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Biological Reviews of the Cambridge... Jun 2024Group-living in animals comes with a number of benefits associated with predator avoidance, foraging, and reproduction. A large proportion of fish species display...
Group-living in animals comes with a number of benefits associated with predator avoidance, foraging, and reproduction. A large proportion of fish species display grouping behaviour. Fish may also be particularly vulnerable to climate-related stressors including thermal variation, hypoxia, and acidification. As climate-related stressors are expected to increase in magnitude and frequency, any effects on fish behaviour may be increased and affect the ability of fish species to cope with changing conditions. Here we conduct a systematic review of the effects of temperature, hypoxia, and acidification on individual sociability and group cohesion in shoaling and schooling fishes. Searches of the published and grey literature were carried out, and studies were included or excluded based on selection criteria. Data from studies were then included in a meta-analysis to examine broad patterns of effects of climate-related stressors in the literature. Evidence was found for a reduction in group cohesion at low oxygen levels, which was stronger in smaller groups. While several studies reported effects of temperature and acidification, there was no consistent effect of either stressor on sociability or cohesion. There was some evidence that marine fishes are more strongly negatively affected by acidification compared with freshwater species, but results are similarly inconsistent and more studies are required. Additional studies of two or more stressors in combination are also needed, although one study found reduced sociability following exposure to acidification and high temperatures. Overall, there is some evidence that hypoxia, and potentially other climate-related environmental changes, impact sociability and group cohesion in fishes. This may reduce survival and adaptability in shoaling and schooling species and have further ecological implications for aquatic systems. However, this synthesis mainly highlights the need for more empirical studies examining the effects of climate-related factors on social behaviour in fishes.
PubMed: 38941355
DOI: 10.1111/brv.13111 -
The Journal of Clinical Investigation Jun 2024Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2α signaling. Identifying means to regulate HIF-2α thus has...
Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2α signaling. Identifying means to regulate HIF-2α thus has potential therapeutic benefit. Acetyl-CoA synthetase 2 (ACSS2) converts acetate to acetyl-CoA and is associated with poor patient prognosis in ccRCC. Here we tested the effects of ACSS2 on HIF-2α and cancer cell metabolism and growth in ccRCC models and clinical samples. ACSS2 inhibition reduced HIF-2α levels and suppressed ccRCC cell line growth in vitro, in vivo, and in cultures of primary ccRCC patient tumors. This treatment reduced glycolytic signaling, cholesterol metabolism, and mitochondrial integrity, all of which are consistent with loss of HIF-2α. Mechanistically, ACSS2 inhibition decreased chromatin accessibility and HIF-2α expression and stability. While HIF-2α protein levels are widely regulated through pVHL-dependent proteolytic degradation, we identify a potential pVHL-independent pathway of degradation via the E3 ligase MUL1. We show that MUL1 can directly interact with HIF-2α and that overexpression of MUL1 decreased HIF-2α levels in a manner partially dependent on ACSS2. These findings identify multiple mechanisms to regulate HIF-2α stability and ACSS2 inhibition as a strategy to complement HIF-2α-targeted therapies and deplete pathogenically stabilized HIF-2α.
Topics: Carcinoma, Renal Cell; Humans; Basic Helix-Loop-Helix Transcription Factors; Kidney Neoplasms; Cell Line, Tumor; Acetate-CoA Ligase; Signal Transduction; Animals; Mice; Gene Expression Regulation, Neoplastic; Von Hippel-Lindau Tumor Suppressor Protein; Ubiquitin-Protein Ligases; Neoplasm Proteins
PubMed: 38941296
DOI: 10.1172/JCI164249 -
JAMA Network Open Jun 2024The efficacy of a semirecumbent position (SRP) in reducing postoperative hypoxemia during anesthesia emergence is unclear despite its widespread use. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The efficacy of a semirecumbent position (SRP) in reducing postoperative hypoxemia during anesthesia emergence is unclear despite its widespread use.
OBJECTIVE
To determine the differences in postoperative hypoxemia between patients in an SRP and a supine position.
DESIGN, SETTING, AND PARTICIPANTS
This randomized clinical trial was performed at a tertiary hospital in China between March 20, 2021, and May 10, 2022. Patients scheduled to undergo laparoscopic upper abdominal surgery under general anesthesia were enrolled. Study recruitment and follow-up are complete.
INTERVENTIONS
Patients were randomized to 1 of the following positions at the end of the operation until leaving the postanesthesia care unit: supine (group S), 15° SRP (group F), or 30° SRP (group T).
MAIN OUTCOMES AND MEASURES
The primary outcome was the incidence of postoperative hypoxemia in the postanesthesia care unit. Severe hypoxemia was also evaluated.
RESULTS
Out of 700 patients (364 men [52.0%]; mean [SD] age, 47.8 [11.3] years), 233 were randomized to group S (126 men [54.1%]; mean [SD] age, 48.2 [10.9] years), 233 to group F (122 men [52.4%]; mean [SD] age, 48.1 [10.9] years), and 234 to group T (118 women [50.4%]; mean [SD] age, 47.2 [12.1] years). Postoperative hypoxemia differed significantly among the 3 groups (group S, 109 of 233 [46.8%]; group F, 105 of 233 [45.1%]; group T, 76 of 234 [32.5%]; P = .002). This difference was statistically significant for groups T vs S (risk ratio [RR], 0.69 [95% CI, 0.55-0.87]; P = .002) and groups T vs F (RR, 0.72 [95% CI, 0.57-0.91]; P = .007), but not for groups F vs S (RR, 0.96 [95% CI, 0.79-1.17]; P = .78). Severe hypoxemia also differed among the 3 groups (group S, 61 of 233 [26.2%]; group F, 53 of 233 [22.7%]; group T, 36 of 234 [15.4%]; P = .01). This difference was statistically significant for groups T vs S (RR, 0.59 [95% CI, 0.41-0.85]; P = .005).
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial of SRP during anesthesia recovery in patients undergoing laparoscopic upper abdominal surgery, postoperative hypoxemia was significantly reduced in group T compared with group F or group S.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR2100045087.
Topics: Humans; Male; Female; Middle Aged; Hypoxia; Postoperative Complications; Patient Positioning; Adult; Anesthesia Recovery Period; Anesthesia, General; China; Laparoscopy; Supine Position; Abdomen
PubMed: 38941098
DOI: 10.1001/jamanetworkopen.2024.16797 -
Stem Cells and Development Jun 2024This study investigates the characteristics of cardiac mesenchymal stem cell-like cells (CMSCLCs) isolated from the right atrial appendage of human donors with ischemia...
This study investigates the characteristics of cardiac mesenchymal stem cell-like cells (CMSCLCs) isolated from the right atrial appendage of human donors with ischemia and a young patient with endocarditis (NE-CMSCLCs). Typical CMSCLCs from ischemic heart patients were derived from coronary artery bypass grafting procedures, and compared against bone marrow mesenchymal stromal cells (BM-MSCs). NE-CMSCLCs had a normal immunophenotype but exhibited enhanced osteogenic differentiation potential, rapid proliferation, reduced senescence, reduced glycolysis, and lower reactive oxygen species generation after oxidative stress compared to typical ischemic CMSCLCs. These differences suggest a unique functional status of NE-CMSCLCs, influenced by the donor health condition. Despite large variances in their paracrine secretome, NE-CMSCLCs retained therapeutic potential, as indicated by their ability to protect hypoxia/reoxygenation-injured human cardiomyocytes, albeit less effectively than typical CMSCLCs. This research describes a unique cell phenotype and underscores the importance of donor health status in the therapeutic efficacy of autologous cardiac cell therapy.
PubMed: 38940748
DOI: 10.1089/scd.2024.0103 -
Cancer Biology & Medicine Jun 2024Angiogenesis is considered a hallmark pathophysiological process in tumor development. Aberrant vasculature resulting from tumor angiogenesis plays a critical role in... (Review)
Review
Angiogenesis is considered a hallmark pathophysiological process in tumor development. Aberrant vasculature resulting from tumor angiogenesis plays a critical role in the development of resistance to breast cancer treatments, exacerbation of tumor hypoxia, decreased effective drug concentrations within tumors, and immune-related mechanisms. Antiangiogenic therapy can counteract these breast cancer resistance factors by promoting tumor vascular normalization. The combination of antiangiogenic therapy with chemotherapy, targeted therapy, or immunotherapy has emerged as a promising approach for overcoming drug resistance in breast cancer. This review examines the mechanisms associated with angiogenesis and the interactions among tumor angiogenesis, the hypoxic tumor microenvironment, drug distribution, and immune mechanisms in breast cancer. Furthermore, this review provides a comprehensive summary of specific antiangiogenic drugs, and relevant studies assessing the reversal of drug resistance in breast cancer. The potential mechanisms underlying these interventions are discussed, and prospects for the clinical application of antiangiogenic therapy to overcome breast cancer treatment resistance are highlighted.
PubMed: 38940663
DOI: 10.20892/j.issn.2095-3941.2023.0515 -
Angewandte Chemie (International Ed. in... Jun 2024Given that type I photosensitizers (PSs) possess a good hypoxic tolerance, developing an innovative tactic to construct type I PSs is crucially important, but remains a...
A Renal Clearable Nano-Assembly with Förster Resonance Energy Transfer Amplified Superoxide Radical and Heat Generation to Overcome Hypoxia Resistance in Phototherapeutics.
Given that type I photosensitizers (PSs) possess a good hypoxic tolerance, developing an innovative tactic to construct type I PSs is crucially important, but remains a challenge. Herein, we present a smart molecular design strategy based on the Förster resonance energy transfer (FRET) mechanism to develop a type I photodynamic therapy (PDT) agent with an encouraging amplification effect for accurate hypoxic tumor therapy. Of note, benefiting from the FRET effect, the obtained nanostructured type I PDT agent (NanoPcSZ) with boosted light-harvesting ability not only amplifies superoxide radical (O2•-) production but also promotes heat generation upon near-infrared light irradiation. These features facilitate NanoPcSZ to realize excellent phototherapeutic response under both normal and hypoxic environments. As a result, both in vitro and in vivo experiments achieved a remarkable improvement in therapeutic efficacy via the combined effect of photothermal action and type I photoreaction. Notably, NanoPcSZ can be eliminated from organs (including the liver, lung, spleen, and kidney) apart from the tumor site and excreted through urine within 24 h of its systemic administration. In this way, the potential biotoxicity of drug accumulation can be avoided and the biosafety can be further enhanced.
PubMed: 38940633
DOI: 10.1002/anie.202411514 -
Analytical Chemistry Jun 2024Several reductases, including nitroreductase, are upregulated under hypoxic conditions characterized by an oxygen-deficient microenvironment. Given that hypoxia is a...
Several reductases, including nitroreductase, are upregulated under hypoxic conditions characterized by an oxygen-deficient microenvironment. Given that hypoxia is a prominent feature of solid tumors, our investigation focused on developing a bioconjugative probe designed for staining tissue under hypoxic conditions, particularly activated by nitroreductase. This probe, developed using our trigger-release-bioconjugation system rooted in the -quinone methide chemistry, exhibited selective activation by nitroreductase and fluorophore labeling within mitochondria and endoplasmic reticulum. As a result, it displayed sustained fluorescence that persisted even after washing steps in cells and tissues. We applied this innovative probe to stain mouse kidney tissue in an acute kidney injury model induced by inadequate oxygen supply. Among various organ tissues examined, only kidney tissue showed significantly higher fluorescence in the injury model compared with the control tissue, as revealed by two-photon microscopic imaging. This research presents a promising avenue for the development of practical staining agents for image-guided tumor surgery.
PubMed: 38940602
DOI: 10.1021/acs.analchem.4c01274 -
Molecular Medicine Reports Aug 2024Elevated levels of blood glucose in patients with ischemic stroke are associated with a worse prognosis. The present study aimed to explore whether hyperglycemia...
Elevated levels of blood glucose in patients with ischemic stroke are associated with a worse prognosis. The present study aimed to explore whether hyperglycemia promotes microglial pyroptosis by increasing the oxygen extraction rate in an acute ischemic stroke model. C57BL/6 mice that underwent middle cerebral artery occlusion were used for assessment of blood glucose level and neurological function. The cerebral oxygen extraction ratio (CERO), oxygen consumption rate (OCR) and partial pressure of brain tissue oxygen (PbtO) were measured. To investigate the significance of the NOD‑like receptor protein 3 (NLRP3) inflammasome, NLRP3 mice were used, and the expression levels of NLRP3, caspase‑1, full‑length gasdermin D (GSDMD‑FL), GSDMD‑N domain (GSDMD‑N), IL‑1β and IL‑18 were evaluated. In addition, Z‑YVAD‑FMK, a caspase‑1 inhibitor, was used to treat microglia to determine whether activation of the NLRP3 inflammasome was required for the enhancing effect of hyperglycemia on pyroptosis. It was revealed that hyperglycemia accelerated cerebral injury in the acute ischemic stroke model, as evidenced by decreased latency to fall and the percentage of foot fault. Hyperglycemia aggravated hypoxia by increasing the oxygen extraction rate, as evidenced by increased CERO and OCR, and decreased PbtO in response to high glucose treatment. Furthermore, hyperglycemia‑induced microglial pyroptosis was confirmed by detection of increased levels of caspase‑1, GSDMD‑N, IL‑1β and IL‑18 and a decreased level of GSDMD‑FL. However, the knockout of NLRP3 attenuated these effects. Pharmacological inhibition of caspase‑1 also reduced the expression levels of GSDMD‑N, IL‑1β and IL‑18 in microglial cells. These results suggested that hyperglycemia stimulated NLRP3 inflammasome activation by increasing the oxygen extraction rate, thus leading to the aggravation of pyroptosis following ischemic stroke.
Topics: Animals; Pyroptosis; Microglia; Ischemic Stroke; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Oxygen; Male; Hyperglycemia; Inflammasomes; Mice, Inbred C57BL; Caspase 1; Disease Models, Animal; Mice, Knockout; Interleukin-1beta; Phosphate-Binding Proteins; Oxygen Consumption; Gasdermins
PubMed: 38940333
DOI: 10.3892/mmr.2024.13270 -
Muscle & Nerve Jun 2024The impact of treatment expectations on active treatment outcomes has not been specifically investigated in neuromuscular disorders. We thus explored in myasthenia...
INTRODUCTION/AIMS
The impact of treatment expectations on active treatment outcomes has not been specifically investigated in neuromuscular disorders. We thus explored in myasthenia gravis (MG) the contribution of patients' pre-treatment expectations combined with an immunosuppressant drug on treatment outcomes.
METHODS
This pilot correlational study involved 17 patients with generalized MG, scheduled to start immunosuppressant azathioprine. At baseline, a healthcare professional administered: (i) the Stanford Expectations of Treatment Scale; (ii) a structured checklist paper form asking patients which side-effects they expected to develop after starting azathioprine, coupled with a standardized framing of statements. Quantitative Myasthenia Gravis (QMG) score and daily dose of concomitant drugs were assessed by neurologists as clinical outcomes. Clinical outcomes and side-effects were re-assessed at 3 and 6 months, and clinical outcomes were monitored at 18 months.
RESULTS
Clinically significant improvement in the QMG scores was achieved at 3 or 6 months. The level of state anxiety appeared to act as moderator of pre-treatment negative expectations (strong, positive, indicative correlation, rs = .733, p = .001). The latter were, in turn, associated with the fulfillment of side-effects that patients expected to develop with the new treatment (moderate, positive, indicative correlation, rs = .699, p = .002). No significant correlation emerged between positive and negative expectations.
DISCUSSION
Our findings show a very quick clinical response and also suggest that patients' expectations and anxiety contributed to treatment outcomes, highlighting the importance of promoting safety messages and education strategies around newly introduced treatments. Future goals include evaluating a larger cohort that includes a matched control group.
PubMed: 38940302
DOI: 10.1002/mus.28189 -
Current Medicinal Chemistry Jun 2024The formation of fibrotic bands in female reproductive system, including the uterus, after abdominal and pelvic surgeries, is an important medical challenge associated...
Lysyl Oxidase-like 2 Dysregulation Increases the Risk of Post-Operative Fibrotic Scars Formation in the Female Reproductive Tract: A Novel Therapeutic Target to Reduce Fibrogenesis.
The formation of fibrotic bands in female reproductive system, including the uterus, after abdominal and pelvic surgeries, is an important medical challenge associated with many complications, including infertility and pain. Investigating the role of different molecules involved in fibrosis and adhesion formation may help in the development of new drugs to prevent this disorder. Lysyl oxidase-like 2 (LoxL2) is a copper-dependent enzyme that catalyzes the cross-linking of collagen and elastin fibers in the extracellular matrix (ECM) to stabilize ECM. Dysregulation of LoxL2 activity resulting from tissue hypoxia and inflammation after gynecological surgeries in the female reproductive tract increases collagen fibers cross-linking and promotes fibrosis. It has been shown that targeting LoxL2 by Lox inhibitors may reduce fibrosis. Considering the expression of LoxL2 in female reproductive organs and its dysregulation in hypoxia and inflammation, it is possible that LoxL2 has therapeutic potential as a drug target in the prevention of adhesions. In this review, we discuss the role of LoxL2 in the promotion of fibrotic processes focusing on its link with inflammatory and hypoxic conditions. We also justify the use of anti- LoxL2 agents as a potential therapeutic strategy for the prevention of post-surgical scar formation.
PubMed: 38939993
DOI: 10.2174/0109298673306240240612055116