxia, a condition of low oxygenation frequently found in triple-negative breast tumors (TNBC), promotes extracellular vesicle (EV) secretion and favors cell invasion, a complex process in which cell morphology is altered, dynamic focal adhesion spots are created, and ECM is re-modeled. Here, we investigated the invasive properties triggered by TNBC-derived hypoxic small EV (SEVh) in vitro in cells cultured under hypoxic and normoxic conditions, using pheno-typical and proteomic approaches. SEVh characterization demonstrated increased protein abundance and diversity over normoxic SEV (SEVn), with enrichment in pro-invasive pathways. In normoxic cells, SEVh promotes invasive behavior through pro-migratory morphology, in-vadopodia development, ECM degradation and matrix metalloprotease (MMP) secretion. Pro-teome profiling of normoxic cells exposed to SEVh determined enrichment in metabolic processes and cell cycle, modulating cell health to escape apoptotic pathways. In hypoxia, SEVh was re-sponsible for proteolytic and catabolic pathway inducement, interfering with integrin availabil-ity and gelatinase expression. Overall, our results demonstrate the importance of hypoxic signal-ing via SEV in tumors for the early establishment of metastasis.
CONCEPT PAPER | doi:10.20944/preprints202206.0145.v1
Subject: Medicine & Pharmacology, Obstetrics & Gynaecology Keywords: ovary; PRP; senescence; rejuvenation; hypoxia; telomere length
Online: 9 June 2022 (11:16:03 CEST)
On a bleak therapeutic landscape unchanged since the 1980’s, IVF with egg donation still stand as the lone medical answer to diminished reserve and premature ovarian insufficiency. Intraovarian platelet-rich plasma (PRP) crossed the horizon in 2016 as hopeful answer to these intertwined problems. The once remote mirage of platelet cytokine effects on gene regulation or telomere stabilization is now in sharper focus, and current work is clarifying how PRP corrects oxidative stress, rectifies tissue hypoxia, downregulates apoptosis, and enhances cellular metabolism. Not yet ready for routine use, this investigational treatment does offer one point of general agreement: How intraovarian PRP results should be classified—Patients are either responders or non-responders. From this, it is intriguing that no published PRP protocol has reported a supranormal ovarian rebound or hyperstimulation effect. This could be explained by baseline age-related ovarian conditions prevalent among poor responders, but since dysregulated or malignant transformations are also absent in other tissue contexts following autologous PRP treatment, the contribution of some platelet product which intrinsically delimits regenerative action cannot be discounted. Here we summarize results with recent experimental and clinical platelet research, framing those most likely to help advance reproductive endocrinology practice.
Subject: Medicine & Pharmacology, Allergology Keywords: Cystathionine gamma-lyase; Hydrogen sulfide; Hypoxia; HUVECs
Online: 23 June 2021 (11:51:08 CEST)
Cystathionine gamma-lyase (CSE) is an essential Hydrogen sulphide (H2S)-producing enzyme that regulates diverse processes related to cardiovascular function. It is crucial to understand how exogenous H2S regulates CSE expression in vascular endothelial cells during hypoxia. We examined the regulatory effect of 100 μM H2S on the transcription and expression of CSE in HUVECs during hypoxia by luciferase assay, Western blotting, and quantitative RT-qPCR. Exogenous H2S influenced the promoter activity of CSE in HUVECs during hypoxia. Compared with 0 μM H2S, 100 μM H2S decreased the mRNA expression of CSE in HUVECs. Compared with 0 μM H2S, 100 μM H2S decreased the protein expression of CSE in HUVECs after 2 h of hypoxia. These findings suggest that vascular endothelial cells can respond to changes in H2S concentration in the blood during hypoxia.
ARTICLE | doi:10.20944/preprints202104.0265.v1
Subject: Medicine & Pharmacology, Allergology Keywords: cancer; hypoxia-inducible factors; HIF3A; expression analysis
Online: 9 April 2021 (14:35:55 CEST)
Background: Hypoxia-inducible factors (HIFs) are transcription factors that get activated and stabilized in the heterodimerized form under hypoxic conditions. The three members of the HIF alpha factors share high structural similarity but have tissue-specific expression patterns. A majority of studies have reported the importance of the HIF1A and HIF2A activity in the survival, proliferation, metastatic potential, and metabolic regulation of hypoxic cancer cells. However, the importance of the expression pattern and activity of HIF3A in a variety of cancers remains unknown. Method and materials: The expression profile of 13 different types of The Cancer Genome Atlas (TCGA) cancer samples were downloaded, normalized and differential gene expression analysis (DGE) was performed to compare the expression pattern of HIF alpha family members in cancer and adjacent normal tissues, as well as at different stages and tumor-sizes. Receiver operating characteristic (ROC) test and survival analysis were carried out to estimate the diagnostic potential of HIF alpha isomers in different cancers, as well as the survival rate of patients with the varying expression levels of HIF alpha factors. Results: The expression status of HIF3A was notably less in all cancer samples in contrast to their adjacent normal tissues. The expression degree of HIF1A varied among distinct types of cancer and the expression degree of HIF2A was lower in nearly all types of cancers. The expression level of HIF alpha isomers did not significantly correlate with different sizes of tumor samples and stages of different tumor tissue samples. HIF3A had very weak diagnostic potential, while HIF2A had better diagnostic potential in most types of cancers compared to HIF1A. Patients who had a higher level of HIF3A had better survival, while the higher expression levels of HIF1A and HIF2A were associated with worse survival in many types of cancers. Conclusion: Our study shows the heterogenous expression pattern of HIF alpha subunits in distinctive kinds of cancers and the influence of HIF3A expression level in the survival of patients with varying types of cancers.
ARTICLE | doi:10.20944/preprints202102.0332.v3
Subject: Medicine & Pharmacology, Allergology Keywords: Angiogenesis; Pulmonary hypertension; Endothelium; PHD2 Deficiency; Hypoxia
Online: 22 March 2021 (15:51:47 CET)
Endothelial autocrine signaling is essential to maintain vascular hemostasis. There is limited in-formation about the role of endothelial autocrine signaling in regulating severe pulmonary vas-cular remodeling during the onset of pulmonary arterial hypertension (PAH). In this study, we employed the first severe PAH mouse model, Egln1Tie2Cre (Tie2Cre-mediated disruption of Egln1) mice, to identify the novel autocrine signaling mediating the pulmonary vascular endothelial cells (PVECs) hyperproliferation and the pathogenesis of PAH. PVECs isolated from Egln1Tie2Cre lung expressed upregulation of many growth factors or angiocrine factors such as CXCL12, and exhib-ited hyperproliferative phenotype in coincident with upregulation of proliferation specific tran-scriptional factor FoxM1. Treatment of CXCL12 on PVECs increased FoxM1 expression, which was blocked by CXCL12 receptor CXCR4 antagonist AMD3100 in culture human PVECs. Endo-thelial specific deletion of Cxcl12 (Egln1/Cxcl12Tie2 Cre) or AMD3100 treatment in Egln1Tie2Cre mice downregulated FoxM1 expression in vivo. We then generated and characterized a novel mouse model with endothelial specific FoxM1 deletion in Egln1Tie2Cre mice (Egln1/Foxm1Tie2Cre), and found that endothelial FoxM1 deletion reduced pulmonary vascular remodeling and right ventricular systolic pressure. Together, our study identified a novel mechanism of endothelial autocrine sig-naling in regulating PVECs hyperproliferation and pulmonary vascular remodeling in PAH.
ARTICLE | doi:10.20944/preprints202011.0198.v1
Subject: Medicine & Pharmacology, Allergology Keywords: angiogenesis; Bidens pilosa; cancer; hypoxia; PDIA4; VEGF
Online: 4 November 2020 (15:20:10 CET)
Simply Summary: Translation of new cancer treatments between pets and human were noticed in comparative oncological investigation. The current study aims at evaluating a polyacetylenic glucoside purified from an edible herb, Bidens pilosa, to present its anti-angiogenic effects. We innovatively find this polyacetylenic glucoside, cytopiloyne, shows anti-angiogenic effect on different in vitro assays and various in vivo animal models under hypoxia. Based on results of this study, cytopiloyne will be a prospective herb angiogenesis inhibitor candidate to control animal or human cancer formation as adjuvant therapy. Abstract: Anti-angiogenesis is a pivotal combination treatment approach in cancer therapy but rare using on companion animals. This study aimed at evaluating the anti-angiogenic effect of a B. pilosa sourced polyacetylenic glucoside, cytopiloyne, on various in vitro assays and in vivo models. We provide evidences showing that CP has anti-angiogenic activities. Firstly, CP inhibited sponge/ Matrigel plug angiogenesis from tumor cells and decreased the survival of tumor cells on hypoxic conditions. Besides, CP declined PKCα protein expression which a protein leads to the growth and spread of tumors under hypoxia. Secondly, inhibitory effects of CP on endothelial angiogenesis were confirmed by chick chorioallantoic membrane assay, tube formation of SVEC4-10 cells and Matrigel plug assay. A dose-dependent CP treatment inhibited 4T1 cells proliferation under hypoxia and migration. It also suppresses VEGF transcription under hypoxia. Finally, we found that CP decreased PDIA4, a novel regulator of cancer growth, expression in endothelial cells. This effect was confirmed by PDIA4 knockout mice with reduced angiogenesis in Matrigel plug assay. Taken together, these results suggest that CP might act as a promising anti-angiogenic herbal agent candidate to be used in animal hypervascularized cancer of veterinary medicine or in combination to control human cancer as adjuvant therapy.
ARTICLE | doi:10.20944/preprints201806.0325.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: heart rate variability, smoking, hypoxia, autonomic dysfunction
Online: 20 June 2018 (15:38:52 CEST)
Background and objectives: Smoking leads to autonomic dysfunction. However, the clinical methods for diagnosing this dysfunction are not sufficient. Since exogenous hypoxia leads to changes in the autonomic cardiac control, the aim of our study was to compare the activity of the autonomic nervous system via heart rate variability (HRV) in young “healthy” smokers and non-smokers before, during and after a short-term exogenous hypoxic exposure. Methods: Twenty-one healthy non-smoking males aged 28.0±7.4 (mean±SD) and fourteen healthy smoking males aged 28.1±4.3 with 9.2±5.6 pack-years were subjected to one-hour hypoxic exposure (FiО2=12.3±1.5%) via hypoxicator (AltiPro 8850 Summit+, Altitude Tech, Canada) with simultaneous recording of electrocardiography and pulse oximetry. HRV data was derived via specific software (Kubios HRV, Finland) by analyzing the pre-hypoxic, hypoxic and post-hypoxic periods. Results: Standard deviation of the intervals between normal beats (SDNN) was higher in non-smokers in the pre-hypoxic period (62.0±32.1 vs 40.3±16.2, p=0.013) but not in hypoxia (75.7±34.8 vs 57.9±18.3, p=0.167). When comparing intragroup HRV changes of shifting from hypoxic to post-hypoxic (normoxic) conditions we found that there is a significant increase in the root mean square of successive RR interval differences (RMSSD) (65.9±40.2 vs 75.1±45.9, p=0.011) and in the high frequency (lnHF) (6.8±1.4 vs 7.2±1.3, p=0.014) and a decrease in LF/HF (3.0±2.3 vs 1.9±1.5, p<0.001), but these changes were observed only in the group of non-smokers. Conclusions: Smoking likely impairs autonomic regulation in young healthy males and may lead to a decreased HRV even before subjective clinical signs and symptoms. Hypoxic exposure test could be applied in clinical practice for early detection of autonomic dysfunction in smokers, because their parasympathetic reactivation is blunted when shifting from hypoxic to normoxic ambient conditions measured by HRV.
ARTICLE | doi:10.20944/preprints201710.0034.v2
Subject: Medicine & Pharmacology, Cardiology Keywords: pharmacokinetics; radiotracers; hypoxia; nuclear imaging; [123I]IAZA
Online: 24 February 2018 (07:21:45 CET)
The objective of this work is to evaluate the potential effect of cardiac stress exercise on the accumulation of [123I]IAZA, a radiopharmaceutical used to image focal tissue hypoxia, in otherwise normal myocardium in healthy volunteers, and to determine the impact of exercise on [123I]IAZA pharmacokinetics. The underlying goal is to establish a rational basis and a baseline for studies of focal myocardial hypoxia in cardiac patients using [123I]IAZA. Three healthy male volunteers ran the ‘Bruce’ treadmill protocol, a clinically-accepted protocol designed to expose myocardial ischemia in patients. The ‘Bruce’ criterion heart rate is 85% of [220 – age]. Approximately one minute before reaching this level, [123I]IAZA (5.0 mCi/0.85 mg) was administered as a slow (1–3 min) single intravenous (i.v.) injection via an indwelling venous catheter. The volunteer continued running for an additional 1 min before being transferred to a gamma camera. Serum samples were collected from the arm contralateral to the administration site at pre-determined intervals from 1 min to 45 h post injection and were analyzed by radio HPLC. Pharmacokinetic (PK) parameters were derived for [123I]IAZA and total radioactivity (total[123I]) using compartmental and noncompartmental analyses. Whole-body planar scintigraphic images were acquired from 0.75 to 24 h after dosing. PK data and scintigraphic images were compared to previously published [123I]IAZA data from healthy volunteers rest. Following exercise stress, both [123I]IAZA and total[123I] exhibited bi-exponential decline profiles, with rapid distribution phases [half-lives (t1/2α) of 1.2 and 1.4 min, respectively], followed by slower elimination phases [t1/2β of 195 and 290 min, respectively]. Total body clearance (CLTB) and the steady state volume of distribution (Vss) were 0.647 L/kg and 185 mL/min, respectively, for [123I]IAZA and 0.785 L/kg and 135 mL/min, respectively, for total[123I]. The t1/2β, CLTB and Vss values were comparable to those reported previously for rested volunteers. The t1/2α was approximately 4-fold shorter for [123I]IAZA and approximately 3-fold shorter for total[123I] under exercise relative to rested subjects. The heart region was visualized in early whole body scintigraphic images, but later images showed no accumulated radioactivity in this region, and no differences from images reported for rested volunteers were apparent. Minimal uptake of radiotracer in myocardium and skeletal muscle was consistent with uptake in non-stressed myocardium. Whole-body scintigrams for [123I]IAZA in exercise-stressed healthy volunteers were indistinguishable from images of non-exercised volunteers. There was no evidence of hypoxia-dependent binding in exercised but otherwise healthy myocardium, supporting the conclusion that exercise stress at Bruce protocol intensity does not induce measurable myocardial hypoxia. Effects of exercise on PK parameters were minimal; specifically, the t1/2α was shortened, reflecting increased cardiac output associated with exercise. It is concluded that because [123I]IAZA was not metabolically bound in exercise-stressed myocardium, a stress test will not create elevated myocardial background that would mask regions of myocardial perfusion deficiency. [123I]IAZA would therefore be suitable for the detection of viable, hypoxic myocardium in patients undergoing stress-test-based diagnosis.
ARTICLE | doi:10.20944/preprints202202.0349.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: Hypoxia-inducible factor; cancer; hypoxia; drug discovery; medicinal chemistry; virtual screening; molecular dynamics simulation; MM-PBSA; Drug discovery
Online: 28 February 2022 (08:40:24 CET)
The main regulatory factors during the adaptation of cancer cells to hypoxic stress are the hypoxia-inducible factors (HIFs), which are being increasingly recognized as an interesting and challenging target for the design of new chemotherapeutic molecules. HIF2A was found to have an large internal hydrophilic cavity within its PAS-B domain, unique to this sub-unit and is suggested to be a possible ligand-binding site. Regulation of HIF2A by cellular molecules is still greatly unknown. In This paper we have employed in-silico techniques, such as molecular docking and dynamic simulation, to design new direct inhibitors against HIF-2A subunit via targeting one of its critical domains and the final top screened molecules have been tested on hypoxic cancer cells for further validation of their inhibitory potential. we targeted the hydrophilic cavity inside the PAS-B domain of the HIF2A to identify novel molecules with a high binding capacity. Virtual Screening methodology was used for molecular docking of NSC library against the target domain inside the HIF2A PAS-B domain with the top 5% compounds with significant MolDock and Re-rank scores were selected for further analysis. The NSC 106416, NSC 217021, NSC 217026, and NSC 215639 compounds were selected based on their docking scores. NSC 215639 had the minimum polar solvation energy and also had a relative strong binding energy. NSC 217026 had the strongest binding energy among other compounds.
ARTICLE | doi:10.20944/preprints202208.0043.v1
Subject: Life Sciences, Biochemistry Keywords: cytoglobin; spheroids; hypoxia; HIF1A; head and neck cancer
Online: 2 August 2022 (06:23:18 CEST)
Cytoglobin has been implicated in a range of pathological conditions including fibrosis and cancer, where cytoglobin expression is linked to hypoxia- and drug-resistance. One disease where there is evidence of a role for cytoglobin is head and neck squamous cell carcinoma, a disease with a poor prognosis and where clinical resistance to platinum-based drugs is common. In the current study, we demonstrate that 3D-culture of head and neck cancer cells (PE/CA-PJ41, Liv-22K) and normal oral keratinocyte cells (NOK-hTERT) results in changes in sensitivity to cisplatin cytotoxicity compared to 2D-cultures. Relative to 2D-cultures, 3D-cultures of PE/CA-PJ41 and NOK-hTERT cells demonstrated increased cisplatin resistance. In contrast, 3D-cultures of Liv-22K cells were more sensitive to cisplatin. Evidence for cisplatin genotoxicity was observed in the form of GADD45A activation in PE/CA-PJ41 cells but not the other two cell types investigated. Furthermore, DNA-strand breaks were also detected by the alkaline comet assay in PE/CA-PJ41 cells although levels were not significantly affected by 3D-culture. Cytoglobin expression levels were elevated by 3D-culture in all three cell lines investigated and there were also changes in expression of genes related to cell division (MKI57, GJB6), cell adhesion (CDH1), stress response (NFkB, NQO1) and apoptosis (Casp3) but these changes were cell line specific. We also observed consistent transcriptional activation of HIF1a in 3D-cultures of all three cell lines, suggestive of hypoxic conditions in spheroids. In support of a direct role of hypoxia in cytoglobin induction, the HIF1a stabiliser cobalt chloride also induced cytoglobin expression in spheroids. Transcriptomic profiling of PE/CA-PJ41 cells over-expressing cytoglobin identified 121 differentially regulated genes, when cells were cultured under hypoxic conditions. Major changes identified included, upregulation of G1/S cell cycle regulation as well as wnt- and RhoGTPase-signalling pathways. In conclusion, 3D-cultures are a useful model to further study the biological function of cytoglobin in head and neck cancer and we provide evidence that further supports a role for cytoglobin in hypoxia-dependent cellular proliferation and phenotypic changes that could contribute to cisplatin resistance in vivo.
Subject: Life Sciences, Biochemistry Keywords: chronic intermittent hypoxia; autophagy; apoptosis; cardiomyocyte damage; calcineurin
Online: 24 June 2021 (14:58:22 CEST)
Calcineurin plays a key role in cardiovascular pathogenesis by exerting pro-apoptotic effects in cardiomyocytes; however, its involvement in the regulation of cardiomyocyte autophagy under chronic intermittent hypoxia (CIH) remains largely unknown. Here we showed that CIH induced calcineurin activity in H9C2 cells, resulting in the attenuation of adenosine monophos-phate-activated protein kinase (AMPK) signaling and inhibition of H9C2 cell autophagy. Au-tophagy, LC3-II levels, and AMPK phosphorylation were significantly elevated in response to CIH in H9C2 cells by day 3; however, these effects were reversed, and calcineurin activity and apoptosis were significantly increased by day 5. The calcineurin inhibitor, FK506, restored AMPK activation and LC3 protein levels, and reduced CIH-induced H9C2 cell apoptosis, while calcineurin overexpression significantly attenuated the increase in LC3 levels and enhanced H9C2 cell apop-tosis. Calcineurin inhibition failed to induce autophagy or alleviate apoptosis in H9C2 cells ex-pressing a dominant negative K45R AMPK mutant. Autophagy downregulation abrogated the protective effects of FK506-mediated calcineurin inhibition. These results indicated that calcineurin suppressed adaptive autophagy during CIH by downregulating AMPK activation. Our findings showed the underlying mechanisms of calcineurin and autophagy regulation during H9C2 cell survival in response to CIH, and suggested a new strategy for preventing CIH-induced cardiomyocyte damage.
ARTICLE | doi:10.20944/preprints202104.0359.v1
Online: 13 April 2021 (13:24:41 CEST)
PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here we investigated how PBRM1 controls HIF-1alpha activity. We find that PBRM1 is required for HIF-1alpha transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1alpha mRNA translation, as absence of PBRM1 results in reduced activly transalting HIF-1alpha mRNA. Interestingly, we find that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1alpha mRNA is m6A modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1alpha mRNA and reduction of YTHDF2 results in reduced HIF-1alpha protein expression in cells. Our results identify a SWI/SNF independent function for PBRM1, interacting with HIF-1alpha mRNA and the epitranscriptome machinery. Furthermore, our results suggests that the epitranscriptome associated proteins play a role in the control of hypoxia signalling pathways
REVIEW | doi:10.20944/preprints202011.0651.v1
Subject: Life Sciences, Biochemistry Keywords: hypoxia; 2-OG dioxygenases; chromatin; transcription, translation; cancer
Online: 25 November 2020 (16:09:12 CET)
Hypoxia — reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance to oxygen sensing are the 2-oxoglutarate (2-OG) dependent dioxygenases (2-OGDs). Of these, Prolyl-hydroxylases have long been recognised to control the levels and function of Hypoxia Inducible Factor (HIF), a master transcriptional regulator in hypoxia, via their hydroxylase activity. However, recent studies are revealing that dioxygenases are involved in almost all aspects of gene regulation, including chromatin organisation, transcription and translation. We highlight the relevance of HIF and 2-OG dioxyenases in the control of gene expression in response to hypoxia and their relevance to human cancers.
ARTICLE | doi:10.20944/preprints201912.0280.v1
Subject: Life Sciences, Genetics Keywords: aerobic glycolysis; caveolin1; hypoxia; monocrotaline; oxidative phosphorylation; RhoA
Online: 21 December 2019 (10:48:00 CET)
Pulmonary hypertension (PH) is a serious disorder with high morbidity and mortality rate. We analyzed the right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), lung histology and transcriptomes of six weeks old male rats with PH induced by: 1) hypoxia (HO), 2) administration of monocrotaline (CM) or 3) administration of monocrotaline and exposure to hypoxia (HM). The results in PH rats were compared to those in control rats (CO). After four weeks exposure, increased RVSP and RVH, pulmonary arterial wall thickening, and alteration of the lung transcriptome were observed in all PH groups. The HM group exhibited the largest alterations and also neointimal lesions and obliteration of lumen in small arteries. We found that the PH increased the expression of caveolin1, matrix metallopeptidase 2 and numerous inflammatory and cell proliferation genes. The cell-cycle, vascular smooth muscle contraction and the oxidative phosphorylation pathways, as well as their interplay were largely perturbed. Our results also suggest that the up-regulated Rhoa (ras homolog family member A) mediates its action through expression coordination with several ATPases. The upregulation of antioxidant genes and the extensive mitochondrial damage observed especially in HM group, indicate metabolic shift towards aerobic glycolysis.
REVIEW | doi:10.20944/preprints201703.0240.v1
Subject: Life Sciences, Molecular Biology Keywords: NF-кB, Hypoxia, Inflammation, IKK, PHDs, Cancer, TAK1, FIH
Online: 31 March 2017 (17:21:52 CEST)
Cancer is often characterised by the presence of hypoxia and inflammation. Paramount to the mechanisms controlling cellular responses under such stress stimuli, are the transcription factor families of Hypoxia Inducible Factor (HIF) and Nuclear Factor of kappa-light-chain-enhancer of activated B cells (NF-кB). Although, a detailed understating of how these transcription factors respond to their cognate stimulus is well established, it is now appreciated that HIF and NF-кB undergo extensive crosstalk, in particular in pathological situations such as cancer. Here, we focus on the current knowledge on how HIF is activated by inflammation and how NF-кB is modulated by hypoxia. We summarise the evidence for the possible mechanism behind this activation and how HIF and NF-кB function impacts cancer, focusing on colorectal, breast and lung cancer. We discuss possible new points of therapeutic intervention aiming to harness the current understanding of the HIF-NF-кB crosstalk.
REVIEW | doi:10.20944/preprints202010.0055.v1
Subject: Life Sciences, Biochemistry Keywords: carbon ions; particle therapy; radiotherapy; radiobiology; hypoxia; RBE; immunotherapy; metastasis
Online: 5 October 2020 (08:16:34 CEST)
Radiotherapy using accelerated charged particles is rapidly growing worldwide. About 85% of the cancer patients receiving particle therapy is irradiated with protons, which have physical advantages compared to X-rays but similar biological response. In addition to the ballistic advantages, heavy ions present specific radiobiological features that can make them attractive for treating radioresistant, hypoxic tumors. An ideal heavy ion should have lower toxicity in the entrance channel (normal tissue), and being exquisitely effective in the target region (tumor). Carbon ions have been chosen because they represent the best combination in this direction. Normal tissue toxicities and second cancer risk are similar to those observed in conventional radiotherapy. In the target region, they have increased relative biological effectiveness and reduced oxygen enhancement ratio compared to X-rays. Some radiobiology properties of densely ionizing carbon ions are so distinct from X-rays and protons that they can be considered as a different “drug” in oncology, and may elicit favorable responses such as increased immune response and reduced angiogenesis and metastatic potential. The radiobiological properties of carbon ions should guide patient selection and treatment protocols to achieve optimal clinical results.
ARTICLE | doi:10.20944/preprints201903.0087.v2
Subject: Medicine & Pharmacology, Other Keywords: tissue hypoxia; sleep disordered breathing; primary snoring; molecular tissue oximeter
Online: 16 August 2019 (06:27:46 CEST)
Pulse oximetry is the current standard for detecting drops in arterial blood oxygen saturation (SpO2) associated with obstructive sleep apnea and hypopnea events in polysomnographic (PSG) testing. In cases of hypoxic challenge, such as occurs during apneic events, regulatory mechanisms restrict blood flow to the skin to preferentially maintain SpO2 for more vital organs. As a result, a measure related to skin tissue oxygenation is likely to be more sensitive to inadequate breathing during sleep than pulse oximetry. Energy Conversion Monitoring (ECM) provides a method for measuring skin tissue oxygen-dependent energy conversion and, as such, is promising for more sensitively detecting sleep disordered breathing (SDB) events compared to pulse oximetry. We hypothesized that ECM would detect hypoxia occurring with SDB events associated with drops in SpO2 but also would detect hypoxic challenge occurring with SDB events not associated with drops in SpO2 (hypopneas defined by a drop in nasal pressure occurring in conjunction with an arousal, respiratory-related arousals, and primary snoring). Primary snoring is of particular interest with respect to the potential of ECM because it is statistically associated with co-morbidities of SDB, such as hypertension, but is not considered pathological because of the lack of a proximal measure of pathology occurring with PSG. In this article we review ECM technology and methodology, present preliminary data indicating that it detects hypoxia occurring in the skin during SDB events that is not detected as blood desaturation by pulse oximetry, and make the case that it is a promising tool for identifying pathology occurring at the mild end of the SDB spectrum.
ARTICLE | doi:10.20944/preprints201811.0266.v1
Subject: Life Sciences, Molecular Biology Keywords: hypobaric hypoxia; myocardium; interstitial space; fibroblasts; fibrosis; succinic acid; rats
Online: 12 November 2018 (05:16:27 CET)
The myocardial extracellular matrix is not a passive entity, but rather a complex and dynamic microenvironment which represents an important structural and signaling system within the myocardium. Understanding the fundamental role of hypoxia and peroxidation in the genesis of many cardiovascular diseases has stimulated the development of strategies that can enhance the energy-producing functions of cells. Revealing the alterations in cardiac metabolism and function associated with sustained exposure to high altitude advances our understanding of hypoxia-related disease. The study was conducted on 26 adult males of Wistar rats weighing 220–310 g, divided into 3 groups. The first control group consisted of 6 intact animals, the second group included 10 rats which were exposed to hypobaric hypoxia without medication for 30 days. Third group was composed of 10 rats, which were medicated by succinic acid solution which was injected intraperitoneally once a day at the rate of 0.5 mL/100 g of animal body weight 15 minutes before hypoxic exposure for 30 days. Fibrosis in the myocardium inevitably leads to increased myocardial stiffness, resulting in systolic and diastolic dysfunction, neurohormonal activation and, ultimately, heart failure Changes in cardiac highenergy phosphate metabolism may underlie the myocardial dysfunction caused by hypobaric hypoxia. Reduced oxygen delivery by microvascular damage, increased perivascular fibrosis associated with reduced cellular oxygen availability may contribute to contractile failure. Succinic acid combined with inosine acts as a high-energy phosphate reserve, to maintain adenosine triphosphate at levels sufficient to support contractile function.
REVIEW | doi:10.20944/preprints201803.0004.v1
Subject: Life Sciences, Molecular Biology Keywords: hypoxia; chromatin; transcriptional repression; repressor complexes; JmjC; histone methylation; HIF
Online: 1 March 2018 (06:36:57 CET)
Hypoxia, or reduced oxygen availability, has been studied extensively for its ability to activate specific genes. Hypoxia induced gene expression is mediated by the HIF transcription factors, although not exclusively so. Despite the great knowledge on the mechanisms by which hypoxia activates genes, much less is known about how hypoxia promotes gene repression. In this review, we discuss the potential mechanisms underlying hypoxia-induced transcriptional repression responses. We highlight HIF-dependent and independent mechanisms, but also the potential roles of dioxygenases with functions at the nucleosome and DNA level. Finally, we discuss recent evidence regarding the involvement of transcriptional repressor complexes in hypoxia.
CONCEPT PAPER | doi:10.20944/preprints202106.0486.v1
Subject: Medicine & Pharmacology, Allergology Keywords: high altitude, chronic hypobaric hypoxia, physiologic adaptation, travel to high altitude cities, high altitude physiology, pulmonary hypertension, lung disease, hemoglobin, tolerance to hypoxia, oxygen content.
Online: 18 June 2021 (15:22:04 CEST)
Acute high altitude illnesses are of great concern for physicians and people traveling to high altitude. High Altitude Pulmonary Edema (HAPE) can be better understood through the Oxygen Transport Triad which involves the Pneumo-Dynamic Pump (Ventilation), the Hemo-Dynamic Pump (Heart and circulation), and Hemoglobin. The two pumps are the first physiologic response upon initial exposure to hypobaric hypoxia. Hemoglobin is the balancing energy-saving time-evolving equilibrating factor. The increased hemoglobin at high altitude reduces the percentage of dissolved oxygen in the arterial oxygen content with respect to sea level. At high altitude, the acid-base balance must be adequately interpreted using the high altitude Van-Slyke correction factors. Pulse-oximetry measurements during breath-holding at high altitude allow for the evaluation of high altitude diseases. The Tolerance to Hypoxia Formula shows that, paradoxically, the higher the altitude the more tolerance to hypoxia. All organisms adapt physiologically and optimally to a high-altitude environment to survive. Reduction of pulmonary hypertension in HAPE through oxygen administration results in a favorable outcome.
BRIEF REPORT | doi:10.20944/preprints202003.0338.v3
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Severe Acute Respiratory Syndrome Coronavirus-2; (soluble) ACE2; eosinophil; asthma; IL-10; Lung fibrosis; hypercapnic acidosis; hypoxia; infarction; hypertension; cardiac dysfunction; respiratory distress; coagulopathy; Angiotensin; renin; Ang (1-7); Ang (1-9); Mas receptor; AT2 receptor
Online: 6 May 2020 (04:40:25 CEST)
The article describes the rational for inhibition of the angiotensin-converting enzyme 2 (ACE2) pathways as specific targets in patients infected by SARS-CoV-2 in order to prevent the establishment of positive feedback loops triggered by COVID-19 in some predisposed subjects. Making use of a large quantity of published reports in which human/rodent ACE2 pathway inhibitors were administered in vivo, it is hypothesized a possible therapeutic pharmacological intervention through an inhibition strategy of the zinc metalloprotease ACE2 and its downstream pathway for SARS-CoV-2 patients. Of even more interest, metal (zinc) chelators and renin inhibitors (both FDA approved drugs) may also work alone or in combination in inhibiting the positive feedback loops, initially triggered by COVID-19 and subsequently sustained by hypoxia independently on viral trigger, when both arms of renin-angiotensin system (ACE2 and ACE) are upregulated, leading to critical, advanced and untreatable stages of the disease.
REVIEW | doi:10.20944/preprints202211.0170.v1
Subject: Life Sciences, Biochemistry Keywords: wound healing; inflammation; microenvironment; stem cells; extracellular matrix; hypoxia; growth factors
Online: 9 November 2022 (03:41:12 CET)
Based on its large surface area and covering the whole human body, the skin body’s largest organ and its main function is protection. Injuries and wound healing involving the skin offer valuable lessons shared with and of relevance to other organ systems and the diseases that impact them. Arguably the most complex human body process, wound healing is a multifaceted process that involves multiple cells and the extracellular matrix (ECM), with each component playing a specific role in the different stages of the healing process. Importantly, studies indicate that cells with stem cell-like properties are present within many of the human tissues and play key roles in case of tissue and cellular injury. Cell-to-cell and cell-to-ECM interactions are salient in wound healing subsequent to an injury. Microenvironment related factors and the variations therein including hypoxia or the abundance of oxygen, the presence/absence of growth factors and cytokines add to the complexity of the wound healing process and impact cell function and result in compromised or enhanced wound healing. This expert review critically examines the advances in biochemical and analytical tools that are enable the analysis of numerous cells and molecules within the wound microenvironment, revealing great cellular heterogeneity as well as novel molecular targets of importance to enhance wound healing. In a broader angle, we emphasize the ways in which wound healing is significant in the search for perfect skin after injury and in many common complex human diseases including cancer. In all, wound healing is a centrepiece of integrative biology research and applications in medicine as well as dermatology as discussed in this review.
Subject: Medicine & Pharmacology, Allergology Keywords: microRNA; sevoflurane; desflurane; hypoxia inducible factor-1α; matrix metalloproteinase 9; glioma
Online: 23 March 2021 (09:14:01 CET)
Inhalational anesthetics was previously reported to suppress glioma cell malignancy, but underlying mechanisms remain unclear. The present study aims to investigate the effects of sevoflurane and desflurane on glioma cell malignancy changes via microRNA (miRNA) modulation. The cultured H4 cells were exposed to 3.6% sevoflurane or 10.3% desflurane for 2 hrs. The miR-138, -210 and -335 expression were determined with qRT-PCR. Cell proliferation and migration were assessed with wound healing assay, Ki67 staining and cell count kit 8 (CCK8) assay with/without miR-138/-210/-335 inhibitor transfections. The miRNA downstream proteins, hypoxia inducible factor-1α (HIF-1α) and matrix metalloproteinase 9 (MMP9), were also determined with immunofluorescent staining. Sevoflurane and desflurane exposure to glioma cells inhibited their proliferation and migration. Sevoflurane exposure increased miR-210 expression whereas desflurane exposure upregulated both miR-138 and miR-335 expressions. The administration of inhibitor of miR-138, -210 or -335 inhibited the suppressing effects of sevoflurane or desflurane on cell proliferation and migration, in line with the HIF-1α and MMP9 expression changes. These data indicated that inhalational anesthetics, sevoflurane and desflurane, inhibited glioma cell malignancy via miRNA upregulation and their downstream effectors, HIF-1α and MMP9, downregulation. The implication of the current study warrants further study.
ARTICLE | doi:10.20944/preprints202007.0527.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Triple Negative Breast Cancer; Cancer Stem Cell; Hypoxia; EGFR; Cisplatin; PDX
Online: 22 July 2020 (11:32:30 CEST)
Development of targeted therapies for triple-negative breast cancer (TNBC) is an unmet medical need. Cisplatin has demonstrated its promising potential for the treatment of TNBC in clinical trials; however, cisplatin treatment is associated with hypoxia that in turn promotes cancer stem cell (CSC) enrichment and drug resistance. Therapeutic approaches to attenuate this may lead to increased cisplatin efficacy in the clinic for the treatment of TNBC. In this report, we analyzed clinical dataset of TNBC and found that TNBC patients possessed higher levels of EGFR and hypoxia gene expression. A similar expression pattern was also observed in cisplatin-resistant ovarian cancer cells. We thus developed a new therapeutic approach to inhibit EGFR and hypoxia by combination of metformin and gefitinib that sensitized TNBC cells to cisplatin and led to the inhibition of both CD44+/CD24- and ALDH+ CSCs. We demonstrated a similar inhibition efficacy on organotypic cultures of TNBC patient samples ex vivo. Since these drugs have already been used frequently in the clinic, this study illustrates a novel, clinically translatable therapeutic approach to treat patients with TNBC.
ARTICLE | doi:10.20944/preprints201805.0106.v1
Subject: Medicine & Pharmacology, Other Keywords: contrast-induced nephropathy; hypoxia-inducible factor 2α; N-acetyl-cysteine; sildenafil
Online: 7 May 2018 (08:15:36 CEST)
Background and objectives: Contrast-induced nephropathy (CIN), is an acute renal damage due to contrast agents. This study is conducted to determine the potential diagnostic value of hypoxia-inducible factor 2-alpha (HIF2-α) and to evaluate the renal protective effects of N-acetyl cysteine (NAC) and sildenafil in a rat CIN model. Material/Methods: This randomized, controlled, interventional animal study was conducted on Wistar rats. Totally, rats (n = 36) were randomly assigned to four groups: control (n = 9), CIN group (n = 9), CIN+NAC group (n = 9), and sildenafil (n = 9). The rat model was used to form iohexol-originated CIN. During the modelling, prophylactic treatment was performed at 24th and 48th hours. After 48 hours of the modelling; blood, urine, tissue samples were obtained for biochemical analyses. HIF-2-α levels were measured in renal tissue, serum and urine samples. Renal sections were performed in order for histopathologic and immunohistochemical evaluations. Results: In the CIN model, HIF-2α levels and other biochemical parameters were significantly increased (p < 0.01). Both sildenafil and NAC, efficiently decreased the renal damage due to contrast agents (p < 0.05). Similarly, after treatment with sildenafil and NAC, HIF-2α levels were significantly decreased (p < 0.05). Conclusions: The current study constructs an experimental base for the use of HIF-2α for clinical prevention and treatment of CIN. Several mechanisms may be postulated for the changes in HIF-2α levels. Besides, the increased HIF-2α levels with CIN and decreased HIF-2α levels after treatment may be used for the treatment and follow-up of patients with CIN.
REVIEW | doi:10.20944/preprints202209.0457.v2
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Anti-angiogenic; HIF-1 α; Normalization-window; research; hypoxia; resistance; SBRT; Immunotherapy
Online: 7 October 2022 (09:45:53 CEST)
Multiple biological pathways manifest and latent, meant for human survival, become a liability in cancer cure. With an increasing understanding of innumerable complex paths, cancer progression and development of resistance is no surprise. For the three “vasculature-immune-phenotypic” fundamental changes, hypoxia is the maestro orchestrating the whole gamut of changes (through the master manipulator - HIF-1 α), simultaneously transactivating hundreds of pro-angiogenic genes. Such a complex molecular bio-network begs the question, “Is our cancer research caught in such a tangled web that we have lost sight of the Spider?”. Hypoxia is this Spider weaving compensatory webs with every intervention/ obstruction. Anti-angiogenic (AAG) research has been conducted mainly in silos – exploring independent paths. This review conceptualizes a convergence of a multitude of research worldwide to a single theme of normalizing vasculature as a primary baseline for overcoming resistance to AAGs or their combinations.
ARTICLE | doi:10.20944/preprints202112.0242.v1
Subject: Life Sciences, Biochemistry Keywords: VHL; von Hippel-Lindau syndrome; ubiquitination; hypoxia; testis; yeast two-hybrid (Y2H)
Online: 14 December 2021 (14:59:05 CET)
Functional impairment of the von Hippel-Lindau (pVHL) tumor suppressor is causative of a familiar increased risk to develop cancer. As E3 substrate recognition particle, pVHL marks for degradation the hypoxia inducible factor 1α (HIF-1α) in normoxic conditions, thus acting as a key regulator of both acute and chronic cell adaptation to hypoxia. Further evidence showed pVHL to also play relevant roles in microtubules stabilization, participate in the formation of the extracellular matrix, as well as to regulate cell senescence and apoptosis. Male mice model carrying VHL gene conditional knockout present significative abnormalities in testis development paired with defects in spermatogenesis and infertility, indicating that pVHL exerts testis-specific roles, at least in mice. Here, we describe 55 novel interactors of the human pVHL obtained by testis-tissue library screening. We show that pVHL interacts with multiple human proteins directly involved in spermatogenesis and reproductive metabolism, suggesting that, in addition to its role in cancer formation, pVHL may be pivotal in the correct gonads development also in human.
REVIEW | doi:10.20944/preprints202109.0511.v1
Subject: Medicine & Pharmacology, Other Keywords: Wound; chronic wound; hypoxia; Lactate; Acidosis; Alkalosis; neoangiogenesis; ECM; Polylactide; polylactide membranes
Online: 30 September 2021 (12:18:52 CEST)
: Over time, we have come to recognize a very complex network of physiological changes enabling wound healing. An immunological process enables the body to distinguish damaged cells and begin a cleaning mechanism by separating damaged proteins and cells with matrix metallopro-teinases, a complement reaction, and free radicals. A wide variety of cell functions help to rebuild new tissue, dependent on energy provision and oxygen supply. Like in an optimized "biorector," disturbance can lead to prolonged healing. One of the earliest investigated local factors is the pH of wounds, studied in close relation to the local perfusion, oxygen tension, and lactate concentration. Granulation tissue with the wrong pH can hinder fibroblast and keratinocyte division and pro-liferation, as well as skin graft takes. Methods for influencing the pH have been tested, such as occlusion and acidification by the topical application of acidic media. In most trials, this has not changed the wound's pH to an acidic one, but it has reduced the strong alkalinity of deeper or chronic wound. Energy provision is essential for all repair processes. New insights into the metabolism of cells have changed the definition of lactate from a waste product to an indispensable energy provider in normoxic and hypoxic conditions. Neovascularization depends on oxygen provision and lactate, signaling hypoxic conditions even under normoxic conditions. An appropriate pH is necessary for successful skin grafting; hypoxia can change the pH of wounds. This review describes the close interconnections between the local lactate levels, metabolism, healing mechanisms, and pH. Furthermore, it analyzes and evaluates the different possible ways to support metabolism, such as lactate enhancement and pH adjustment. The aim of wound treatment must be the optimization of all these components. Therefore, the role of lactate and its influence on wound healing in acute and chronic wounds will be assessed.
ARTICLE | doi:10.20944/preprints202011.0204.v1
Subject: Medicine & Pharmacology, Allergology Keywords: hypoxia; cisplatin sensitivity; mitochondrial fission; ROS; head and neck squamous cell carcinoma
Online: 5 November 2020 (10:02:19 CET)
Chemotherapy treatment based on Cisplatin (CDDP) is established as the drug of choice for head and neck squamous cell carcinoma (HNSCC). Malignant tumors respond to microenvironment alteration through a dynamic balance of mitochondrial fission and fusion. HNSCC is known to have hypoxic conditions, yet the effects and underlying mechanisms of hypoxia on chemosensitivity and mitochondrial dynamics remain unclear. We found that hypoxia promoted mitochondrial fission and CDDP sensitivity in HNSCC cells. Importantly, Mff was shown to be correlated with chemosensitivity in clinical samples of HNSCC that underwent a hypoxic condition. Hypoxia-inducible factor 1 α-subunit (HIF-1α) dramatically increased Mff transcriptional expression and directly bound to Mff. Hypoxia enhanced the release of reactive oxygen species (ROS) and upregulated the expression of Mff via HIF-1α in HNSCC cells. ROS depletion in HNSCC cells attenuated HIF-1α, Mff expression, and mitochondrial fission. Moreover, a knockdown of Mff suppressed hypoxia-induced mitochondrial fission and decreased CDDP chemosensitivity in vivo and in vitro. Our findings revealed that the hypoxia-induced release of ROS promoted mitochondrial fission and CDDP chemosensitivity via the regulation of HIF-1α/Mff in HNSCC cells, indicating that Mff may serve as a new biomarker to predict neoadjuvant chemosensitivity in HNSCC patients
REVIEW | doi:10.20944/preprints202003.0285.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: HIF-1α; NQO1; hypoxia; angiogenesis; cancer; protein:protein interactions; ligand binding; proteasomal degradation
Online: 18 March 2020 (08:45:33 CET)
HIF-1α is a master regulator of oxygen homeostasis involved in different stages of cancer development. Thus, HIF-1α inhibition represents an interesting target for anti-cancer therapy. It was recently shown that HIF-1α interaction with NQO1 inhibits its proteasomal degradation, thus suggesting that targeting the stability of NQO1 could led to destabilization of HIF-1α as a therapeutic approach. Since the molecular interactions of NQO1 with HIF-1α are beginning to be unraveled, we review here our current knowledge on the intracellular functions and stability of NQO1, its pharmacological modulation by small ligands, and the molecular determinants of its roles as a chaperone of many different proteins including cancer-associated factors such as p53 and p73α. This knowledge is then discussed in the context of potentially targeting the intracellular stability of HIF-1α by acting on its chaperone, NQO1. This could result in novel anti-cancer therapies.
ARTICLE | doi:10.20944/preprints202001.0110.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: oxidative stress; reactive oxygen species; hypoxia-reoxygenation; GluN2B; CNS neuron; Gelidium amansii
Online: 11 January 2020 (14:05:37 CET)
Oxidative stress is known to be critically implicated in the pathophysiology of several neurological disorders, including Alzheimer’s disease and ischemic stroke. The remarkable neurotrophic activity of Gelidium amansii, has been reported consistently in a series of our previous studies, inspired us to investigate whether this popular agarophyte could protect against hypoxia/reoxygenation (H/R)-induced oxidative injury in hippocampal neurons. The primary culture of hippocampal neurons challenged with H/R suffered from a significant loss of cell survival, accompanied by apoptosis and necrosis, DNA damage, generation of reactive oxygen species (ROS), and dissipation of mitochondrial membrane potential (MMP) which were successfully attenuated when the neuronal cultures were preconditioned with GAE, an optimized ethanolic extract of G. amansii. Moreover, the expression of N-methyl-D-acetate receptor subunit 2B (GluN2B), an extrasynaptic glutamate receptor, was significantly repressed in GAE-treated neurons as compared to those without GAE intervention. Together, this study demonstrates that GAE attenuated H/R-induced oxidative injury in hippocampal neurons through, at least in part, a potential neuroprotective mechanism that involves inhibition of GluN2B-mediated excitotoxicity and suppression of ROS production, and suggest that this edible seaweed could be a potential source of bioactive metabolites having therapeutic significance against oxidative stress-related neurodegeneration, including ischemic stroke and neurodegenerative diseases.
REVIEW | doi:10.20944/preprints202005.0284.v1
Subject: Life Sciences, Other Keywords: hypoxia; HIF-1α; partial EMT; collective migration; inflammatory breast cancer; E-cadherin; metastasis
Online: 17 May 2020 (08:19:42 CEST)
Epithelial-mesenchymal transition (EMT) is a cellular biological process involved in migration of primary cancer cells to secondary sites facilitating metastasis. Besides, EMT also confers properties such as stemness, drug resistance and immune evasion which can aid a successful colonization at the distant site. EMT is not a binary process; recent evidence suggests that cells in partial EMT or hybrid E/M phenotype(s) can have enhanced stemness and drug resistance as compared to those undergoing a complete EMT. Moreover, partial EMT enables collective migration of cells as clusters of circulating tumor cells or emboli, further endorsing that cells in hybrid E/M phenotypes may be the ‘fittest’ for metastasis. Here, we review mechanisms and implications of hybrid E/M phenotypes, including their reported association with hypoxia. Hypoxia-driven activation of HIF-1α can drive EMT. In addition, cyclic hypoxia, as compared to acute or chronic hypoxia, shows the highest levels of active HIF-1α and can augment cancer aggressiveness to a greater extent, including enriching for a partial EMT phenotype. We also discuss how metastasis is influenced by hypoxia, partial EMT and collective cell migration, and call for a better understanding of interconnections among these mechanisms. We discuss the known regulators of hypoxia, hybrid EMT and collective cell migration and highlight the gaps which needs to be filled for connecting these three axes which will increase our understanding of dynamics of metastasis and help control it more effectively.
REVIEW | doi:10.20944/preprints202206.0034.v1
Subject: Biology, Physiology Keywords: Ca2+ signaling; TRP channels; SOC channels; PIEZO channels tumour acidic microenvironment; hypoxia; tumour progression
Online: 2 June 2022 (11:10:23 CEST)
Solid tumours are characterized by an altered microenvironment (TME) from the physi-cochemical point of view, displaying a highly hypoxic and acidic interstitial fluid. Hy-poxia results from uncontrolled proliferation, aberrant vascularization and altered can-cer cell metabolism. Tumour cellular apparatus adapt to hypoxia by altering its metab-olism and behaviour, increasing its migratory and metastatic abilities by acquisition of a mesenchymal phenotype and selection of aggressive tumour cell clones. Extracellular acidosis is considered a cancer hallmark, acting as a driver of cancer aggressiveness by promoting tumour metastasis and chemoresistance by selecting for more aggressive cell phenotypes, although the underlying mechanism is still not clear. In this context, Ca2+ channels represent good target candidates due to their ability to integrate signals from the TME. Ca2+ channels are pH and hypoxia sensors and alterations in Ca2+ homeostasis in cancer progression and vascularization have been extensively reported. The present review will focus on Ca2+ permeable ion channels, with a major focus on TRP, SOC and PIEZO channels, that are modulated by tumour hypoxia and acidosis as well as the role of the resulted altered Ca2+ signals on cancer progression hallmarks. A deeper compre-hension of the Ca2+ signaling and acidic pH/hypoxia interplay will break new ground for the discovery of alternative and attractive therapeutics targets.
REVIEW | doi:10.20944/preprints202210.0450.v1
Subject: Life Sciences, Biochemistry Keywords: Tumor microenvironment; stromal cells; immune cells; ECM; cancer hallmarks; hypoxia; exosomes; drug resistance; targeted therapy
Online: 28 October 2022 (09:57:34 CEST)
Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis and highlight various ways through which tumor cells reprogram normal cells including into phenotypes that are pro-tumorigenic including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to formation of new vascular networks in order to actively promote and sustain tumor growth via supply of oxygen and nutrients whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to targeting of tumor cells. Re-programming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centred therapies under investigations.
REVIEW | doi:10.20944/preprints202205.0030.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: animal models; cardiac aftereffects; COVID-19; hypoxia; echocardiogram; pulmonary hypertension; right ventricular dilatation; right ventricular hypertrophy
Online: 5 May 2022 (09:36:47 CEST)
COVID-19 affects many organs in our body, including the heart and lungs. COVID-19 cases that require hospitalization often exhibit pulmonary hypertension (PH) due to changes in the lung microvasculature in which the blood vessels become stiff, damaged, or narrow, causing increased pulmonary arterial pressure. This review examines the hypothesis that PH can lead to right ventricular hypertrophy (RVH) as a long-lasting aftereffect of COVID-19. Recent studies have shown that significant percentages of hospitalized patients develop right ventricular hypertension and right ventricular dilatation (RVD), which may lead to right ventricular failure and death. Despite recommendations for echocardiogram reports to include right ventricular wall thickness to assess RVH, few published reports have reported this parameter. Relevant studies on animal models of PH in which the timing of PH can be precisely controlled suggest that one to three weeks of PH can cause RVH. Thus, according to the hypothesis proposed here COVID-19 patients who have long-lasting severe disease (e.g., needed to be on a ventilator for one or more weeks) accompanied by PH and RVD may develop RVH as a long-lasting sequela outlasting the infection itself. Echocardiogram studies of recovered COVID-19 patients may determine whether oft-reported cardiovascular sequelae include RVH.
ARTICLE | doi:10.20944/preprints201911.0081.v1
Subject: Life Sciences, Virology Keywords: Kaposi’s sarcoma-associated herpesvirus (KSHV); human herpesvirus-8; zebrafish; ddPCR; xenotransplantation; primary effusion lymphoma (PEL); hypoxia
Online: 8 November 2019 (03:23:22 CET)
Kaposi’s sarcoma associated-herpesvirus (KSHV, also known as human herpesvirus-8) is a gammaherpesvirus that establishes life-long infection in human B lymphocytes. KSHV infection is typically asymptomatic but immunosuppression can predispose KSHV-infected individuals to primary effusion lymphoma (PEL); a malignancy driven by aberrant proliferation of latently infected B lymphocytes, and supported by pro-inflammatory cytokines and angiogenic factors produced by cells that succumb to lytic viral replication. Here, we report the development of the first in vivo model for a virally-induced lymphoma in zebrafish, whereby KSHV-infected PEL tumour cells engraft and proliferate in the yolk sac of zebrafish larvae. Using a PEL cell line engineered to produce the viral lytic switch protein RTA in the presence of doxycycline, we demonstrate drug-inducible reactivation from KSHV latency in vivo, which enabled real-time observation and evaluation of latent and lytic phases of KSHV infection. In addition, we developed a sensitive droplet digital PCR method to monitor latent and lytic viral gene expression and host cell gene expression in xenografts. The zebrafish yolk sac is not well-vascularized and using fluorogenic assays we confirmed that this site provides a hypoxic environment that may mimic the microenvironment of some human tumors. We found that PEL cell proliferation in xenografts was dependent on the host hypoxia-dependent translation initiation factor, eukaryotic initiation factor 4E2 (eIF4E2). This demonstrates that the zebrafish yolk sac is a functionally hypoxic environment and xenografted cells must switch to dedicated hypoxic gene expression machinery to survive and proliferate. The establishment of the PEL xenograft model enables future studies that exploit the innate advantages of the zebrafish as a model for genetic and pharmacologic screens.
ARTICLE | doi:10.20944/preprints201906.0301.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: tumor blood vessel; Tumor Angiogenic Inhibition Triggered Necrosis (TAITN); CXCR4 antagonist; oral squamous cell carcinoma; hypoxia
Online: 28 June 2019 (15:18:43 CEST)
CXCR4 is a chemokine receptor crucial in tumor progression, although the angiogenic role of CXCR4 in oral squamous cell carcinoma (OSCC) has not been investigated. Here we show that CXCR4 is crucial for tumor angiogenesis thereby supports tumor survival in OSCC. Immunohistochemistry on human clinical specimens revealed that CXCR4 and a tumor vasculature marker CD34 were co-distributed in tumor vessels in human OSCC specimens. To ask the effects of CXCR4 inhibition, we treated the OSCC-xenografted mice with AMD3100, so-called plerixafor, an antagonist of CXCR4. Notably, we found a unique pathophysiological structure defined as Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) induced by the CXCR4 antagonism. Treatment with AMD3100 increased necrotic area with the induction of hypoxia-inducible factor-1α in the xenografted tumors, suggesting that AMD3100-induced TAITN was involved in hypoxia and ischemia. Taken together, we demonstrated that CXCR4 plays a crucial role in tumor angiogenesis required for OSCC progression, whereas TAITN induced by CXCR4 antagonism could be an effective anti-angiogenic therapeutic strategy in OSCC treatment.
REVIEW | doi:10.20944/preprints201809.0364.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: clear cell renal cell carcinoma; hypoxia inducible factors (HIFs); selenium; PD-L1; miRNA; VEGF; mTOR inhibitors
Online: 19 September 2018 (05:10:22 CEST)
In the last two decades, the discovery of various pathways involved in renal cell carcinoma (RCC) have led to the development of biologically-driven targeted therapies. Hypoxia inducible factors (HIFs), angiogenic growth factors, von Hippel-Lindau (VHL) gene mutations and oncogenic miRNAs play essential roles in the pathogenesis and drug resistance of clear cell renal cell carcinoma. These insights have led to the development of VEGF inhibitors, mTOR inhibitors and immunotherapeutic agents which have significantly improved outcomes of patients with advanced RCC. HIF inhibitors will be a valuable asset in the growing therapeutic armamentarium of RCC. Various histone deacetylase (HDAC)inhibitors, including selenium and agents such as PT2385 and PT2977, are being explored in various clinical trials as potential HIF inhibitors to ameliorate the outcomes of RCC patients. In this article, we will review the current treatment options and highlight the potential role of selenium in the modulation of drug resistance biomarkers expressed in ccRCC tumors.
ARTICLE | doi:10.20944/preprints202210.0180.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: C-reactive protein; STEMI; AMI; CRP apheresis; CMR; MRI; infarct size; inflammation; inflammatory mediators; ischaemia; hypoxia; phagocytosis
Online: 12 October 2022 (13:41:12 CEST)
In the multicenter, non-randomized, exploratory C-reactive protein (CRP) Apheresis in Myocardial Infarction (CAMI-1) study, CRP apheresis after ST-Elevation Myocardial Infarction (STEMI) significantly decreased blood CRP concentrations in humans. Cardiac damage was assessed by Cardiac Magnetic Resonance (CMR1) 3-9 d after onset of STEMI symptoms and quantified by myocardial infarct size (IS; %), left ventricular ejection fraction (LVEF; %), circumferential strain (CS) and longitudinal strain (LS) Compared with the control group (n=34), cardiac damage was significantly lower in the apheresis group (n=32). These findings suggested improved wound healing due to CRP apheresis already within few days after the STEMI event. In the current supplementary data analysis of CAMI-1, we have tested by a follow-up CMR (CMR2) after an average of 88 (65-177) d whether the effect of CRP apheresis is clinically maintained. After this time period wound healing in STEMI is considered complete. Whereas patients with low CRP production and a CRP gradient cut off of <0.6 mg/L/h in the hours after STEMI (9 of 32 patients in the CRP apheresis group) did not significantly benefit from CRP apheresis in CMR2, patients with high CRP production and a CRP gradient cut off of >0.6 mg/L/h (23 of 32 patients in the CRP apheresis group) showed significant treatment benefit. In the latter patients, CMR2 revealed a lower IS (-5.4%; p=0.05), a better LVEF (+6.4%; p=0.03), and an improved CS (-6.1%; p=0.005). No significant improvement, however, was observed for LS (-2.9%; p=0.1). These data suggest a sustained positive effect of CRP apheresis on the heart physiology in STEMI patients with high CRP production well beyond the period of its application. The data demonstrate the sustainability of the CRP removal from plasma which is associated with less scar tissue.
ARTICLE | doi:10.20944/preprints202206.0214.v1
Subject: Life Sciences, Genetics Keywords: Adra1b; cardiac ischemia; hypoxia; Crem; gene expression control; gene expression coordination; gene hierarchy; heart failure; transcriptomic stoichiometry
Online: 15 June 2022 (07:37:53 CEST)
Decades of research identified numerous gene biomarkers of cardiac diseases whose restored sequence or/and expression level was hoped to recover the normal cardiac function. However, each human has unique and dynamic pathophysiological characteristics resulting from the unrepeatable combination of favoring factors such are: race, sex, age, medical history, diet, stress, exposure to toxins, habits etc. As such, no treatment fits everybody and finding personalized solutions is a top priority for medicine of 21st century. The Genomic Fabric Paradigm (GFP) provides the most theoretically possible comprehensive characterization of the transcriptome, its alterations in disease and recovery following a treatment. By attaching to each gene the independent average expression level, expression variation and expression coordination with each other gene, GFP delivers thousands times more information than the traditional analysis. This report presents the theoretical bases of the GFP and some applications to our microarray data from mouse models of post ischemic, and constant and intermittent hypoxia-induced heart failure. The GFP analyses revealed novel transcriptomic aspects of the gene expression control and networking under ischemic conditions. Through all-inclusive characterization of the transcriptome and the unrepeatable gene hierarchy in each condition, GFP is an essential avenue towards development of a truly personalized cardiogenomic therapy.
REVIEW | doi:10.20944/preprints202012.0112.v1
Subject: Life Sciences, Biochemistry Keywords: Hypoxia; HIF-1α; HIF-2α; Posttranslational modifications; Phosphorylation; Acetylation; Ubiquitination; Sumoylation; S-Nitrosylation; Signalling; cystein phosphorylation; methylation
Online: 4 December 2020 (13:45:45 CET)
The hypoxia signalling pathway enables adaptation of cells to decreased oxygen availability. When oxygen becomes limiting, the central transcription factors of the pathway, hypoxia-inducible factors (HIFs), are stabilised and activated to induce the expression of hypoxia-regulated genes, thereby maintaining cellular homeostasis. Whilst hydroxylation has been thoroughly described as the major and canonical modification of the HIF-α subunits, regulating both HIF stability and activity, a range of other post-translational modifications decorating the entire protein play also a crucial role in altering HIF localisation, stability, and activity. These modifications, their conservation throughout evolution and their effects on HIF-dependent signalling are discussed in this review.
REVIEW | doi:10.20944/preprints202005.0085.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: COVID-19; HAPE; high-altitude; tolerance to hypoxia; oxygen transport triad; Cov-2; SARS; pneumonia; ventilators; EPO
Online: 5 May 2020 (15:26:05 CEST)
The critical hypoxia in COVID-19 patients during this pandemic, has taken away many lives all around the globe. The mechanism has been poorly understood and initially, word got around that it was a SARS (Severe Acute Respiratory Syndrome) pneumonia. The atypical images in lung computerized axial tomography (CAT) scans were alarming. This immediately alerted everyone including poor countries to purchase lacking sophisticated ventilator equipment. However, in some countries, even 88% of the patients on ventilators lost their lives. New observations and pathological findings are gradually clarifying the disease. What seems evident is that it is not only one disease but several, with different responses in different countries and different altitudes. The critical hypoxia and «gasping» present in some patients are not totally understood. It was mentioned that it could be like a High-Altitude Pulmonary Edema (HAPE). Hereby, as high-altitude medicine and hypoxia physiology specialists, we compare the pathophysiology with that of high-altitude exposure in order to understand the mechanisms involved. Some differences in lung radiological images along with transmission and viral attack mechanisms are discussed. The oxygen transport triad used at high-altitude can be applied on this pathology in order to propose even the use of erythropoietin (EPO) early in the treatment. The immune system is the most important long-term survival tool, so we suggest a short-term strategy: the use of special Earth open-circuit astronaut-resembling suits with effective outside air filtering re-breathing mechanisms in order to return to work and daily activities, without contamination risk. Thereby, the curve can be flattened without quarantine and the economy could recover.
REVIEW | doi:10.20944/preprints202212.0030.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Blood Pressure; Cardiovascular Disorder; Hypertension; Hypotension; Hypoxia; Baroreflex; Hemorrhagic Shock; Hypovolemic Shock; Vasopressure; Resuscitation; Centhaquine (Lyfaquin); Sympathetic System; Parasympathetic System; Adrenoreceptors
Online: 2 December 2022 (02:00:06 CET)
The pressure exerted on the heart and blood vessels because of blood flow is considered as an important parameter for the cardiovascular function. It determines sufficient blood perfusion as well as transportation of nutrition, oxygen and other essential factors to every organ. Pressure in the primary arteries located near the heart and the brain, known as central blood pressure (CBP), while in peripheral arteries, known as peripheral blood pressure (PBP). Normally, CBP and PBP are correlated; however, cardiovascular disorders interfere their regulation and affect the blood flow in vital organs and accessory organs, differently. Therefore, understanding each of them in normal and disease conditions is essential for managing various cardiovascular disorders and increasing their treatment outcomes. In this review, we have described the control systems (neural, hormonal, osmotic and cellular) of the blood pressure and its regulation in hypovolemic shock using centhaquine (Lyfaquin®) as a resuscitative agent.
REVIEW | doi:10.20944/preprints201908.0186.v1
Subject: Life Sciences, Immunology Keywords: heat shock protein (HSP); extracellular vesicle (EV); exosome; oncosome; immune evasion; resistance-associated secretory phenotype (RASP); EMT; hypoxia; biomarker; liquid biopsy
Online: 17 August 2019 (16:15:01 CEST)
Extracellular vesicles (EV) released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP), by which immune evasion can be established. Heat shock proteins (HSPs) are an evolutionarily conserved family of molecular chaperones, which stabilize proteins, minimize protein misfolding and aggregation within the cell, besides facilitating protein translocation, refolding and degradation. (i) Releases of extracellular HSPs (ex-HSP) and EV-associated HSPs (EV-HSP) are essential in RASP, by which molecular cotransfer of HSPs with oncogenic factors into recipient cells can promote cancer progression and resistance against stress such as hypoxia, radiation, chemicals, and immune system. (ii) RASP of tumor cells can eject anticancer drugs, molecularly targeted therapeutics, and immune checkpoint inhibitors with EVs. (iii) Cytotoxic lipids can be also released from tumor cells as RASP. Nevertheless, ex-HSP and EV-HSP can play immunostimulatory and immunosuppressive roles by binding to receptors such as LRP1/CD91/A2MR, scavenger receptors, and toll-like receptors expressed on recipient cells. Liquid biopsy of HSPs in body fluids may be useful in diagnosis, prognosis, and treatment in cancer. Regarding HSP90-targeted therapeutics, we summarize the pros, cons, and problem solutions in this review. Although production of HSPs are canonically induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), recent studies discovered that production of HSPs is also regulated by matrix metalloproteinase 3 (MMP3) and heterochromatin protein 1 (HP1) and production of cochaperone CDC37 is reciprocally regulated by myeloid zinc finger 1 (MZF1) and SCAN-D1.
REVIEW | doi:10.20944/preprints202204.0118.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS-CoV-2-infection; dehydration; hypoalbuminemia; pulmonary hypoxia; hyaline memrane; pulmonary engorgement; lung weight; acute respiratory distress syndrome; diffuse alveolar damage (DAD)
Online: 13 April 2022 (08:27:30 CEST)
ABSTRACT Two years after first patients approached the emergency rooms of hospitals in Wuhan becouse of respiratory distress,thousend of SARS-CoV-2 infected persons continue to die every day worldwide.SARS-CoV-2-infected patients undergo a process of dehydration and malnutrition before they develop respiratory problems and approach the emergency room of a hospital.This is,in many cases, the consequence of high fever which causes massive loss of fluids. In addition loss of appetite, is responsible for the deficit of protein intake.Most of the virus-infected patients admitted to the emergency room are therefore hypovolemic and hypoproteinemic and suffer of respiratory distress accompanied by ground grass opacities at CT-scan of the lungs.Critically ill patients are treated following the guidelines for treatment of septic shock but with „conservative“ fluid replacement and administration of diuretics to assure sufficient hourly urine production. The combination of conservative fluid administration with reduced protein content in the enterally administered diet, together with administration of diuretics, has severe hemodynamic consequenses in mostly aged,dehydrated,critically ill patients. Many of them will develop acute kidney injury in the next 24 hours.In most of the cases, patients continue to loose weight by loosing skeletal muscle mass. Ischemic damage in the lung capillaries is responsible for the acute respiratory distreass syndrome (ARDS) and for the hallmark of autoptic findings,diffuse alveolar damage (DAD) characterized by hyaline membrane formation,fluid invasion of the alveoli recruitment of some inflammatory cells and progressive arrest of blood flow in the pulmonary vessels.The consequence is progressive congestion , increase of lung weight and progressive hypoxia (progressive severity of ARDS).Sequestration of blood in the lungs worsen hypovolemia and ischemia in different organs.This is most probably responsible for recruitment of inflammatory cells and for persistance of elevated serum levels of positive acute-phase markers and of hypoalbuminemia. Autoptic studies have been performed mostly in patients who died in the ICU after SARS-CoV-2-infection because of progessive ARDS.In those patients, tubulus epithelium necrosis in the kidney is a frequent finding as it has been the case in the first SARS-CoV-1 pandemic.In the death certification charts, many times weeks after first symptoms have started ,cardiac arrest is the cause of death after respitatory insufficiency.Replacement therapy with sufficient amount of fluid and albumin should be part of the early individualized life-saving supportive measures avoiding mechanical ventilation.
REVIEW | doi:10.20944/preprints202207.0171.v1
Subject: Medicine & Pharmacology, Behavioral Neuroscience Keywords: Alzheimer’s; aging; amygdala; brain plasticity; CA1; CA3; chronic stress; cognition; GABA; HIF-1; hippocampus; hypoxia; neurogenesis; Parkinson’s; prefrontal cortex; PSA-NCAM; ROS; spatial learning
Online: 12 July 2022 (04:25:55 CEST)
Stress plays a central role in functioning for all life forms. As humans, we experience stress in a multitude of ways through various types of stimuli. Due to the constancy of stressors in our lives, the nervous system has learned to allosterically adapt to the stimuli, but when the body cannot adapt, chronic stress can have morphological and degenerative impacts on neuroanatomy and cognitive function that may or may not be reversible. This literature review aimed to identify the specific neuroanatomical structures impacted most by the long-term effects of chronic stress and the subsequent relationship the morphological changes had on cognitive function in rodent models. We examined articles published from PubMed, Google Scholar, and Science Direct, while focusing the search on anatomical and neurodegenerative effects associated with chronic stress stimuli. The degenerative effects of various types simulated physiological chronic stress showed the most impact on neurogenesis and neuronal development, brain plasticity, and spatial learning and memory with association to the hippocampus. The hippocampus, amygdala, prefrontal cortex, and hypothalamic-pituitary-adrenal axis (HPA) all had reversible and non-reversible morphological alterations, which also had a direct impact on the brain’s cognitive abilities. While studies regarding chronic stress are still being conducted, future research may be able to further highlight why stressful stimuli can particularly impact these structures and the tangential impacts that it may have on related or adjacent structures.
REVIEW | doi:10.20944/preprints201912.0386.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: resistance-associated secretory phenotype (RASP); extracellular vesicle (EV); exosome; oncosome; drug resistance; epithelial-mesenchymal transition (EMT); heat shock protein (HSP); cell stress response; hypoxia; acidosis; tumor immunology
Online: 29 December 2019 (13:46:21 CET)
Extracellular vesicles (EVs), such as exosomes or oncosomes are released with molecules unfavorable for survival from cells. In addition, accumulating evidence has shown that tumor cells often eject anti-cancer drugs such as chemotherapeutics and targeted drugs within EVs, a novel mechanism of drug resistance. The EV-releasing, drug resistance phenotype is often coupled with cellular dedifferentiation and transformation, cells undergoing epithelial-mesenchymal transition (EMT) and taking on a cancer stem cell phenotype. Recent studies have shown that the release of EVs is also involved in immunosuppression. The concept of the resistance-associated secretory phenotype (RASP) is reviewed herein.
REVIEW | doi:10.20944/preprints201805.0413.v1
Subject: Life Sciences, Other Keywords: silver nanoparticles; nanosilver; endocytosis; oxidative stress; reactive oxygen species; inflammation; wound healing; hypoxia; mitochondria; endoplasmic reticulum stress; unfolded protein response; autophagy; apoptosis; angiogenesis; epigenetics; genotoxicity; cancer; anti-cancer
Online: 28 May 2018 (15:51:12 CEST)
Nanosilver plays an important role in nanoscience and nanotechnology, and is becoming increasingly used for applications in nanomedicine. Nanosilver ranges in size from one to one hundred nanometers. Smaller particles more readily enter cells and interact with the cellular components. The exposure dose, particle size, coating, and aggregation state of the nanosilver, as well as the cell type or organism that it is tested on, all have a large determining factor on the effect and potential toxicity of nanosilver. A high exposure dose to nanosilver alters the cellular stress responses and initiates cascades of signaling that can eventually trigger organelle autophagy and apoptosis. This review summarizes the current knowledge of the effects of nanosilver on cellular metabolic function and response to stress. Both the causative effects of nanosilver on oxidative stress, endoplasmic reticulum stress, and hypoxic stress, as well as the effects of nanosilver on the responses to such stresses, are outlined. The interactions and effects of nanosilver on cellular uptake, oxidative stress (reactive oxygen species), inflammation, hypoxic response, mitochondrial function, endoplasmic reticulum function and the unfolded protein response, autophagy and apoptosis, angiogenesis, epigenetics, genotoxicity, and cancer development and tumorigenesis, as well as other pathway alterations are examined in this review.
REVIEW | doi:10.20944/preprints202206.0316.v1
Subject: Life Sciences, Immunology Keywords: Cancer surgery; Cancer radiotherapy; Cancer immunotherapy; Cancer stroma; Cancer-associated fibroblasts; Carcinogenesis; Cancer resistance to immunotherapy; Exosomes; Hypoxia; Neutrophil extracellular traps; Sphingomyelin; Neutral sphingomyelinase; Tumor microenvironment; Tumor-associated macrophages
Online: 22 June 2022 (10:25:07 CEST)
The central reason behind emergence of clinically-detectable tumors is evasion from immune surveillance due to lack of cancer cells surface membrane expression of tumor-specific peptides in association with MHC class I molecules, concealment of natural killer cells-activating molecules, and absence of inflammation resulting from inefficient stimulation of innate immunity receptors and co-stimulatory molecules. The tumor microenvironment (TME) also contributes to tumor initiation, progression and resistance to therapeutic interventions because of its dense, fibrogenic, barrier-like composition, aberrant vasculature, and production of cytokines and chemokines responsible for recruitment of immune suppressive cells, notably myeloid-derived suppressor cells, M2 macrophages, regulatory T cells, extracellular trap-forming neutrophils, and cancer-associated fibroblasts. We herein show that the relentless efforts and strategies to overcome the TME elusive tumor-promoting impact produced contrasting, opposed, controversial effects, characterized by limited efficacy and proven adversity, and most importantly deterred from attempts to discover and counteract the fundamental inherent mechanisms initiating, and not consequent to, carcinogenesis.