Microglia respond to Alzheimer's disease (AD) with varied transcriptional responses. We show that oligomeric Aß (oAß) induces the expression of Hif1a and Egln3 in microglia in vitro, together with the transcription of the type I interferon signature (IFNS) genes in a PHD3-dependent manner. We identify FOXO3 as a repressor of IFNS, whose abundance decreases upon PHD3 induction in response to oAß. In vivo, loss of PHD3 correlates with abrogation of the IFNS and activation of the disease-associated microglia signature, an increase in microglia proximity to Aß plaques and phagocytosis of both Aß and small plaques. PHD3 deficiency mitigated the Aß plaque-associated neuropathology and rescued behavioral deficits of an AD mouse model. Last, we demonstrate that microglial PHD3 overexpression in the absence of Aß pathology is sufficient to induce the IFNS and behavioral alterations. Together, our data strongly indicate that the inactivation of the PHD3-FOXO3 axis controls the microglial IFNS in a cell autonomous manner, improving AD outcome.

Acute respiratory distress syndrome (ARDS) is a severe inflammatory disorder characterized by acute respiratory failure, alveolar barrier dysfunction, edema, and dysregulated alveolar macrophage-mediated pulmonary inflammation. Despite advancements in treatment strategies, the mortality rate in patients with ARDS remains high, ranging from 40-60 %. Current approaches are limited to supportive care, necessitating the exploration of effective therapeutic options such as suppressing broad inflammatory responses. Although Cirsium japonicum leaves possess anti-inflammatory properties, their specific effects on ARDS have not yet been investigated.

The anti-inflammatory activity of Cirsium japonicum extract (CJE) was investigated in a lipopolysaccharide (LPS)-induced ARDS model.

CJE significantly attenuated LPS-induced lung injury, including reduced alveolar wall thickness, inflammatory cell infiltration, proteinaceous debris, and hyaline membranes. Moreover, CJE repressed infiltration of inflammatory cells and pro-inflammatory gene expression in bronchoalveolar lavage fluid. Concordantly, CJE mitigated alveolar macrophage activation, which consequently reduced neutrophil chemoattractic infiltration. Additionally, CJE suppressed NLRP3 and HIF1α expression in the lungs of the ARDS mouse. Similarly, LPS-induced NLRP3 and HIF1α pathway-associated inflammatory and glycolytic gene expressions significantly diminished by CJE in murine alveolar macrophage cell line, MH-S cells, and bone marrow-derived macrophages.

CJE suppressed multiple inflammatory responses through the regulation of NLRP3 and HIF1α signaling-related gene expression in macrophages of LPS-induced ARDS mice. These results suggest that CJE has therapeutic potential for treating patients with ARDS via macrophage regulation.

Liver regeneration after hepatectomy follows accurate coordination with the body's specific requirements1-3. However, the molecular mechanisms, factors and particular hepatocyte population influencing its efficiency remain unclear. Here we report on a unique regeneration mechanism involving unconventional RPB5 prefoldin interactor 1 (URI1), which exclusively colocalizes with, binds to and activates glutamine synthase (GS) in pericentral hepatocytes. Genetic GS or URI1 depletion in mouse pericentral hepatocytes increases circulating glutamate levels, accelerating liver regeneration after two-third hepatectomy. Conversely, mouse hepatocytic URI1 overexpression hinders liver restoration, which can be reversed by elevating glutamate through supplementation or genetic GS depletion. Glutamate metabolically reprograms bone-marrow-derived macrophages, stabilizing HIF1α, which transcriptionally activates WNT3 to promote YAP1-dependent hepatocyte proliferation, boosting liver regeneration. GS regulation by URI1 is a mechanism that maintains optimal glutamate levels, probably to spatiotemporally fine-tune liver growth in accordance with the body's homeostasis and nutrient supply. Accordingly, in acute and chronic injury models, including in cirrhotic mice with low glutamate levels and in early mortality after liver resection, as well as in mice undergoing 90% hepatectomy, glutamate addition enhances hepatocyte proliferation and survival. Furthermore, URI1 and GS expression co-localize in human hepatocytes and correlate with WNT3 in immune cells across liver disease stages. Glutamate supplementation may therefore support liver regeneration, benefiting patients awaiting transplants or recovering from hepatectomy.

Hypoxia plays a pivotal role in modulating immune responses, especially in neutrophils, which are essential components of the innate immune system. Hypoxia-inducible factor (HIF)-1α, a key transcription factor in hypoxic adaptation, regulates cellular metabolism and inflammatory responses. However, the impact of HIF-1α-dependent glycolysis on the formation of neutrophil extracellular traps (known as NETosis) under hypoxic conditions remains unclear.

We employed two established neutrophil models, neutrophils isolated from human whole blood and DMSO-induced dHL-60 cells, to explore the role of HIF-1α in regulating glycolysis and its influence on NETosis under hypoxic conditions. We utilized western blotting, immunofluorescence staining, ELISA, and flow cytometry to evaluate the expression of key glycolytic enzymes and NETosis markers under hypoxia. Additionally, the effects of inhibiting HIF-1α with LW6 and blocking the glycolytic pathway with Bay-876 were investigated.

HIF-1α-dependent glycolysis, through the upregulation of key glycolytic enzymes, significantly enhances NETosis under hypoxic conditions. Pharmacological inhibition of HIF-1α with LW6 and glycolytic blockade with Bay-876 markedly reduced NETosis, underscoring the crucial role of metabolic reprogramming in neutrophil function during hypoxia.

This study provides novel insights into the interplay between metabolic reprogramming and NETosis in response to hypoxic stress. We identify HIF-1α-dependent glycolysis as a key driver of NETs formation, advancing our understanding of the mechanisms underlying hypoxia-related inflammatory diseases. These findings also suggest that targeting metabolic pathways may offer potential therapeutic strategies for modulating immune responses in hypoxia-associated disorders.

Metabolic aberrations are fundamental to the complex pathophysiology and challenges associated with diabetic wound healing. These alterations, induced by the diabetic environment, trigger a cascade of events that disrupt the normal wound-healing process. Key factors in this metabolic alternation include chronic hyperglycemia, insulin resistance, and dysregulated lipid and amino acid metabolism. In this review, we summarize the underlying mechanisms driving these metabolic changes in diabetic wounds, while emphasizing the broad implications of these disturbances. Additionally, we discuss therapeutic approaches that target these metabolic anomalies and how their integration with existing wound-healing treatments may yield synergistic effects, offering promising avenues for innovative therapies.

Macrophages are pivotal in osteoarthritis (OA) pathogenesis, as their dysregulated polarization can contribute to chronic inflammatory processes. This review explores the molecular and metabolic mechanisms that influence macrophage polarization and identifies potential strategies for OA treatment. Currently, non-surgical treatments for OA focus only on symptom management, and their efficacy is limited; thus, mesenchymal stem/stromal cells (MSCs) have gained attention for their anti-inflammatory and immunomodulatory capabilities. Emerging evidence suggests that small extracellular vesicles (sEVs) derived from MSCs can modulate macrophage function, thus offering potential therapeutic benefits in OA. Additionally, the transfer of mitochondria from MSCs to macrophages has shown promise in enhancing mitochondrial functionality and steering macrophages toward an anti-inflammatory M2-like phenotype. While further research is needed to confirm these findings, MSC-based strategies, including the use of sEVs and mitochondrial transfer, hold great promise for the treatment of OA and other chronic inflammatory diseases.

HIF-1α plays a critical role in shaping macrophage phenotype and effector function. We have previously shown that tissue-resident alveolar macrophages (TR-AMs) have extremely low glycolytic capacity at steady-state but can shift toward glycolysis under hypoxic conditions. Here, we generated mice with tamoxifen-inducible myeloid lineage cell specific deletion of Hif1a (Hif1afl/fl:LysM-CreERT2+/-) and from these mice, we isolated TR-AMs and bone marrow-derived macrophages (BMDMs) in which Hif1a is deleted. We show that TR-AM HIF-1α is required for the glycolytic shift under prolyl hydroxylase inhibition but is dispensable at steady-state for inflammatory effector function. In contrast, HIF-1α deletion in BMDMs led to diminished glycolytic capacity at steady-state and reduced inflammatory capacity, but higher mitochondrial function. Gene set enrichment analysis revealed enhanced c-Myc transcriptional activity in Hif1a-/- BMDMs, and upregulation of gene pathways related to ribosomal biogenesis and cellular proliferation. We conclude that HIF-1α regulates mitochondrial function in BMDMs but not in TR-AMs. The findings highlight the heterogeneity of HIF-1α function in distinct macrophage populations and provide new insight into how HIF-1α regulates gene expression, inflammation, and metabolism in different types of macrophages.

Bone tissue is renowned for its regenerative capabilities, yet handling extensive defects and complex fractures presents considerable medical challenges. Osteoimmunology, studying the complex mechanism of the mutual influence within the range of immunity and skeletal systems, has highlighted the indispensable function of immune reactions in the process of bone integration. This procedure, primarily immune-driven, fosters new bone formation around implants instead of relying solely on osteogenic mechanisms. Traditionally, implant research has emphasized bone bonding and osteoinduction, often overlooking the significant influence of immune interactions. Implants pose risks including donor site morbidity, decreased bioactivity, and pathogen transmission risks. To mitigate these, implant surfaces are modified through altering local factors such as electrical fields and applying physical treatments to change roughness, hydrophilicity, and nanotopography. These modifications aim to regulate immune reactions at the surface of the bone implant, improving osseointegration and the repair of bone. This review examines the types of immune cells in osseointegration, especially the pivotal function that macrophages serve in the regeneration of bone tissue, and investigates key implant features-morphology, wettability, cytokine interaction, and metal ion and bioactive molecule adsorption-that impact immune responses. These insights underscore the immune system's importance in bone repair and advance osteoimmunology as essential for developing strategies to control bone immune responses, enhancing implant integration and bone regeneration.

Cutaneous leishmaniasis (CL) contributes significantly to the global burden of neglected tropical diseases, with 12 million people currently infected with Leishmania parasites. CL encompasses a range of disease manifestations, from self-healing skin lesions to permanent disfigurations. Currently there is no vaccine available, and many patients are refractory to treatment, emphasizing the need for new therapeutic targets. Previous work demonstrated macrophage HIF-α-mediated lymphangiogenesis is necessary to achieve efficient wound resolution during murine L. major infection. Here, we investigate the role of macrophage HIF-α signaling independent of lymphangiogenesis. We sought to determine the relative contributions of the parasite and the host-mediated inflammation in the lesional microenvironment to myeloid HIF-α signaling. Because HIF-α activation can be detected in infected and bystander macrophages in leishmanial lesions, we hypothesize it is the host's inflammatory response and microenvironment, rather than the parasite, that triggers HIF-α activation. To address this, macrophages from mice with intact HIF-α signaling (LysMCreARNTf/+) or mice with deleted HIF-α signaling (LysMCreARNTf/f) were subjected to RNASequencing after L. major infection and under pro-inflammatory stimulus. We report that L. major infection alone is enough to induce some minor HIF-α-dependent transcriptomic changes, while infection with L. major in combination with pro-inflammatory stimuli induces numerous transcriptomic changes that are both dependent and independent of HIF-α signaling. Additionally, by coupling transcriptomic analysis with several pathway analyses, we found HIF-α suppresses pathways involved in protein translation during L. major infection in a pro-inflammatory environment. Together these findings show L. major induces a HIF-α-dependent transcriptomic program, but HIF-α only suppresses protein translation in a pro-inflammatory environment. Thus, this work indicates the host inflammatory response, rather than the parasite, largely contributes to myeloid HIF-α signaling during Leishmania infection.

The recently identified histone modification lysine lactylation can be stimulated by L-lactate and glycolysis. Although the chemical group added upon lysine lactylation was originally proposed to be the L-enantiomer of lactate (KL-la), two isomeric modifications, lysine D-lactylation (KD-la) and N-ε-(carboxyethyl) lysine (Kce), also exist in cells, with their precursors being metabolites of glycolysis. The dynamic regulation and differences among these three modifications in response to hypoxia remain poorly understood. In this study, we demonstrate that intracellular KL-la, but not KD-la or Kce, is up-regulated in response to hypoxia. Depletion of glyoxalase enzymes, GLO1 and GLO2, had minimal impact on KD-la, Kce, or hypoxia-induced KL-la. Conversely, blocking glycolytic flux to L-lactate under hypoxic conditions by knocking out lactate dehydrogenase A/B completely abolished the induction of KL-la but increased KD-la and Kce. We further observed a correlation between the level of KL-la and hypoxia-inducible factor 1 alpha (HIF-1α) expression under hypoxic conditions and when small molecules were used to stabilize HIF-1α in the normoxia condition. Our result demonstrated that there is a strong correlation between HIF-1α and KL-la in lung cancer tissues and that patient samples with higher grade tend to have higher KL-la levels. Using a proteomics approach, we quantified 66 KL-la sites that were up-regulated by hypoxia and demonstrated that p300/CBP contributes to hypoxia-induced KL-la. Collectively, our study demonstrates that KL-la, rather than KD-la or Kce, is the prevailing lysine lactylation in response to hypoxia. Our results therefore demonstrate a link between KL-la and the hypoxia-induced adaptation of tumor cells.

Periodontitis is recognized as one of the most prevalent oral dysbiotic inflammatory diseases, ultimately leading to the irreversible destruction of periodontal tissues. Macrophages play a pivotal role in the development and progression of periodontitis, and the feasibility of targeting them therapeutically has been established. Since metabolic switching significantly contributes to macrophage regulation, conducting an in-depth review of macrophage metabolism in periodontitis may serve as the foundation for developing innovative treatments.

This paper has been carefully reviewed to provide a comprehensive overview of the roles played by macrophages in periodontitis and associated comorbidities. Initially, detailed presentations on the metabolic reprogramming of macrophages, including glucose, lipid, and amino acid metabolism, were provided. Subsequently, dominating macrophage phenotype and metabolism under lipopolysaccharide (LPS) stimulation or during periodontitis were presented with emphasize on critical molecules involved. Furthermore, in recognition of the close association between periodontitis and several comorbidities, the interaction among macrophage metabolism, periodontitis, and related metabolic diseases, was thoroughly discussed.

Through the examination of current research on macrophage metabolic reprogramming induced by periodontitis, this review provides potential immunometabolic therapeutic targets for the future and raises many important, yet unstudied, subjects for follow-up.

Periodontitis is recognized as one of the most prevalent oral dysbiotic inflammatory diseases, ultimately leading to the irreversible destruction of periodontal tissues. Macrophages play a pivotal role in the development and progression of periodontitis, and the feasibility of targeting them therapeutically has been established. Since metabolic switching significantly contributes to macrophage regulation, conducting an in-depth review of macrophage metabolism in periodontitis may serve as the foundation for developing innovative treatments.

This paper has been carefully reviewed to provide a comprehensive overview of the roles played by macrophages in periodontitis and associated comorbidities. Initially, detailed presentations on the metabolic reprogramming of macrophages, including glucose, lipid, and amino acid metabolism, were provided. Subsequently, dominating macrophage phenotype and metabolism under lipopolysaccharide (LPS) stimulation or during periodontitis were presented with emphasize on critical molecules involved. Furthermore, in recognition of the close association between periodontitis and several comorbidities, the interaction among macrophage metabolism, periodontitis, and related metabolic diseases, was thoroughly discussed.

Through the examination of current research on macrophage metabolic reprogramming induced by periodontitis, this review provides potential immunometabolic therapeutic targets for the future and raises many important, yet unstudied, subjects for follow-up.

The joint dysfunction caused by osteoarthritis (OA) is increasingly becoming a major challenge in global healthcare, and there is currently no effective strategy to prevent the progression of OA. Therefore, better elucidating the relevant mechanisms of OA occurrence and development will provide theoretical basis for formulating new prevention and control strategies. Due to long-term exposure of cartilage tissue to the hypoxic microenvironment of joints, metabolic reprogramming changes occur. Hypoxia-inducible factor-1alpha (HIF-1α), as a core gene regulating hypoxia response in vivo, plays an important regulatory role in the hypoxic metabolism of chondrocytes. HIF-1α adapts to the hypoxic microenvironment by regulating metabolic reprogramming changes such as glycolysis, oxidative phosphorylation (OXPHOS), amino acid metabolism, and lipid metabolism in OA chondrocytes. In addition, HIF-1α also regulates macrophage polarization and synovial inflammation, chondrocytes degeneration and extracellular matrix (ECM) degradation, subchondral bone remodeling and angiogenesis in the hypoxic microenvironment of OA, and affects the pathophysiological progression of OA. Consequently, the regulation of chondrocytes metabolic reprogramming by HIF-1α has become an important therapeutic target for OA. Therefore, this article reviews the mechanism of hypoxia affecting chondrocyte metabolic reprogramming, focusing on the regulatory mechanism of HIF-1α on chondrocyte metabolic reprogramming, and summarizes potential effective ingredients or targets targeting chondrocyte metabolic reprogramming, in order to provide more beneficial basis for the prevention and treatment of clinical OA and the development of effective drugs.

Immunometabolism has emerged as a key area of focus in immunology and has the potential to lead to new treatments for immune-related diseases. It is well-established that glycolytic metabolism is essential for adaptation to hypoxia and for macrophage inflammatory function. Macrophages have been shown to upregulate their glycolytic metabolism in response to pathogens and pathogen-associated molecular patterns such as LPS. As a direct link to the external environment, the lungs' distinctive nutrient composition and multiple macrophage subtypes provide a unique opportunity to study macrophage metabolism. This review aims to highlight how the steady-state airway and severely inflamed airway offer divergent environments for macrophage glycolytic metabolism. We describe the differences in glycolytic metabolism between tissue-resident alveolar macrophages, and other lung macrophages at steady-state and during inflammation/injury. We also provide an overview of experimental guidelines on how to assess metabolism at the cellular level using Seahorse-based bioenergetic analysis including a review of pharmacologic agents used to inhibit or activate glycolysis.

Despite being heavily infiltrated by immune cells, tuberculosis (TB) granulomas often subvert the host response to Mycobacterium tuberculosis (Mtb) infection and support bacterial persistence. We previously discovered that human TB granulomas are enriched for immunosuppressive factors typically associated with tumor-immune evasion, raising the intriguing possibility that they promote tolerance to infection. In this study, our goal was to identify the prime drivers for establishing this tolerogenic niche and to determine if the magnitude of this response correlates with bacterial persistence. To do this, we conducted a multimodal spatial analysis of 52 granulomas from 16 non-human primates (NHP) who were infected with low dose Mtb for 9-12 weeks. Notably, each granuloma's bacterial burden was individually quantified allowing us to directly ask how granuloma spatial structure and function relate to infection control. We found that a universal feature of TB granulomas was partitioning of the myeloid core into two distinct metabolic environments, one of which is hypoxic. This hypoxic environment associated with pathologic immune cell states, dysfunctional cellular organization of the granuloma, and a near-complete blockade of lymphocyte infiltration that would be required for a successful host response. The extent of these hypoxia-associated features correlated with worsened bacterial burden. We conclude that hypoxia governs immune cell state and organization within granulomas and is a potent driver of subverted immunity during TB.

Macrophages, which tend to aggregate in the hypoxic regions of tissues, have a significant impact on disease progression and outcome because of their plastic responsiveness to hypoxia, particularly in the early stages. Understanding macrophages'participation in hypoxia-related disorders requires demonstrating the impact of acute hypoxia on their survival, phenotype, and function.

Here we conducted a systematic evaluation of macrophage responses to hypoxia over 24 and 48 h including cell growth and activity, inflamatory response, macrophage polarization and transcriptional and metabolic changes.

We found that acute hypoxia suppresses macrophage proliferation and phagocytosis function with a parallel change of transcriptome re-programming and metabolic re-modeling. Although macrophages accumulate transcriptome heterogeneity based on oxygen concentration and culture period, genes involved in hypoxia response, chemotaxis, and glycolytic process were commonly altered during acute hypoxia. Furthermore, the pro-inflammatory response of macrophages was activated during acute hypoxia concomitantly with an enhanced anti-inflammatory regulatory mechanism characterized by increased M2 macrophage population and anti-inflammatory metabolite itaconic acid. Aside from increased glycolysis, the key intermediates in the pentose phosphate pathway significantly increased, such as fructose 1,6-bisphosphate (fold change: 7.8), 6-phosphogluconate (fold change: 6.1), and ribose 5-phosphate (fold change: 3.9), which indicated that the pentose phosphate pathway was an important compensatory metabolic regulation that rules for the response of macrophages to acute hypoxia.

These findings highlight that acute hypoxia suppresses macrophage viability and phagocytosis, while acute hypoxia modifies the transcriptome and metabolome in specific inflammatory responses and metabolic pathways to facilitate the adaptation of macrophage in hypoxic conditions.

Obstructive sleep apnea (OSA) is the most common type of sleep apnea, which leads to episodes of intermittent hypoxia due to obstruction of the upper airway. A key feature of OSA is the upregulation and stabilization of hypoxia-inducible factor 1 (HIF-1), a crucial metabolic regulator that facilitates rapid adaptation to changes in oxygen availability. Adenosine A2A receptor (A2AR), a major adenosine receptor, regulates HIF-1 under hypoxic conditions, exerting anti-inflammatory properties and affecting lipid metabolism. The present study explored the roles of A2AR in OSA regulation, specifically focusing on its effects via the PI3K/Akt/HIF-1 pathway. The findings enhance our understanding the pharmacological potential of A2AR in OSA management and suggest future research directions in exploring its clinical applications.

African swine fever virus (ASFV) is a severe threat to the global pig industry, and domestic pigs mostly develop severe clinical manifestations upon viral invasion. Currently, there is no available vaccine against ASFV. Its capsid structural protein p72 is one of the immuno-dominant proteins. In this study, we unexpectedly obtained a p72 mutant protein (p72∆377-428) which deleted the aa 377-428 within p72 and had stable and high expression in E. coli. Using SWISS-MODEL 1.0 software, the prediction showed that p72∆377-428 was quite distinct from the wild-type p72 protein in structure. p72∆377-428 induced stronger antibody production in mice on day 42 and 56 post immunization and could recognize ASFV-infected swine sera. p72∆377-428 reduced IFN-γ production in the splenocytes from p72∆377-428-immunized mice and p72∆377-428-treated swine macrophages compared to p72. p72∆377-428 also decreased the production of pro-inflammatory cytokine genes, including IL-1β, IL-6, and IL-12, compared to p72 in mice. Further, we found that p72∆377-428 reduced the induction of pro-inflammatory cytokine genes by inhibiting AKT phosphorylation and HIF1α expression. Taken together, these findings have implications for immunological function and the corresponding mechanism of ASFV p72, and our study indicates that p72∆377-428 could serve as a novel candidate for ASFV vaccines and diagnostic reagents.

Pulmonary fibrosis (PF) is a chronic, progressive, and irreversible lung interstitial disease of unknown etiology with a fatal outcome. M2 macrophages have been recognized to play a significant role in PF pathogenesis. The role of protein hypoxia-inducible factor 1-α (HIF-1α) in M2 macrophage polarization in PF is largely unknown. This study aimed to investigate the role of macrophage HIF-1α in the regulation of PF.

PF was induced in C57BL/6 mice by the intratracheal injection of bleomycin (BLM), and small hairpin RNA (shRNA) lentiviral construct specifically targeting HIF-1α were designed for in vitro and in vivo experiments. In the in vitro experiment, bone marrow-derived macrophages (BMDMs) were used to explore molecular mechanism analysis. In the in vivo experiment, mice were administered BLM intratracheally on day 0, treated with shRNA on day 7, and sacrificed on day 21. Histopathological techniques (H&E and Masson's trichrome staining) were used to evaluate PF severity. Western blot, immunofluorescence, quantitative real-time PCR, and flow cytometry were performed to explore the underlying mechanisms.

HIF-1α was upregulated and macrophages polarized toward M2 phenotype in BLM-induced mouse pulmonary fibrosis models. By constructing HIF-1α knockdown shRNA lentiviral construct, we found that the knockdown of HIF-1α in macrophages significantly suppressed M2-type polarization in vitro, hence alleviating fibrosis in lung epithelial cells. Further results revealed that HIF-1α in macrophages promoted M2-type polarization by mediating the signal transducer and activator of transcription 6 (STAT6) arginine methylation. Meanwhile, its arginine methylation modification site is at position Arg27. Further experiments indicated that the regulation of STAT6 arginine methylation by HIF-1α mainly depended on the protein arginine methyltransferase 1 (PRMT1). Finally, animal experiments demonstrated that Knockdown of HIF-1α, PRMT1, and STAT6 relieved the BLM-induced pulmonary fibrosis of mice.

HIF-1α may act as a novel factor to promote macrophage of the M2 program. Therapeutic approaches to target macrophage HIF-1α may act as a new therapeutic strategy to combat PF in the future.

Venovenous extracorporeal membrane oxygenation (VV-ECMO) is an effective lung protection strategy that avoids ventilator-induced lung injury. However, appropriate respiratory settings for VV-ECMO are yet to be established. This study aimed to elucidate the effects of ventilation under VV-ECMO using a newly developed rat VV-ECMO model and analyzed gene expression profiles.

Rats were assigned to three groups of five rats each: spontaneous breathing, conventional-protective ventilation, and ultra-protective ventilation. The conventional protective and ultraprotective ventilation groups received volume-controlled ventilation at a frequency of 60 and 20 beats/min, with tidal volumes of 6 and 3 mL/kg, respectively. VV-ECMO was performed at a pump flow rate of 20-30 mL/kg/min. At 120 min post initiation of VV-ECMO, rats were euthanized, and their lungs were harvested. Changes in gene expression were assessed using microarray analysis.

Gene expression profile analyses revealed lowest expression of inflammation/immune promotion, cytotoxicity, and cell proliferation related genes (Defa5, Prg2, Siglec8, Atf3, Rnd1, Ctsg, and Gc), and the highest expression of inflammation/immune suppression related genes (Pp2d1) in the spontaneous breathing group as compared to that in the other two mechanical ventilation groups.

The findings of this study demonstrated that spontaneous breathing was the least invasive respiratory setting under VV-ECMO. Further, mechanical ventilation may be associated with lung injury even at low ventilation frequency and tidal volume.

Buerger's disease is characterised by peripheral ischaemia due to occlusion of small- and medium-sized arteries in the extremities. This report describes a case of Buerger's disease in a 51-year-old male who presented with findings resembling systemic sclerosis (SSc). The patient exhibited Raynaud's phenomenon in year 2015, which developed to skin hardening, nail avulsion, and ulceration of the right fingers in year 2018. Diagnostic testing showed positive microvasculopathy on nailfold videocapillaroscopy (NVC) and positive fibrosis on skin biopsy. Although the patient fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc, several findings in this case were atypical for SSc, including left-right asymmetry in finger involvement, nail loss, and negative autoantibody tests. Contrast-enhanced computed tomography showed poor perfusion of the right ulnar artery, and a heavy smoking history was established in the patient case. Therefore, based on Shionoya's criteria, he was diagnosed with a case of Buerger's disease confined to the upper extremity. Smoking cessation and vasodilator therapy resulted in the prompt resolution of ischaemic symptoms, skin hardening, and ulcerations. Furthermore, NVC abnormalities improved, and ulnar artery occlusion showed reperfusion on repeat testing. The present case suggests that hypoxaemia-driven microvasculopathy may contribute to vascular occlusion and skin fibrosis observed in this atypical presentation.

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.

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.

Inflammatory bowel disease (IBD)-associated fibrosis causes significant morbidity. Mechanisms are poorly understood but implicate the microbiota, especially adherent-invasive Escherichia coli (AIEC). We previously demonstrated that AIEC producing the metallophore yersiniabactin (Ybt) promotes intestinal fibrosis in an IBD mouse model. Since macrophages interpret microbial signals and influence inflammation/tissue remodeling, we hypothesized that Ybt metal sequestration disrupts this process. Here, we show that macrophages are abundant in human IBD-fibrosis tissue and mouse fibrotic lesions, where they co-localize with AIEC. Ybt induces profibrotic gene expression in macrophages via stabilization and nuclear translocation of hypoxia-inducible factor 1-alpha (HIF-1α), a metal-dependent immune regulator. Importantly, Ybt-producing AIEC deplete macrophage intracellular zinc and stabilize HIF-1α through inhibition of zinc-dependent HIF-1α hydroxylation. HIF-1α+ macrophages localize to sites of disease activity in human IBD-fibrosis strictures and mouse fibrotic lesions, highlighting their physiological relevance. Our findings reveal microbiota-mediated metal sequestration as a profibrotic trigger targeting macrophages in the inflamed intestine.

Recent research has suggested imbalances in gut microbiota composition as contributors to cardiac aging. An individual's physical condition, along with lifestyle-associated factors, including diet and medication, are significant determinants of gut microbiota composition. This review discusses evidence of bidirectional associations between aging and gut microbiota, identifying gut microbiota-derived metabolites as potential regulators of cardiac aging. It summarizes the effects of gut microbiota on cardiac aging diseases, including cardiac hypertrophy and fibrosis, heart failure, and atrial fibrillation. Furthermore, this review discusses the potential anti-aging effects of modifying gut microbiota composition through dietary and pharmacological interventions. Lastly, it underscores critical knowledge gaps and outlines future research directions. Given the current limited understanding of the direct relationship between gut microbiota and cardiac aging, there is an urgent need for preclinical and clinical investigations into the mechanistic interactions between gut microbiota and cardiac aging. Such endeavors hold promise for shedding light on the pathophysiology of cardiac aging and uncovering new therapeutic targets for cardiac aging diseases.

Myocardial infarction (MI) mobilizes macrophages, the central protagonists of tissue repair in the infarcted heart. Although necessary for repair, macrophages also contribute to adverse remodeling and progression to heart failure. In this context, specific targeting of inflammatory macrophage activation may attenuate maladaptive responses and enhance cardiac repair. Allograft inflammatory factor 1 (AIF1) is a macrophage-specific protein expressed in a variety of inflammatory settings, but its function after MI is unknown. Here we identify a maladaptive role for macrophage AIF1 after MI in mice. Mechanistic studies show that AIF1 increases actin remodeling in macrophages to promote reactive oxygen species-dependent activation of hypoxia-inducible factor (HIF)-1α. This directs a switch to glycolytic metabolism to fuel macrophage-mediated inflammation, adverse ventricular remodeling and progression to heart failure. Targeted knockdown of Aif1 using antisense oligonucleotides improved cardiac repair, supporting further exploration of macrophage AIF1 as a therapeutic target after MI.

The clinical management of neuropathic pain (NP) remains a significant challenge, as current pharmacological treatments do not fully meet clinical needs. Nicorandil, a potassium ATP channel agonist widely used in cardiovascular medicine, has recently been shown to have significant potential for analgesia. This study aimed to investigate the effects and mechanisms of nicorandil in a chronic constriction injury (CCI) mouse model. Nicorandil significantly alleviated pain hypersensitivity and reduced neuronal injury in the sciatic nerve (SN) and dorsal root ganglion (DRG) post-CCI. Nicorandil primarily affected endothelial cells and Schwann cells in the sciatic nerve, restoring the expression of the KATP channel subunit Kir6.2. Furthermore, nicorandil attenuated the hypoxia-induced apoptosis program in sciatic nerve endothelial cells, leading to reduced expression of apoptotic proteins, which provided significant endothelial protection, improved blood-nerve barrier leakage, and decreased the release of DRG inflammatory factors and pain neurotransmitter substance P. In vitro, nicorandil attenuated the apoptosis of human umbilical vein endothelial cells (HUVECs) in a hypoxic environment while maintaining cellular functions. In addition, administering the KATP channel inhibitor glibenclamide in vitro further confirmed the crucial role of Kir6.2 in reducing endothelial hypoxic stress, as confirmed by transmission electron microscopy and behavioural experiments. Overall, these findings indicate that nicorandil significantly ameliorates CCI-induced NP in mice by targeting Kir6.2 in sciatic nerve endothelial cells, thus inhibiting pain sensitization.

Sirtuins are the major players in host immunometabolic regulation. However, the role of sirtuins in the modulation of the immune metabolism pertaining to salmonellosis is largely unknown. Here, our investigation focussed on the role of two important sirtuins, SIRT1 and SIRT3, shedding light on their impact on intracellular Salmonella's metabolic switch and pathogenesis establishment. Our study indicated the ability of the live Salmonella Typhimurium to differentially regulate the levels of SIRT1 and SIRT3 for maintaining the high glycolytic metabolism and low fatty acid metabolism in Salmonella. Perturbing SIRT1 or SIRT3 through knockdown or inhibition resulted in a remarkable shift in the host metabolism to low fatty acid oxidation and high glycolysis. This switch led to decreased proliferation of Salmonella in the macrophages. Further, Salmonella-induced higher levels of SIRT1 and SIRT3 led to a skewed polarization state of the macrophages from a pro-inflammatory M1 state toward an immunosuppressive M2, making it more conducive for the intracellular life of Salmonella. Alongside, governing immunological functions by modulating p65 NF-κB acetylation, SIRT1, and SIRT3 also skew Salmonella-induced host metabolic switch by regulating the acetylation status of HIF-1α and PDHA1. Interestingly, though knockdown of SIRT1/3 attenuated Salmonella proliferation in macrophages, in in vivo mice model of infection, inhibition or knockdown of SIRT1/3 led to more dissemination and higher organ burden, which can be attributed to enhanced ROS and IL-6 production. Our study hence reports for the first time that Salmonella modulates SIRT1/3 levels to maintain its own metabolism for successful pathogenesis.

HIF-1α plays a crucial regulatory role in vascular calcification (VC), primarily influencing the osteogenic differentiation of VSMCs through oxygen-sensing mechanisms. Under hypoxic conditions, the stability of HIF-1α increases, avoiding PHD and VHL protein-mediated degradation, which promotes its accumulation in cells and then activates gene expressions related to calcification. Additionally, HIF-1α modulates the metabolic state of VSMCs by regulating the pathways that govern the switch between glycolysis and oxidative phosphorylation, thereby further advancing the calcification process. The interaction between HIF-1α and other signaling pathways, such as nuclear factor-κB, Notch, and Wnt/β-catenin, creates a complex regulatory network that serves as a critical driving force in VC. Therefore, a deeper understanding of the role and regulatory mechanism of the HIF-1α signaling during the development and progression of VC is of great significance, as it is not only a key molecular marker for understanding the pathological mechanisms of VC but also represents a promising target for future anti-calcification therapies.

Granulomas, organized aggregates of immune cells which form in response to Mycobacterium tuberculosis (Mtb), are characteristic but not exclusive of tuberculosis (TB). Despite existing investigations on TB granulomas, the determinants that differentiate host-protective granulomas from granulomas that contribute to TB pathogenesis are often disputed. Thus, the goal of this narrative review is to help clarify the existing literature on such determinants. We adopt the a priori view that TB granulomas are host-protective organelles and discuss the molecular and cellular determinants that induce protective granulomas and those that promote their failure. While reports about protective TB granulomas and their failure may initially seem contradictory, it is increasingly recognized that either deficiencies or excesses of the molecular and cellular components in TB granuloma formation may be detrimental to the host. More specifically, insufficient or excessive expression/representation of the following components have been reported to skew granulomas toward the less protective phenotype: (i) epithelioid macrophages; (ii) type 1 adaptive immune response; (iii) type 2 adaptive immune response; (iv) tumor necrosis factor; (v) interleukin-12; (vi) interleukin-17; (vii) matrix metalloproteinases; (viii) hypoxia in the TB granulomas; (ix) hypoxia inducible factor-1 alpha; (x) aerobic glycolysis; (xi) indoleamine 2,3-dioxygenase activity; (xii) heme oxygenase-1 activity; (xiii) immune checkpoint; (xiv) leukotriene A4 hydrolase activity; (xv) nuclear-factor-kappa B; and (xvi) transforming growth factor-beta. Rather, more precise and timely coordinated immune responses appear essential for eradication or containment of Mtb infection. Since there are several animal models of infection with Mtb, other species within the Mtb complex, and the surrogate Mycobacterium marinum - whether natural (cattle, elephants) or experimental (zebrafish, mouse, guinea pig, rabbit, mini pig, goat, non-human primate) infections - we also compared the TB granulomatous response and other pathologic lung lesions in various animals infected with one of these mycobacteria with that of human pulmonary TB. Identifying components that dictate the formation of host-protective granulomas and the circumstances that result in their failure can enhance our understanding of the macrocosm of human TB and facilitate the development of novel remedies - whether they be direct therapeutics or indirect interventions - to efficiently eliminate Mtb infection and prevent its pathologic sequelae.

Intestine epithelial hypoxia-inducible factor-1α (HIF-1α) plays a critical role in maintaining gut barrier function. The aim of this study was to determine whether pharmacological or genetic activation of intestinal HIF-1α ameliorates western diet-induced metabolic dysfunction-associated steatotic liver disease.

Metabolic effects of pharmacological activation of HIF-1α by dimethyloxalylglycine were evaluated in HIF-α luciferase reporter (ODD-luc) mice. Male and/or female intestinal epithelial-specific Hif1α overexpression mice (Hif1αLSL/LSL;VilERcre) and wild-type littermates (Hif1αLSL/LSL) were fed with regular chow diet, high fructose (HFr) or high-fat (60% Kcal) high-fructose diet (HFHFr) for 8 weeks. Metabolic phenotypes were profiled.

Dimethyloxalylglycine treatment led to increased intestine HIF-α luciferase activity and decreased blood glucose levels in HFr diet-fed male ODD-luc mice. Male Hif1αLSL/LSL;VilERcre mice exhibited markedly improved glucose tolerance compared to Hif1αLSL/LSL mice in response to HFr diet. Eight weeks HFHFr feeding led to obesity in both Hif1αLSL/LSL;VilERcre and Hif1αLSL/LSL mice. However, male Hif1αLSL/LSL;VilERcre mice exhibited markedly attenuated hepatic steatosis along with reduced liver size and liver weight compared to male Hif1αLSL/LSL mice. Moreover, HFHFr-induced systemic inflammatory responses were mitigated in male Hif1αLSL/LSL;VilERcre mice compared to male Hif1αLSL/LSL mice, and those responses were not evident in female mice. Ileum RNA-seq analysis revealed that glycolysis/gluconeogenesis was up in male Hif1αLSL/LSL;VilERcre mice, accompanied by increased epithelial cell proliferation. Moreover, an in vitro study showed that HIF stabilization enhances glycolysis in intestine organoids.

Our data provide evidence that pharmacological or genetic activation of intestinal HIF-1α markedly ameliorates western diet-induced metabolic dysfunction-associated steatotic liver disease in a sex-dependent manner. The underlying mechanism is likely attributed to HIF-1α activation-induced upregulation of glycolysis, which, in turn, leads to enhanced epithelial cell proliferation and augmented gut barrier function.