Search Results (142)

Background/Objectives: Colorectal cancer (CRC) patients undergoing chemotherapy often experience anemia, oxidative stress, and immune suppression, significantly impacting their quality of life and treatment outcomes. Normobaric oxygen (NBO) therapy, which delivers oxygen at atmospheric pressure with an elevated oxygen concentration, has shown the potential to enhance erythropoiesis, reduce oxidative stress, and modulate immune function. However, its efficacy in CRC patients remains underexplored. This study aims to evaluate the effects of NBO exposures on (1) supporting erythropoiesis by measuring erythropoietin (EPO) levels and hypoxia-inducible factor 1-alpha (HIF-1α), (2) reducing oxidative stress and improving stress and emotional well-being, and (3) modulating immune function by assessing cytokine profiles. Secondary objectives include assessing the impact of NBO on patient-reported outcome measures (PROMs) such as stress, anxiety, depression, and quality of life. Methods: This is a prospective, randomized, double-blind, placebo-controlled clinical trial. A total of 254 CRC patients undergoing chemotherapy will be randomized 1:1 to receive either active NBO therapy (n = 127, study group) or placebo NBO therapy (n = 127, control group). The intervention will consist of 10 NBO sessions over five weeks. Primary outcomes include biomarkers of erythropoiesis, oxidative stress, and immune response. Secondary outcomes assess quality of life and psychological well-being. Data will be collected at baseline, mid-intervention, post-intervention, and during two follow-up visits (3 and 6 months post-intervention). Results: The study hypothesizes that NBO therapy will improve erythropoiesis, reduce oxidative stress, and enhance immune function in CRC patients, leading to improved quality of life and clinical outcomes. Conclusions: Findings from this trial may establish NBO as a novel supportive therapy for CRC patients undergoing chemotherapy. Full article

The yak (Bos grunniens) has exceptional hypoxia resilience, making it an ideal model for studying high-altitude adaptation. Here, we investigated the effects of oxygen concentration on yak cardiac fibroblast proliferation and the underlying molecular regulatory pathways using RNA sequencing (RNA-seq) and metabolic analyses. Decreased oxygen levels significantly inhibited cardiac fibroblast proliferation and activity. Intriguingly, while the mitochondrial DNA (mtDNA) content remained stable, we observed coordinated upregulation of mtDNA-encoded oxidative phosphorylation components. Live-cell metabolic assessment further demonstrated that hypoxia led to mitochondrial respiratory inhibition and enhanced glycolysis. RNA-seq analysis identified key hypoxia adaptation genes, including glycolysis regulators (e.g., HK2, TPI1), and hypoxia-inducible factor 1-alpha (HIF-1α), with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses highlighting their involvement in metabolic regulation. The protein–protein interaction network identified three consensus hub genes across five topological algorithms (CCNA2, PLK1, and TP53) that may be involved in hypoxia adaptation. These findings highlight the importance of metabolic reprogramming underlying yak adaptation to hypoxia, providing valuable molecular insights into the mechanisms underlying high-altitude survival. Full article

The hypothalamic-pituitary-adrenal (HPA) axis plays an important regulatory role in inflammatory responses to systemic or local infection in the host. A high-calorie diet, which can aggravate pediatric pneumonia and delay recovery, is intimately associated with HPA axis disorder; however, its underlying mechanisms remain unknown. This study examined whether the mechanism by which a high-calorie diet aggravates pneumonia is related to HPA axis disorder. In this study, juvenile rats were fed a high-calorie diet and/or nebulized with lipopolysaccharide (LPS) for model construction. Our data shows that a high-calorie diet increases interleukin-1 beta(IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels in lung tissues and aggravates LPS-induced inflammatory injury in the lungs of juvenile rats. Additionally, we found that a high-calorie diet decreases the expression level of serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in juvenile rats with pneumonia, resulting in HPA axis disorder. Hypothalamus proteomics and Western blot results proved that a high-calorie diet upregulated the expression level of hypothalamus hypoxia-inducible factor-1 alpha (HIF-1α) in juvenile rats with pneumonia, and this mechanism is associated with reduced HIF-1α ubiquitination. We further observed that HPA axis disorder was significantly abated and inflammatory damage in rat lung tissues was significantly alleviated after in vivo HIF-1α pathway inhibition. This shows that pneumonia aggravation by a high-calorie diet is associated with interference in the HIF-1α-mediated HPA axis. A high-calorie diet boosts HIF-1α signaling in the hypothalamus and exacerbates LPS-induced pneumonia by disrupting the HPA axis. This sheds light on lung inflammation and strengthens the lung-brain connection. Full article

Andrographolide (AP), a bioactive compound from Andrographis paniculata, is known for its anti-inflammatory and antioxidant properties, both essential for wound healing. However, its effects on energy metabolism during tissue repair and its role in UVB-induced photoaging remain poorly understood. This study explored AP’s multitarget therapeutic effects on wound healing under photoaging conditions (PhA/WH) using network pharmacology and experimental validation. Scratch wound assays showed that AP promoted keratinocyte migration in UVB-exposed HaCaT cells. Bioinformatic analysis identified 10 key targets in PhA/WH, including TNF-α, IL-1β, JUN, PPARγ, MAPK3, TP53, TGFB1, HIF-1α, PTGS2, and CTNNB1. AP suppressed UVB-induced pro-inflammatory gene expression (IL-1β, IL-6, IL-8, and COX-2) and inhibited the phosphorylation of ERK1/2 and P38, while enhancing Hypoxia-Inducible Factor-1alpha (HIF-1α) and peroxisome proliferator-activated receptors (PPARγ) expression. GC/MS-based metabolomics revealed that AP reversed UVB-induced disruptions in fatty acid metabolism, glycolysis/gluconeogenesis, and tricarboxylic acid (TCA) cycle, indicating its role in restoring the metabolic balance necessary for tissue regeneration. In conclusion, andrographolide modulates key inflammatory and metabolic pathways involved in wound repair and photoaging. These mechanistic insights contribute to a better understanding of the molecular processes underlying skin regeneration under photodamage and may inform future therapeutic strategies. Full article

Hepatocellular carcinoma (HCC) is a commonly diagnosed malignancy, with the treatment for transplant-ineligible localized disease traditionally relying on locoregional therapies, such as surgical resection, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE). Systemic therapy has historically been reserved for advanced, unresectable HCC. However, lenvatinib, an oral multikinase inhibitor, has recently gained traction as part of a multimodal approach for localized HCC in combination with locoregional treatments. An upfront TACE or TARE can induce tumor hypoxia, leading to the upregulation of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF), which promotes tumor angiogenesis and progression. The rationale for combining lenvatinib with a locoregional therapy is to enhance tumor shrinkage while preserving liver function before a definitive intervention. Clinical trials, such as TACTICS and LAUNCH, have demonstrated improved outcomes with this approach. Additionally, retrospective studies, including those incorporating immune checkpoint inhibitors, have reported further benefits. This review explores the combination of lenvatinib with various locoregional modalities, including TARE, microwave ablation (MWA), and radiofrequency ablation (RFA), highlighting their indications and clinical outcomes. Furthermore, we discuss the ongoing and upcoming clinical trials investigating the integration of systemic agents with locoregional therapies for intermediate-stage HCC, including EMERALD-1, EMERALD-3, LEAP-012, and CheckMate 74W. Full article

Phytochemical investigation and bioactivity evaluation of terpenoids from the Croton species were conducted. The chemical composition of C. sylvaticus was explored using chemical phytochemical screening techniques and dereplication of ¹³C NMR data using MixONat software (v. 1.0.1). Natural products with diverse structural features were identified in the dichloromethane extract of trunk bark. These include monoterpenoids, sesquiterpenoids, diterpenoids, triterpenoids, along with other minor metabolites, such as steroids, saponins, and fatty acids. Further purification of this extract led to the isolation of three major secondary metabolites, acetyl aleuritolic acid, caryophyllene oxide, and phytol. These secondary metabolites were reported for the first time in C. sylvaticus. The isolated compounds were structurally compared to known anticancer terpenoids previously identified in two other Congolese Croton species. Through molecular docking studies, the predicted binding affinities of the identified compounds were assessed, and possible structure–activity relationships (SAR) were proposed. Two structurally characterized receptors—the human androgen receptor (HAR, PDB ID: 1E3G) and hypoxia-inducible factor 1-alpha (HIF-1α, PDB ID: 3KCX), known for their involvement in cancer-related pathways, were used for molecular docking investigations. Among the tested compounds, 1, 2, 3, and 12 were identified as having strong-to-moderate predicted binding affinities to both protein targets, along with favorable drug-like properties according to the ADMET analysis. This investigation could justify the use of Croton plants in traditional medicine. In addition, our study highlights the potential of the Congolese Croton species as sources of bioactive secondary metabolites. Full article

Ciliopathies are disorders that affect primary or secondary cellular cilia or structures associated with ciliary function. Primary cilia (PC) are essential for metabolic regulation and embryonic development, and pathogenic variants in cilia-related genes are linked to several pediatric conditions, including renal-hepatic diseases and congenital defects. Biliary atresia (BA) is a progressive infantile cholangiopathy and the leading cause of pediatric liver transplantation. Although the exact etiology of BA remains unclear, evidence suggests a multifactorial pathogenesis influenced by both genetic and environmental factors. Patients with BA and laterality defects exhibit genetic variants associated with ciliopathies. Interestingly, even isolated BA without extrahepatic anomalies presents morphological and functional ciliary abnormalities, suggesting that environmental triggers may disrupt the ciliary function. Among these factors, hypoxia has emerged as a potential modulator of this dysfunction. Hypoxia-inducible factor 1-alpha (HIF-1α) plays a central role in hepatic responses to oxygen deprivation, influencing bile duct remodeling and fibrosis, which are key processes in BA progression. This review explores the crosstalk between hypoxia and hepatic ciliopathies, with a focus on BA. It discusses the molecular mechanisms through which hypoxia may drive disease progression and examines the therapeutic potential of targeting hypoxia-related pathways. Understanding how oxygen deprivation influences ciliary function may open new avenues for treating biliary ciliopathies and improving patient outcomes. Full article

Osteoporosis is a prevalent metabolic bone disorder characterized by decreased bone mineral density and increased fracture risk, particularly among aging populations. While conventional pharmacological treatments exist, they often have adverse effects, necessitating the search for alternative therapies. Resveratrol, a naturally occurring polyphenol, has gained significant attention for its potential osteoprotective properties through various molecular mechanisms. This systematic review aims to comprehensively analyze the molecular pathways through which resveratrol protects against osteoporosis. Using an advanced search strategy in the Scopus, PubMed, and Web of Science databases, we identified 513 potentially relevant articles. After title and abstract screening, followed by full-text review, 28 studies met the inclusion criteria. The selected studies comprised 14 in vitro studies, 8 mixed in vitro and in vivo studies, 6 in vivo studies, and 1 cross-sectional study in postmenopausal women. Our findings indicate that resveratrol exerts its osteoprotective effects by enhancing osteoblast differentiation through the activation of the Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/Akt), Sirtuin 1 (SIRT1), AMP-Activated Protein Kinase (AMPK), and GATA Binding Protein 1 (GATA-1) pathways while simultaneously inhibiting osteoclastogenesis by suppressing Mitogen-Activated Protein Kinase (MAPK) and TNF Receptor-Associated Factor 6/Transforming Growth Factor-β-Activated Kinase 1 (TRAF6/TAK1). Additionally, resveratrol mitigates oxidative stress and inflammation-induced bone loss by activating the Hippo Signaling Pathway/Yes-Associated Protein (Hippo/YAP) and Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) pathways and suppressing Reactive Oxygen Species/Hypoxia-Inducible Factor-1 Alpha (ROS/HIF-1α) and NADPH Oxidase 4/Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (Nox4/NF-κB). Despite promising preclinical findings, the low bioavailability of resveratrol remains a significant challenge, highlighting the need for novel delivery strategies to improve its therapeutic potential. This review provides critical insights into the molecular mechanisms of resveratrol in bone health, supporting its potential as a natural alternative for osteoporosis prevention and treatment. Further clinical studies are required to validate its efficacy and establish optimal dosing strategies. Full article

Autoimmune-induced alopecia, such as alopecia areata, involves immune-mediated damage to hair follicles, leading to significant hair loss. Emerging therapies that stabilize hypoxia-inducible factor 1-alpha (HIF-1α) show promise in counteracting follicular degradation and supporting hair regrowth. This communication highlights the potential of iron chelators, specifically deferoxamine (DFO) and deferiprone (DFP), to stabilize HIF-1α by reducing iron availability, thereby promoting vascularization, cellular proliferation, and a regenerative environment in the hair follicle niche. Clinical trials with iron chelators demonstrated improvements in hair density, thickness, and elasticity, as well as a reduction in hair loss by up to 66.8% over six months. These findings underscore the therapeutic potential of iron chelators in autoimmune alopecia management. Future research should explore the synergistic use of iron chelators with immune-modulating therapies, positioning them as viable options in the evolving field of alopecia treatment. Full article

Background and Objectives: Diabetic hepatopathy, characterized by hepatic hypoxia and metabolic dysregulation, has a rising global incidence and prevalence, with limited effective treatments. Hepatic hypoxia activates hypoxia-inducible factor-1 alpha (HIF-1α), regulating sphingolipid metabolism and elevating ceramide, a key factor in insulin resistance. Puerarin (Pue), a flavonoid derived from Pueraria lobata, exhibits therapeutic effects in diabetes, but its effects on hypoxia-related hepatic metabolism are unclear. This study investigates Pue’s mechanisms in modulating hepatic metabolism, focusing on HIF-1α and sphingolipid metabolism. Methods: Using bioinformatics and molecular docking, HIF-1α was identified as a key target in diabetic liver disease, confirmed via drug affinity responsive target stability. In vitro experiments utilized insulin-resistant HepG2 cells to assess glucose intake and HIF-1α expression. In vivo, type 2 diabetes mellitus (T2DM) was induced in mice using a high-fat diet and streptozotocin injections. Pue administration was evaluated for its effects on fasting blood glucose, oral glucose tolerance, and hepatoprotective effects. Liver metabolomics and qPCR/Western blot analyses were conducted to assess metabolic pathways. Results: Pue increased glucose uptake in HepG2 cells and bound HIF-1α. Pue reduced HIF-1α expression in HepG2 cells, an effect attenuated by the HIF-1α stabilizer DMOG. Pue improved fasting blood glucose, oral glucose tolerance, and hepatoprotective effects in T2DM mice, which DMOG reversed. Metabolomics revealed that Pue modulates sphingolipid metabolism, decreasing ceramide content. qPCR and Western blot results confirmed that Pue dramatically decreases HIF-1α and SPTLC2 expression. Conclusions: Pue improves diabetic hepatopathy by reducing ceramide expression through the HIF-1α/SPTLC2 pathway, offering a novel therapeutic strategy for diabetes management. Full article

Hypoxic damage to retinal pigment epithelial (RPE) cells and subsequent neovascularization are key factors in the pathogenesis of branch retinal vein occlusion (BRVO). Naringin (NG), a naturally occurring flavanone glycoside, has demonstrated significant antioxidant and anti-neovascular activities. However, the regulatory effects and mechanisms of NG on ferroptosis in BRVO are yet to be explored. Our study aimed to investigate the protective effects of NG on RPE cells under hypoxic stress and to elucidate the underlying molecular mechanisms. Our findings revealed that NG significantly reduced cytotoxicity induced by cobaltous chloride (CoCl₂) and also inhibited vascular proliferation in the retina, thereby attenuating choroidal neovascularization. NG pretreatment largely countered the overproduction of reactive oxygen species (ROS) and malondialdehyde (MDA) triggered by hypoxic damage, while also restoring levels of the antioxidants glutathione (GSH) and superoxide dismutase (SOD). Furthermore, NG pretreatment significantly activated the expression of hypoxia-inducible factor-1 alpha (HIF-1α) and its downstream heme oxygenase-1 (HO-1) and NADPH dehydrogenase (NQO1). In conclusion, NG not only inhibits neovascularization but also alleviates inflammation in RPE cells by modulating the HO-1/GPX4 pathway to inhibit ferroptosis. These findings highlight the potential of NG as a promising therapeutic agent for the treatment of BRVO. Full article

Background: Lung cancer remains the leading cause of cancer-related deaths worldwide, with non-small cell lung carcinomas (NSCLCs) comprising the majority of cases. Among the common driver mutations, KRAS plays a critical role in guiding treatment strategies. This study evaluates the expression of programmed death-ligand 1 (PD-L1) and hypoxia-inducible factor 1-alpha (HIF-1α) in KRAS-mutant NSCLCs and investigates their associations with clinicopathological findings. Methods: A total of 85 cases with KRAS mutations were analyzed. Immunohistochemical staining for HIF-1α and PD-L1 was performed, and their relationships with mutation status and prognostic variables were assessed. Results: A significant correlation was identified between HIF-1α expression and PD-L1 expression in tumor cells. While the KRAS G12C mutation was not significantly associated with HIF-1α expression in tumor cells, it demonstrated a notable relationship with HIF-1α expression in the tumor microenvironment and PD-L1 expression. However, PD-L1 and HIF-1α expression did not significantly influence overall survival outcomes. Conclusions: Expression of PD-L1 was positively correlated with HIF-1α, which may provide evidence for a novel therapy targeting PD-L1 and HIF-1α in NSCLC. Further comprehensive studies are warranted to elucidate the prognostic implications of tumor–microenvironment and mutation interactions. Full article

Silver carp is a critically significant species in freshwater aquaculture in China, characterized by its limited tolerance to hypoxia. In this study, a significant SNP locus at Chr8: 29647765 (T/C) associated with hypoxia tolerance traits was identified in Changfeng silver carp, and the homozygotic CC genotype exhibited higher hypoxic tolerance than the homozygotic TT and heterozygotic TC genotypes. Under hypoxic conditions, the hemoglobin concentration increased, with the CC genotype demonstrating a significantly higher level compared with the TT genotype; the activities of antioxidant enzymes including catalase and superoxide dismutase were significantly higher in the CC genotype than in the other genotypes; the area of the gill lamellae was significantly smaller in the CC genotype than in the TT and TC genotypes; and the number of apoptotic cells in the brain was significantly lower in the CC genotype than in the TT and TC genotypes. Sequence analysis showed that this SNP was located in the promoter region of the cathepsin C (CTSC) gene. The expression levels of the CTSC gene were analyzed across the three genotypes, revealing that the CC genotype exhibited significantly lower expression compared with the TT and TC genotypes under hypoxia. This finding suggests that the SNP associated with the CC genotype leads to reduced CTSC expression, which may facilitate better physiological adaptation to hypoxia. Analysis of the promoter region of CTSC found a unique predicted hypoxia-inducible factor 1-alpha (HIF-1α) binding site (CGTG) in the T genotype, implying that the differential expression of CTSC among the three genotypes under hypoxic stress may be regulated by HIF-1α, a transcription factor integral to hypoxia adaptation, thereby affecting hypoxia tolerance, which further affects the immune response of the Changfeng silver carp in response to the hypoxic environment. Although SNPs represent significant genetic determinants, their phenotypic effects are predominantly mediated through complex interactions within gene regulatory networks and environmental influences. This study identified an effective SNP site in Changfeng silver carp, providing valuable guidance for future selective breeding and the development of new hypoxia-tolerant varieties. Full article

The prevalence and deaths from esophageal cancer (EC) have recently increased. Although therapeutic strategies depend on the EC stage and recurrence, such as surgical intervention, chemotherapy, radiation therapy, chemoradiation therapy, targeted therapy, and immunotherapy, a more effective and novel treatment for EC is still required. This review briefly describes and summarizes some insightful oncotargets involved in the metabolic modulation of EC, including (1) cancer stem cells (CSCs) for EC progression, poor prognosis, tumor recurrence, and therapy resistance; (2) retinoic acid receptors (RARs) for esophageal carcinogenesis and regeneration; (3) phosphofructokinase (PFK) for EC-reprogrammed glycolysis; (4) lactate dehydrogenase (LDH) as an EC peripheral blood biomarker; and (5) hypoxia-inducible factor-1 alpha (HIF-1α) for the tumor microenvironment under hypoxic conditions. Moreover, the aforementioned oncotargets can be modulated by mutant TP53 and have their own features in the carcinogenesis, differentiation, proliferation, and metastasis of EC. Thus, the clarification of pharmacological mechanisms regarding the interaction between mutant TP53 and the abovementioned oncotargets could provide precise and perspective opinions for minimizing prediction errors, reducing therapy resistance, and developing novel drugs against EC. Full article

Peripheral blood mononuclear cells’ (PBMCs) mitochondrial respiration is impaired and likely involved in myocardial injury and heart failure pathophysiology, but its response to acute and severe hypoxia, often associated with such diseases, is largely unknown in humans. We therefore determined the effects of acute hypoxia on PBMC mitochondrial respiration and ROS production in healthy volunteers exposed to controlled oxygen reduction, achieving an inspired oxygen fraction of 10.5%. We also investigated potential relationships with gene expression of key biomarkers of hypoxia, succinate and inflammation, as hypoxia and inflammation share common mechanisms involved in cardiovascular disease. Unlike global mitochondrial respiration, hypoxemia with a spO₂ ≤ 80% significantly reduced PBMC complex II respiration (from 6.5 ± 1.2 to 3.1 ± 0.5 pmol/s/10⁶ cell, p = 0.04). Complex II activity correlated positively with spO₂ (r = 0.63, p = 0.02) and inversely correlated with the succinate receptor SUCNR1 (r = −0.68), the alpha-subunit of the hypoxia-inducible factor (HIF-1α, r = −0.61), the chemokine ligand-9 (r = −0.68) and interferon-stimulated gene 15 (r = −0.75). In conclusion, severe hypoxia specifically impairs complex II respiration in association with succinate, inflammation and HIF-1α pathway interactions in human PBMCs. These results support further studies investigating whether modulation of complex II activity might modify the inflammatory and metabolic alterations observed in heart failure. Full article