Evaluation of the Chetomin effect on histopathological features in a murine acute spinal cord injury model.

Background: Several research studies have been focused on improving the treatment and prognosis of acute spinal cord injury, as part of this initiative we investigated the use of Chetomin to reduce the inflammatory response in this pathology. Methods: An experimental, prospective, cross-sectional study was performed using 42 Wistar rats where we analyzed the effect of Chetomin compared to methylprednisolone administered 1 and 8 h after the spinal cord injury in a murine model. Results: Chetomin administration 8h post-injury decreased IL-6 and VEGF expression; and, and its administration 1h post-injury decreased NF-kB expression. Conclusions: Chetomin has anti-inflammatory effects in acute spinal cord injury, whether these effects are observable with other proinflammatory markers should be investigated.

Carbon monoxide as a negative feedback mechanism on HIF-1α in the progression of metabolic-associated fatty liver disease.

Metabolic-associated fatty liver disease (MAFLD) encompasses various chronic liver conditions, yet lacks approved drugs. Hypoxia-inducible factor-1α (HIF-1α) is pivotal in MAFLD development. Our prior research highlighted the efficacy of the nano-designed carbon monoxide (CO) donor, targeting HIF-1α in a mouse hepatic steatosis model. Given heme oxygenase-1 (HO-1, a major downstream molecule of HIF-1α) as the primary source of intrinsic CO, we hypothesized that upregulation of HO-1/CO, responsive to HIF-1α, forms a negative feedback loop regulating MAFLD progression. In this study, we explored the potential negative feedback mechanism of CO on HIF-1α and its downstream effects on MAFLD advancement. HIF-1α emerges early in hepatic steatosis induced by a high-fat (HF) diet, triggering increased HO-1 and inflammation. SMA/CORM2 effectively suppresses HIF-1α and steatosis progression when administered within the initial week of HF diet initiation but loses impact later. In adipose tissues, concurrent metabolic dysfunction and inflammation with HIF-1α activation suggest adipose tissue expansion initiates HF-induced steatosis, triggering hypoxia and liver inflammation. Notably, in an in vitro study using mouse hepatocytes treated with fatty acids, downregulating HO-1 intensified HIF-1α induction at moderate fatty acid concentrations. However, this effect diminished at high concentrations. These results suggest the HIF-1α-HO-1-CO axis as a feedback loop under physiological and mild pathological conditions. Excessive HIF-1α upregulation in pathological conditions overwhelms the CO feedback loop. Additional CO application effectively suppresses HIF-1α and disease progression, indicating potential application for MAFLD control.

HIF-1α induced FGF18 alleviates renal ischemia/reperfusion injury via YAP.

Acute kidney injury (AKI) is a devastating clinical condition characterized by an abrupt loss of renal function. The pathophysiology of AKI involves diverse processes and elements, of which survival and regeneration have been established to be significant hallmarks. And early studies have confirmed the fundamental role of FGFs in the regulation of AKI pathology, although the association between FGF18 and AKI still remains elusive. Our study demonstrates a substantial up-regulation of FGF18 in the renal tubules of mice subjected to ischemia. Notably, targeted overexpression of FGF18 effectively mitigates the impairment of kidney function induced by AKI. Mechanistically, FGF18 facilitates cell proliferation and anti-apoptosis in RTECs by enhancing the expression of YAP and facilitating its translocation to the nucleus. Aside from that, we also discovered that the substantial expression of FGF18 under ischemic conditions is HIF-1α dependent. This study aims to uncover the inherent mechanism behind the beneficial effects of FGF18 in attenuating AKI. By doing so, it aims to offer novel insights into the development of therapeutic strategies for AKI.

Pectolinarigenin alleviates calcium oxalate-induced renal inflammation and oxidative stress by binding to HIF-1α.

Calcium oxalate (CaOx) crystals are the main constituents of renal crystals in humans and induce tubular lumen damage in renal tubules, leading to renal calcium deposition and kidney stone formation. Oxidative stress and inflammation play important roles in regulating calcium oxalate-induced injury. Here, we evaluated the efficacy in inhibiting oxidation and inflammation of pectinolinarigenin, a biologically active natural metabolite, in CaOx nephrocalcinosis and further explored its targets of action. First, we developed cellular and mouse models of calcium oxalate renal nephrocalcinosis and identified the onset of oxidative stress and inflammation according to experimental data. We found that pectolinarigenin inhibited this onset while reducing renal crystal deposition. Network pharmacology was subsequently utilized to screen for hypoxia-inducible factor-1α (HIF-1α), a regulator involved in the body's release and over-oxidation of inflammatory factors. Finally, molecular docking, cellular thermal shift assay, and other experiments to detect HIF-1α expression showed that pectolinarigenin directly combined with HIF-1α and prevented downstream reactive oxygen species activation and release. Our results indicate that pectolinarigenin can target and inhibit HIF-1α-mediated inflammatory responses and oxidative stress damage and be a novel drug for CaOx nephrocalcinosis treatment.

Taurine reduces glycolysis of pig skeletal muscle by inhibiting HIF-1α signaling.

The aim of this study was to investigate the effect of taurine on skeletal muscle glycolysis in pigs. The results showed that dietary supplementation of taurine significantly reduced the activities of hexokinase (HK), phosphofructose kinase (PFK), and pyruvate kinase (PK) in finishing pigs. Meanwhile, taurine reduced the protein and mRNA expression levels of hypoxia inducible factor 1α (HIF-1α) and the mRNA expression of glycolytic enzyme related genes (such as HK type II, HK Ⅱ; pyruvate kinase M2, PKM2; lactate dehydrogenase A, LDHA). In addition, taurine reduced the expression of HIF-1α, lactate content, and the expression of glycolysis related genes in porcine myotubes. These results suggest that taurine may regulate glycolysis in skeletal muscle of finishing pigs through the HIF-1α signaling pathway. To further investigate the mechanism by which taurine affects skeletal glycolysis, HIF-1α activator dimethyloxalyl glycine (DMOG) was used to treat porcine myotubes, our results showed that DMOG significantly increased the protein and mRNA expression levels of HIF-1α, lactate content, and glycolytic enzyme (HK, PFK, PK, and LDH) activity, but taurine treatment significantly inhibited this effect. Taken together, these results of in vivo and in vitro experiments revealed that taurine reduces skeletal muscle glycolysis by inhibiting HIF-1α signaling.

Pilot Study on the Effect of Patient Condition and Clinical Parameters on Hypoxia-Induced Factor Expression: HIF1A, EPAS1 and HIF3A in Human Colostrum Cells.

Hypoxia-inducible factor 1 (HIF-1) may play a role in mammary gland development, milk production and secretion in mammals. Due to the limited number of scientific reports on the expression of HIF genes in colostrum cells, it was decided to examine the expression of HIF1A, HIF3A and EPAS1 in the these cells, collected from 35 patients who voluntarily agreed to provide their biological material for research, were informed about the purpose of the study and signed a consent to participate in it. The expression of HIF genes was assessed using qPCR. Additionally, the influence of clinical parameters (method of delivery, occurrence of stillbirths in previous pregnancies, BMI level before pregnancy and at the moment of delivery, presence of hypertension during pregnancy, presence of Escherichia coli in vaginal culture, iron supplement and heparin intake during pregnancy) on the gene expression was assessed, revealing statistically significant correlations. The expression of HIF1A was 3.5-fold higher in the case of patients with the presence of E. coli in vaginal culture (p = 0.041) and 2.5 times higher (p = 0.031) in samples from women who used heparin during pregnancy. Approximately 1.7-fold higher expression of the EPAS1 was observed in women who did not supplement iron during pregnancy (p = 0.046). To our knowledge, these are the first studies showing the relationship between HIF expression in cells from breast milk and the method of delivery and health condition of women giving birth. The assessment of HIF expression requires deeper examination in a larger study group, and the results of further studies will allow to determine whether HIF can become biomarkers in pregnancy pathology states.

Immp2l Deficiency Induced Granulosa Cell Senescence Through STAT1/ATF4 Mediated UPRmt and STAT1/(ATF4)/HIF1α/BNIP3 Mediated Mitophagy: Prevented by Enocyanin.

Dysfunctional mitochondria producing excessive ROS are the main factors that cause ovarian aging. Immp2l deficiency causes mitochondrial dysfunction and excessive ROS production, leading to ovarian aging, which is attributed to granulosa cell senescence. The pathway controlling mitochondrial proteostasis and mitochondrial homeostasis of the UPRmt and mitophagy are closely related with the ROS and cell senescence. Our results suggest that Immp2l knockout led to granulosa cell senescence, and enocyanin treatment alleviated Immp2l deficiency-induced granulosa cell senescence, which was accompanied by improvements in mitochondrial function and reduced ROS levels. Interestingly, redox-related protein modifications, including S-glutathionylation and S-nitrosylation, were markedly increased in Immp2l-knockout granulosa cells, and were markedly reduced by enocyanin treatment. Furthermore, STAT1 was significantly increased in Immp2l-knockout granulosa cells and reduced by enocyanin treatment. The co-IP results suggest that the expression of STAT1 was controlled by S-glutathionylation and S-nitrosylation, but not phosphorylation. The UPRmt was impaired in Immp2l-deficient granulosa cells, and unfolded and misfolded proteins aggregated in mitochondria. Then, the HIF1α/BNIP3-mediated mitophagy pathway was activated, but mitophagy was impaired due to the reduced fusion of mitophagosomes and lysosomes. The excessive aggregation of mitochondria increased ROS production, leading to senescence. Hence, Enocyanin treatment alleviated granulosa cell senescence through STAT1/ATF4-mediated UPRmt and STAT1/(ATF4)/HIF1α/BNIP3-mediated mitophagy.

PTGES is involved in myofibroblast differentiation via HIF-1α-dependent glycolysis pathway.

Lung cancer is the leading cause of cancer-related deaths worldwide. Patients with lung cancer usually exhibit poor prognoses and low 5-year survival rates. Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both chronic lung dysfunctions resulting in lung fibrosis and increased risk of lung cancer. Myofibroblasts contribute to the progression of asthma, COPD and IPF, leading to fibrosis in the airway and lungs. A growing body of evidence demonstrates that metabolic reprogramming is a major hallmark of fibrosis, being important in the progression of fibrosis. Using gene expression microarray, we identified and validated that the lipid metabolic pathway was upregulated in lung fibroblasts upon interleukin (IL)-4, IL-13 and tumour necrosis factor (TNF)-α treatment. In this study, we described that prostaglandin E synthase (PTGES) was upregulated in lung fibroblasts after IL-4, IL-13 and TNF-α treatments. PTGES increased α-SMA levels and promoted lung fibroblast cell migration and invasion abilities. Furthermore, PTGES was upregulated in a lung fibrosis rat model in vivo. PTGES increased AKT phosphorylation, leading to activation of the HIF-1α-glycolysis pathway in lung fibroblast cells. HIF-1α inhibitor or 2-DG treatments reduced α-SMA expression in recombinant PTGES (rPTGES)-treated lung fibroblast cells. Targeting PGE2 signalling in PTGES-overexpressing cells by a PTGES inhibitor reduced α-SMA expression. In conclusion, the results of this study demonstrate that PTGES increases the expression of myofibroblast marker via HIF-1α-dependent glycolysis and contributes to myofibroblast differentiation.

Orexin A protects against cerebral ischemia-reperfusion injury by enhancing reperfusion in ischemic cortex via HIF-1α-ET-1/eNOS pathway.

The purpose of this study was to investigate the protective effect and underlying mechanism of orexin A on cerebral ischemia-reperfusion injury, specifically through vasodilation mediated by the hypoxia inducible factor-1α (HIF-1α)-Endothelin-1(ET-1)/endothelial nitric oxide synthase (eNOS) pathway. A model of middle cerebral artery occlusion was established in both wild-type SD rats with exogenous orexin A intervention and in orexin A transgenic rats. Neurological deficit scores and cerebral infarction areas were assessed, and ischemic cortical blood flow was monitored. Gene and protein expression levels of HIF-1α, HIF-2α, ET-1, and three types of NOS were detected using real-time RT-qPCR and Western blot analysis, respectively. Additionally, nitric oxide (NO) levels in the cortex were analyzed through biochemical detection methods. Orexin A demonstrated a protective effect by reducing cerebral infarction and improving neurological deficits, which was achieved by increasing cortical blood flow during reperfusion. This protective mechanism was associated with upregulated HIF-1α expression, downregulated ET-1 expression, upregulated eNOS expression, and increased NO production. This study demonstrates the protective effect of orexin A on cerebral ischemia-reperfusion injury, achieved by regulating the release of vasomotor substances to enhance cortical blood flow during reperfusion. These findings suggest that orexin A may represent a potential therapeutic strategy for ischemic stroke.

TME-responsive nanoplatform for multimodal imaging-guided synergistic precision therapy of esophageal cancer via inhibiting HIF-1α signal pathway.

Esophageal cancer (EC) is the sixth leading cause of cancer-related deaths, and its treatment poses significant challenges. In recent years, photodynamic, photothermal, and chemodynamic therapies have emerged as alternative strategies for tumor intervention. However, limitations such as poor tumor targeting, insufficient microenvironment responsiveness, and unclear mechanisms hinder their application. In this study, we found that hypoxia-inducible factor 1 alpha (HIF-1α) was highly expressed in clinical EC samples, which contributed to tumor malignancy and metastasis. We developed a carbon dots (CDs)-based tumor microenvironment (TME)-responsive nanoplatform, CDs-MnO2-Au-Cet (CMAC), designed for multimodal imaging-guided precision therapy in EC. Both in vitro and in vivo experiments demonstrated that CMAC effectively targeted and imaged EC cells and tissues. CMAC significantly inhibited tumor growth by inducing apoptosis and reducing lung metastasis. Mechanistically, CMAC administration led to a substantial downregulation of HIF-1α and its downstream targets, GLUT1 and MMP9. In summary, we presented a novel nanoplatform for imaging-guided synergistic therapy in EC, which demonstrated excellent anti-tumor growth and metastasis capabilities, along with favorable biocompatibility. This study laid the groundwork for developing innovative theranostic strategies for EC.

Investigating the regulatory mechanism of glucose metabolism by ubiquitin-like protein MNSFß.

BACKGROUND: Monoclonal nonspecific suppressor factor ß (MNSFß), a ubiquitously expressed member of the ubiquitin-like protein family, is associated with diverse cell regulatory functions. It has been implicated in glycolysis regulation and cell proliferation enhancement in the macrophage-like cell line Raw264.7. This study aims to show that HIF-1α regulates MNSFß-mediated metabolic reprogramming. METHODS AND RESULTS: In Raw264.7 cells, MNSFß siRNA increased the oxygen consumption rate and reactive oxygen species (ROS) production but decreased ATP levels. Cells with MNSFß knockdown showed a markedly increased ATP reduction rate upon the addition of oligomycin, a mitochondrial ATP synthase inhibitor. In addition, MNSFß siRNA decreased the expression levels of mRNA and protein of HIF-1α-a regulator of glucose metabolism. Evaluation of the effect of MNSFß on glucose metabolism in murine peritoneal macrophages revealed no changes in lactate production, glucose consumption, or ROS production. CONCLUSION: MNSFß affects both glycolysis and mitochondrial metabolism, suggesting HIF-1α involvement in the MNSFß-regulated glucose metabolism in Raw264.7 cells.

HIF-1α stabilization inhibits Japanese encephalitis virus propagation and neurotoxicity via autophagy pathways.

Japanese encephalitis (JE) is a widespread flavivirus that induces brain inflammation and affects the central nervous system (CNS). Deferoxamine, an iron chelator, has shown promising results in stabilizing HIF-1α, a protein that improves hypoxic conditions, offers protective effects against neurological, and neurodegenerative diseases. This study aimed to assess the impact of HIF-1α stabilization during JEV infection using SH-SY5Y neuroblastoma cell lines as a model. Our findings demonstrated that deferoxamine treatment increased HIF-1α protein levels, leading to a reduction in JEV propagation. Moreover, RT-PCR analysis revealed that deferoxamine ameliorated JEV-induced neuroinflammation and neurotoxicity. We proved that inducing HIF-1α is essential for having an impact of deferoxamine against JEV-mediated neurotoxicity. Thus, our findings offer a potential therapeutic approach to mitigate the detrimental effects of JEV infection on neuronal cells. Further investigations also demonstrated that deferoxamine could reverse JEV-induced autophagy inhibition by stabilizing HIF-1α, which plays a crucial role in mitigating neuronal cell damage and neuroinflammation. Based on our data, HIF-1α stabilization emerges as a vital factor against JEV infection in the neurons, highlighting deferoxamine as a promising and innovative target for developing anti-JEV agents.

The triple combination DBDx alleviates cytokine storm and related lung injury.

Cytokine storm is a life-threatening disorder, and therapeutic treatments are urgently needed. Here, we investigated the anti-cytokine storm efficacy of DBDx, a triple drug combination composed of dipyridamole, ubenimex and dexamethasone. Evaluated by lipopolysaccharide (LPS)-induced cytokine storm murine model, DBDx significantly improved survival rate and prolonged survival time of the model mice. Notably, the efficacy of DBDx was higher than that of dipyridamole, ubenimex and dexamethasone. Determined by ELISA, DBDx significantly reduced the LPS-stimulated serum levels of TNF-α, IL-6 and IL-1ß in mice. Luminex assay showed that DBDx suppressed the serum levels of a wide variety of inflammatory cytokines and chemokines, which was more potent than dexamethasone alone. Otherwise, DBDx exerted similar inhibitory effects on cytokine profiles in bronchoalveolar lavage fluid. Histopathological observation showed that DBDx significantly reduced the LPS-induced thickening of alveolar septum, indicating its suppression of capillary congestion, edema and neutrophil infiltration in the lung. Ultra-structure analysis showed that DBDx suppressed the LPS-induced morphological changes of microvilli in type II pneumocytes. In vitro experiment showed that DBDx inhibited IL-6 and TNF-α secretion in THP-1 cells, and downregulated TLR4/NF-κB/HIF-1α signaling pathway. All of these results demonstrate that DBDx, a triple combination of clinical orally-administered drugs, can alleviate cytokine storm and related lung injury. DBDx is beneficial for treating cytokine storm disorders.

Blocking the HIF-1α/glycolysis axis inhibits allergic airway inflammation by reducing ILC2 metabolism and function.

BACKGROUND: The role of lung group 2 innate lymphoid cell (ILC2) activation in allergic asthma is increasingly established. However, the regulatory mechanisms underlying hypoxia-inducible factor-1α (HIF-1α)-mediated glycolysis in ILC2-mediated allergic airway inflammation remain unclear. OBJECTIVE: To investigate the role of the HIF-1α/glycolysis axis in ILC2-mediated allergic airway inflammation. METHODS: Glycolysis and HIF-1α inhibitors were used to identify their effect on the function and glucose metabolism of mouse and human ILC2s in vivo and vitro. Blocking glycolysis and HIF-1α in mice under interleukin-33 (IL-33) stimulation were performed to test ILC2 responses. Conditional HIF-1α-deficient mice were used to confirm the specific role of HIF-1α in ILC2-driven airway inflammation models. Transcriptomic, metabolic, and chromatin immunoprecipitation analyses were performed to elucidate the underlying mechanism. RESULTS: HIF-1α is involved in ILC2 metabolism and is crucial in allergic airway inflammation. Single-cell sequencing data analysis and qPCR confirmation revealed a significant upregulation of glycolysis-related genes, particularly HIF-1α, in murine lung ILC2s after IL-33 intranasal administration or injection. Treatment with the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) and the HIF-1α inhibitor 2-methoxyestradiol (2-ME) abrogated inflammation by suppressing ILC2s function. Conditional HIF-1α-deficient mice showed reduced ILC2 response and airway inflammation induced upon IL-33 or house dust mite (HDM) stimulation. Transcriptome and metabolic analyses revealed significantly impaired glycolysis in lung ILC2s in conditional HIF-1α knockout mice compared to that in their littermate controls. Chromatin immunoprecipitation results confirmed the transcriptional downregulation of glycolysis-related genes in HIF-1α-knockout and 2-DG-treated mice. Furthermore, impaired HIF-1α/glycolysis axis activation is correlated with downregulated ILC2 in patients with asthma. CONCLUSION: The HIF-1α/glycolysis axis is critical for controlling ILC2 responses in allergic airway inflammation and has potential immunotherapeutic value in asthma.

How lactate affects immune strategies in lymphoma.

Tumor cells undergo metabolic reprogramming through shared pathways, resulting in a hypoxic, acidic, and highly permeable internal tumor microenvironment (TME). Lactate, once only regarded as a waste product of glycolysis, has an inseparable dual role with tumor immunity. It can not only provide a carbon source for immune cells to enhance immunity but also help the immune escape through a variety of ways. Lymphoma also depends on the proliferation signal of TME. This review focuses on the dynamic process of lactate metabolism and immune function changes in lymphoma and aims to comprehensively summarize and explore which genes, transcription factors, and pathways affect the biological changes and functions of immune cells. To deeply understand the complex and multifaceted role of lactate metabolism and immunity in lymphoma, the combination of lactate targeted therapy and classical immunotherapy will be a promising development direction in the future.

Role of Hypoxic Secretome from Mesenchymal Stem Cells in Enhancing Tissue Repair: Regulatory Effects on HIF-1α, VEGF, and Fibroblast in a Sphincterotomy Rat Model.

Background: Fecal incontinence (FI) is the inability to control bowel movements, resulting in fecal leakage. If left untreated, FI can seriously impact the long-term well-being of individuals affected. Recently, using secretome has become a promising new treatment method. The secretome combines growth factors released outside cells during stem cell development, such as mesenchymal stem cells. It consists of soluble proteins, nucleic acids, fats, and extracellular vesicles, which contribute to different cell processes. The primary aim is to assess the impact of hypoxic secretome administration on accelerating wound healing through the HIF-1α pathway in a post-sphincterotomy rat model. Methods: The study was conducted with two distinct groups of 10 rats each, the control and treatment groups, which were injected with hypoxic secretome at 0.3 mL. The inclusion criteria for the rats were as follows: male gender, belonging to the Sprague-Dawley strain, aged between 12 to 16 weeks, with an average body weight ranging from 240 to 250 grams. Results: There was an increase in HIF-1α gene expression in both groups. The treatment group 37 was significantly higher on day 42 (p = 0.001). VEGF increased significantly in the treatment 38 group on day 42 (p = 0.015). The neovascularization score increased significantly in the treatment 39 group during the first 24 hours (p = 0.004). The fibroblast score increased significantly in the 40 treatment group in the first 24 hours (p = 0.000) and 42 days (p = 0.035). After being given secretome, there was a higher increase in % collagen area and collagen area (µm2) in the treatment group compared to the control group (27,77 vs 11.01) and (419.027,66 vs 186.694,16). Conclusion: The use of hypoxic secretome has a significant effect as a choice for the treatment of anal sphincter injury after sphincterotomy through the HIF-1α-VEGF-Fibroblast pathway.

Multidimensional screening of Astragalus membranaceus small molecules to mitigate carbon ion radiation-induced bystander effects.

Existing studies have shown that Astragalus membranaceus (AM) and its active ingredients astragalus polysaccharides, oninon, and astragalus methyl glycosides can attenuate X-ray radiation-induced injury. However, there are no studies on how isoliquiritigenin (ISL) attenuate the bystander effect of bone marrow mesenchymal stem cells (BMSCs) induced by carbon ion radiation therapy for lung cancer. This study aimed to investigate the AM-derived small molecule ISL to enhance radiotherapy sensitivity by attenuating the carbon ion radiation-induced bystander effect (RIBE) in BMSCs to elucidate its mechanism of action. In this study, we established a C57BL/6 mouse lung cancer transplantation tumor model in vivo and a co-culture model of A549 cells and BMSCs in vitro, and the models were successfully treated with carbon ions. In further work, we used flow cytometry, immunofluorescence, Western blot, enzyme-linked immunosorbent assay (ELISA), inhibitor, short hairpin RNA (shRNA), Cell Counting Kit-8 (CCK-8), and other methods to illustrate the mechanism. In the next experiments, we found that ISL combined with carbon ion radiotherapy had a significant anti-tumor effect and protected BMSCs from radiation damage. The aim of this study was to investigate the potential of ISL in enhancing the sensitivity of lung cancer cells to radiotherapy and attenuating RIBE in both in vitro and in vivo settings. Traditional Chinese medicine combined with radiation therapy is a promising and innovative treatment for non-small cell lung cancer. These results establish a theoretical foundation for further clinical development of ISL as a potential radiosensitizer option.

Araloside A alleviates sepsis-induced acute lung injury via PHD2/HIF-1α in macrophages.

BACKGROUND: Acute lung injury (ALI)-induced acute respiratory syndromes is a critical pathological sequala of sepsis. Araloside A (ARA), extracted from Aralia taibaiensis, possesses anti-oxidative and pro-apoptotic effects, as well as a protective effect against inflammatory diseases such as gastric ulcers. However, its impact on progression of ALI remains unknown. This study seeks to assess the therapeutic effect of ARA in sepsis-induced ALI, and to elucidate the underlying mechanism. METHODS: Sepsis-induced ALI was induced in C57BL/6 mice using lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) along with simultaneous administration of ARA. In vitro, bone marrow-derived macrophages (BMDMs) and RAW264.7 cells were exposed to LPS to activate proinflammatory macrophages in the presence/absence of ARA. RNA sequencing of BMDMs was then conducted to elucidate the detailed mechanism. RESULTS: Treatment of mice with ARA led to a significant reduction in serum level of inflammatory cytokines, ameliorated sepsis-induced ALI (i.e., impaired barrier integrity, cell apoptosis), and increased survival of septic mice. In vitro, ARA effectively inhibited activation of proinflammatory BMDMs. In addition, RNA sequencing revealed that the PHD2/HIF-1α signaling played a critical role in the anti-inflammatory effects of ARA. ARA suppressed proinflammatory macrophages to ameliorate lung inflammation in septic mice by restoring PHD2/HIF-1α signaling. CONCLUSIONS: ARA prevented mice from the fatal effects of sepsis by restoring PHD2/HIF-1α signaling, thereby inhibiting activation of proinflammatory macrophages. These findings suggest that ARA could be a promising therapy for sepsis-induced ALI.

Macrophage migration inhibitory factor facilitates replication of Senecavirus A by enhancing the glycolysis via hypoxia inducible factor 1 alpha.

Senecavirus A (SVA) induced porcine idiopathic vesicular disease (PIVD) has been spread worldwide due to persistent infection, causing economic losses in swine industry. Host factors play an important role in replication of SVA, while, the interaction of migration inhibitory factor (MIF) and the virus has not been verified. Here, MIF facilitates the replication of SVA by enhancing the glycolysis via hypoxia-inducible factor alpha (HIF-1α) was reported. SVA infection up-regulates the expression of MIF in 3D4/21 cells, and infection experiment of cells with overexpression and interference expression of MIF showed that MIF facilitates the replication of SVA. MIF promoted the glycolysis in SVA infection to facilitate its replication by enhancing the accumulation of lactate and decreasing the production of adenosine triphosphate (ATP) and inhibiting the expression of retinoic acid-inducible gene I (RIG-I), mitochondrial antiviral-signaling protein (MAVS), interferon regulatory factor 3 (IRF3), interferon-beta (IFN-ß), IFN-α, interferon-stimulating gene 15 (ISG15), and ISG56. Meanwhile, specific inhibitor verified MIF facilitates the replication of SVA by enhancing glycolysis. Further results showed MIF induces the increased expression of HIF-1α, which enhances MIF-induced glycolysis. These results provide new data on host factors in replication of SVA, as well as better understanding the role of MIF in virus infection.

Decoding the role of HIF-1α in immunoregulation in Litopenaeus vannamei under hypoxic stress.

Hypoxia poses a significant challenge to aquatic organisms, especially Litopenaeus vannamei (L. vannamei), which play a vital role in the global aquaculture industry. Hypoxia-inducible factor 1α (HIF-1α) is a pivotal regulator of the organism's adaptation to hypoxic conditions. To understand of how HIF-1α affects the immunity of L. vannamei under hypoxic conditions, we conducted a thorough study involving various approaches. These included observing tissue morphology, analyzing the expression of immune-related genes, assessing the activities of immune-related enzymes, and exploring immune-related pathways. Our study revealed that RNA interference (RNAi)-mediated knockdown of HIF-1α markedly reduced HIF-1α expression in the gill (75-95 %), whereas the reduction ranged from 2 to 43 % in the hepatopancreas. Knockdown of HIF-1α resulted in increased damage to both gill and hepatopancreatic tissues in hypoxic conditions. Additionally, immune-related genes, including Astakine (AST), Hemocyanin (HC), and Ferritin (FT), as well as immune-related enzymes such as Acid Phosphatase (ACP), Alkaline Phosphatase (AKP), and Phenoloxidase (PO), exhibited intricate regulatory patterns in response to hypoxia stress following the knockdown of HIF-1α. Transcriptome analysis revealed that HIF-1α knockdown significantly impacts multiple signaling pathways, including the JAK-STAT signaling pathway, Th17 cell differentiation pathways, PI3K-Akt signaling pathway, ErbB signaling pathway, MAPK signaling pathway, chemokine signaling pathway, ribosomal pathways, apoptosis, lysosomes and arachidonic acid metabolism. These alterations disrupt the organism's immune balance and interfere with normal metabolic processes, potentially leading to various immune-related diseases. We speculate that the weakened immune response resulting from HIF-1 inhibition is due to the reduced metabolic capacity, and the existence of a direct regulatory relationship between them requires further exploration. This study greatly advances our understanding of the vital role that HIF-1α plays in regulating immune responses in shrimp under hypoxic conditions, thereby deepening our comprehension of this critical biological mechanism.