Itaconate alleviates anesthesia/surgery-induced cognitive impairment by activating a Nrf2-dependent anti-neuroinflammation and neurogenesis via gut-brain axis.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice. METHODS: A POCD animal model was established by performing aseptic laparotomy in 18-month-old male C57BL/6 mice under isoflurane anesthesia while maintaining spontaneous ventilation. OI was intraperitoneally injected into the mice after surgery. Primary microglia and neurons were isolated and treated to lipopolysaccharide (LPS), isoflurane, and OI. Cognitive function, neuroinflammatory responses, as well as levels of gut microbiota and their metabolites were evaluated. To determine the mechanisms underlying the therapeutic effects of OI in POCD, ML385, an antagonist of Nrf2, was administered intraperitoneally. Cognitive function, neuroinflammatory responses, endogenous neurogenesis, neuronal apoptosis, and Nrf2/extracellular signal-related kinases (ERK) signaling pathway were evaluated. RESULTS: Our findings revealed that OI treatment significantly alleviated anesthesia/surgery-induced cognitive impairment, concomitant with reduced levels of the neuroinflammatory cytokines IL-1ß and IL-6, as well as suppressed activation of microglia and astrocytes in the hippocampus. Similarly, OI treatment inhibited the expression of IL-1ß and IL-6 in LPS and isoflurane-induced primary microglia in vitro. Intraperitoneal administration of OI led to alterations in the gut microbiota and promoted the production of microbiota-derived metabolites associated with neurogenesis. We further confirmed that OI promoted endogenous neurogenesis and inhibited neuronal apoptosis in the hippocampal dentate gyrus of aged mice. Mechanistically, we observed a decrease in Nrf2 expression in hippocampal neurons both in vitro and in vivo, which was reversed by OI treatment. We found that Nrf2 was required for OI treatment to inhibit neuroinflammation in POCD. The enhanced POCD recovery and promotion of neurogenesis triggered by OI exposure were, at least partially, mediated by the activation of the Nrf2/ERK signaling pathway. CONCLUSIONS: Our findings demonstrate that OI can attenuate anesthesia/surgery-induced cognitive impairment by stabilizing the gut microbiota and activating Nrf2 signaling to restrict neuroinflammation and promote neurogenesis. Boosting endogenous itaconate or supplementation with exogenous itaconate derivatives may represent novel strategies for the treatment of POCD.

[Possibilities of «therapeutic retargeting¼ of 3-hydroxypyridine and succinic acid derivatives due to their dopaminergic action]. / Vozmozhnosti «terapevticheskogo perenatselivaniya¼ proizvodnykh 3-oksipiridina i yantarnoi kisloty, obuslovlennye ikh dofaminergicheskim deistviem.

The review is devoted to a comparative analysis of the clinical efficacy of the original domestic derivatives of 3-hydroxypyridine and succinic acid (emoxipine, reamberin and mexidol) in comparison with the results of an experimental study of their dopaminergic action. The position that the dopaminomimetic activity of emoxipin, reamberin and mexidol largely determines their anti-ischemic, antihypoxic, insulin-potentiating neuroprotective, nootropic and antidepressant potential has been substantiated. A comparative analysis of the safety profile of emoxipine, reamberin and mexidol was carried out, taking into account potential and real side-effects caused by iatrogenic deviations from the eudopaminergic state. It has been shown that mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate), which is simultaneously a derivative of 3-hydroxypyridine and succinic acid, has the best balance of efficacy and safety. A generalized assessment of the available data on the successful use of off-label derivatives of 3-hydroxypyridine and succinic acid indicates the advisability of a significant expansion of indications for their clinical use. The authors resume that the «therapeutic retargeting¼ of emoxipin, reamberin and mexidol (i.e. their use for qualitatively new indications) will contribute to progress in the treatment of socially significant and most common diseases.

Huanglian Jiedu Wan intervened with "Shi-Re Shanghuo" syndrome through regulating immune balance mediated by biomarker succinate.

With increasing stress in daily life and work, subhealth conditions induced by "Shi-Re Shanghuo" syndrome was gradually universal. "Huanglian Jiedu Wan" (HLJDW) was the first new syndrome Chinese medicine approved for the treatment of "Shi-Re Shanghuo" with promising clinical efficacy. Preliminary small-sample clinical studies have identified some notable biomarkers (succinate, 4-hydroxynonenal, etc.). However, the correlation and underlying mechanism between these biomarkers of HLJDW intervention on "Shi-Re Shanghuo" syndrome remained ambiguous. Therefore, this study was designed as a randomized, double-blind, multicenter, placebo-controlled Phase II clinical trial, employing integrated analysis techniques such as non-targeted and targeted metabolomics, salivary microbiota, proteomics, parallel peaction monitoring, molecular docking and surface plasmon resonance (SPR). The results of the correlation analysis indicated that HLJDW could mediate the balance between inflammation and immunity through succinate produced via host and microbial source to intervene "Shi-Re Shanghuo" syndrome. Further through the HIF1α/MMP9 pathway, succinate regulated downstream arachidonic acid metabolism, particularly the lipid peroxidation product 4-hydroxynonenal. Finally, an animal model of recurrent oral ulcers induced by "Shi-Re Shang Huo" was established and HLJDW was used for intervention, key essential indicators (succinate, glutamine, 4-hydroxynonenal, arachidonic acid metabolism) essential in the potential pathway HIF1α/MMP9 discovered in clinical practice were validated. The results were found to be consistent with our clinical findings. Taken together, succinate was observed as an important signal that triggered immune responses, which might serve as a key regulatory metabolic switch or marker of "Shi-Re Shanghuo" syndrome treated with HLJDW.

[Pathogenetic approaches to the correction of vascular homeostasis in patients with COVID-19: A review].

The adverse outcomes in patients with COVID-19 in the initial phase of the disease are often due to the development of cytokine storm, endothelial dysfunction, shifts in the hemostasis system, microangiopathy, angiocentric inflammation, and pathological angiogenesis, which require targeted therapy. Unfortunately, to date, there is still no drug with proven high efficacy. This review is to analyse the literature data on the pathogenesis of vascular homeostasis lesions and possible ways to correct the existing shifts in patients with COVID-19. When the oxygen content in the tissue decreases, one of the most important mechanisms of adaptation is the activation of the succinate oxidase pathway, but under conditions of prolonged hypoxia and intoxication, the succinate reserve is rapidly depleted. That is why exogenous of succinic acid can enhance the adaptive capabilities of the organism and improve the prognosis in patients with COVID-19. Succinic acid preparations contribute to normalization of energy exchange and reduction of oxidative stress, especially in combination with inosine, nicotinamide and riboflavin and are widely used in clinical practice in various nosological forms. Taking into account the analysis of data on the mechanisms of clinical effects of succinate-containing preparations, this group of drugs can be considered as promising with regard to the correction of vascular disorders in COVID-19.

[Potential for infusion correction of COVID-19-associated endotheliopathy].

AIM: To evaluate the relationship between the systemic inflammatory response and the severity of COVID-19-associated endotheliopathy and the effect of succinate-containing crystalloid solution (sodium meglumine succinate) on it in patients with severe COVID-19. MATERIALS AND METHODS: Clinical and laboratory parameters of 53 intensive care unit's patients with COVID-19 complicated by community-acquired bilateral multisegmental pneumonia were analyzed. Intensive therapy complex of 27 patients (study group) included daily infusion of 1.5% solution of sodium meglumine succinate (Reamberin) in the daily dose of 10 ml/kg for at least 11 days (or during the whole stay in the unit). A similar volume of Ringer's solution was present in the control group of 26 patients. The levels of endotheliocytosis, homocysteine, and systemic inflammatory response were determined at all stages of the study. RESULTS: The evaluation of endotheliopathy degree in the meglumine succinate group showed a significant reduction of initially elevated levels of endotheliemia and homocysteinemia at all study stages. The pattern of changes in the study group was highly correlated (r=0.90-0.96) with the dynamics of systemic inflammatory response parameters-fibrinogenemia, C-reactive protein and interleukin-6 levels. As normalization of the immune imbalance, we regarded the termination of lymphopenia in the Reamberin group. CONCLUSION: Early inclusion of Reamberin infusion into intensive therapy of severe COVID-19, in comparison with Ringer's solution, leads to significant and stable correction of the severity of systemic inflammatory response, which in turn is naturally reflected in the severity of endothelial dysfunction, multiple organ failure, and also leads to a decrease in 28-day mortality.

α-Tocopherol Polyethylene Glycol 1000 Succinate-Based Cationic Liposome for the Intracellular Delivery of Doxorubicin in MDA-MB-231 Triple-Negative Breast Cancer Cell Line.

Present research work reports the development of doxorubicin (DOX) loaded α-tocopherol polyethylene glycol 1000 succinate (TPGS)-coated cationic liposomes. The developed formulation was evaluated for its anticancer potential and intracellular uptake against the MDA-MB-231 breast cancer cell line. Moreover, hemocompatibility studies were also done on human blood red blood cells for the determination of blood compatibility. The prepared doxorubicin-loaded TPGS liposomes (DOX-LIPO-TPGS) and doxorubicin-loaded cationic liposomes (DOX-LIPO+-TPGS) reveal vesicle size (177.5 ± 2.5 and 201.7 ± 2.3 nm), polydispersity index (0.189 ± 0.01 and 0.218 ± 0.02), zeta potential (-36.9 ± 0.7 and 42 ± 0.9 mv), and % entrapment efficiency (65.88% ± 3.7% and 74.5% ± 3.9%). Furthermore, in vitro, drug release kinetics of the drug alone and drug from formulation shows sustained release behavior of developed formulation with 99.98% in 12 h and 80.98% release of the drug in 72 h, respectively. In addition, cytotoxicity studies and cellular DOX uptake on the MDA-MB-231 breast cancer cell line depict higher cytotoxic and drug uptake potential with better hemocompatibility of DOX-LIPO+-TPGS with respect to DOX. The data from the study revealed that TPGS plays an important role in enhancing the formulation's quality attributes like stability, drug release, cytotoxicity, and hemocompatibility behavior. This may serve that TPGS-coated cationic liposome as a vital candidate for the treatment of cancer and drug delivery in case of breast cancer.

[Dopaminergic potential of domestic 3-hydroxypyridine and succinic acid derivatives and prospects for their therapeutic «retargeting¼]. / Dofaminergicheskii potentsial otechestvennykh proizvodnykh 3-oksipiridina i yantarnoi kisloty i perspektivy ikh terapevticheskogo «perenatselivaniya¼.

The review is devoted to the assessment of the pharmacological effects of 3-hydroxypyridine and succinic acid derivatives (emoxipin, reamberin and mexidol) from the standpoint of their dopaminergic activity. A systematic analysis of the data has been performed, allowing us to consider emoxipin, reamberin and mexidol as «normalizers of dopaminergic neurotransmission¼, the dopaminergic action of which in its phenotype corresponds to the effects of partial dopamine receptor agonists. The position that the dopaminergic effect, antioxidant and antidepressant potential of drugs containing 2-ethyl-6-methyl-3-oxypyridine (emoxipine and mexidol) are associated with their inhibitory effect on monoamine oxidase-A (MAO-A) has been substantiated. A direct relationship between the stimulating effect of succinate-containing drugs (reamberin and mexidol) on MAO-B, their prooxidant activity, insulin-potentiating and antidepressant effects was analyzed. A hypothesis has been put forward on the general pathological significance of dopaminergic regulation disorders, the correction of which with the 3-hydroxypyridine and succinic acid derivatives can be considered as a promising strategy for improving the complex therapy of socially significant and common human diseases.

Itaconate-producing neutrophils regulate local and systemic inflammation following trauma.

Modulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of cellular metabolism in regulating cell fate and function, tendon injuries that undergo normal and aberrant repair were evaluated by metabolic profiling to determine its impact on healing outcomes. Metabolomics revealed an increasing abundance of the immunomodulatory metabolite itaconate within the injury site. Subsequent single-cell RNA-Seq and molecular and metabolomic validation identified a highly mature neutrophil subtype, not macrophages, as the primary producers of itaconate following trauma. These mature itaconate-producing neutrophils were highly inflammatory, producing cytokines that promote local injury fibrosis before cycling back to the bone marrow. In the bone marrow, itaconate was shown to alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby regulating systemic inflammation. Therapeutically, exogenous itaconate was found to reduce injury-site inflammation, promoting tenogenic differentiation and impairing aberrant vascularization with disease-ameliorating effects. These results present an intriguing role for cycling neutrophils as a sensor of inflammation induced by injury - potentially regulating immune cell production in the bone marrow through delivery of endogenously produced itaconate - and demonstrate a therapeutic potential for exogenous itaconate following tendon injury.

[The successful use of Cytoflavin in the patient with postaveny syndrome]. / Uspeshnoe primenenie Tsitoflavina u patsientki s postkovidnym sindromom.

A clinical observation of the use of Cytoflavin according to a two-stage scheme (10.0 ml intravenously drip per 200 ml of 0.9% sodium chloride solution for 10 days, followed by a transition to a tablet form of 2 tablets 2 times/day for 25 days) in a patient with postcovid syndrome with pronounced vegetative and neurocognitive disorders. The effectiveness of therapy was confirmed by an improvement in heart rate variability and a decrease in the severity of depression, anxiety (on the HADS scale) and the level of autonomic dysfunction (on the COMPASS-31 scale). The significant changes in levels of fatigue (on a scale MFI) is not marked. The obtained results can serve as a basis for further research.

Succinate pretreatment attenuates intestinal ischemia-reperfusion injury by inhibiting necroptosis and inflammation via upregulating Klf4.

Intestinal ischemia-reperfusion (I/R) injury is a common pathophysiological process in various diseases, and the disruption of the intestinal barrier composed of tight junction proteins is the initiating factor, which then leads to a large number of bacteria and endotoxins in the intestine into the bloodstream causing stress and distant organ damage. The release of inflammatory mediators and abnormal programmed death of intestinal epithelial cells are important factors of intestinal barrier damage. Succinate is an intermediate product of the tricarboxylic acid cycle with anti-inflammatory and pro-angiogenic activities, but its role in the maintenance of intestinal barrier homeostasis after I/R has not been fully elucidated. In this study, we explored the effect of succinate on intestinal ischemia-reperfusion injury and the possible mechanism of its role by flow cytometry, western blotting, real-time quantitative PCR and immunostaining. The results of pretreatment with succinate in the mouse intestinal I/R model and IEC-6 cells hypoxia-reoxygenation (H/R) model revealed a reduction in tissue damage, necroptosis and associated inflammation due to ischemia-reperfusion. Furthermore, it was found that the protective effect of succinate pretreatment may be associated with the transcriptional upregulation of the inflammatory protein KLF4 and the protective effect of intestinal barrier of succinate was diminished after inhibition of KLF4. Thus, our results suggest that succinate can exert a protective effect in intestinal ischemia-reperfusion injury through upregulation of KLF4 and also demonstrate the potential therapeutic value of succinate pretreatment in acute I/R injury of the intestine.

Itaconate: A Potent Macrophage Immunomodulator.

With advances in immunometabolic studies, more and more evidence has shown that metabolic changes profoundly affect the immune function of macrophages. The tricarboxylic acid cycle is a central metabolic pathway of cells. Itaconate, a byproduct of the tricarboxylic acid cycle, is an emerging metabolic small molecule that regulates macrophage inflammation and has received much attention for its potent anti-inflammatory effects in recent years. Itaconate regulates macrophage function through multiple mechanisms and has demonstrated promising therapeutic potential in a variety of immune and inflammatory diseases. New progress in the mechanism of itaconate continues to be made, but it also implies complexity in its action and a need for a more comprehensive understanding of its role in macrophages. In this article, we review the primary mechanisms and current research progress of itaconate in regulating macrophage immune metabolism, hoping to provide new insights and directions for future research and disease treatment.

[Infusion therapy with reamberin in military conditions]. / Ispol'zovanie rastvora reamberina v voennykh usloviyakh.

The article is devoted to infusion therapy with Reamberin 1.5% (Meglumine sodium succinate) in patients with various traumatic injuries. The authors substantiate the relevance and significance of this issue. Specifics and purposes of therapy are considered. The authors reviewed national studies devoted to clinical aspects and determined the main directions of therapy in emergency patients with mechanical injuries, burns, traumatic brain injury and cognitive impairment caused by combat trauma. Moreover, experimental studies of protective properties of Reamberin under combined action of cold, vibration and immobilization, as well as acute massive blood loss are analyzed.

Application of metabolomics in urolithiasis: the discovery and usage of succinate.

Urinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events. It has been shown that the occurrence of calcium oxalate monohydrate (COM) during stone formation is regulated by crystal growth modifiers. Although crystallization inhibitors have been recognized as a therapeutic modality for decades, limited progress has been made in the discovery of effective modifiers to intervene with stone disease. In this study, we have used metabolomics technologies, a powerful approach to identify biomarkers by screening the urine components of the dynamic progression in a bladder stone model. By in-depth mining and analysis of metabolomics data, we have screened five differential metabolites. Through density functional theory studies and bulk crystallization, we found that three of them (salicyluric, gentisic acid and succinate) could effectively inhibit nucleation in vitro. We thereby assessed the impact of the inhibitors with an EG-induced rat model for kidney stones. Notably, succinate, a key player in the tricarboxylic acid cycle, could decrease kidney calcium deposition and injury in the model. Transcriptomic analysis further showed that the protective effect of succinate was mainly through anti-inflammation, inhibition of cell adhesion and osteogenic differentiation. These findings indicated that succinate may provide a new therapeutic option for urinary stones.

Grossamide attenuates inflammation by balancing macrophage polarization through metabolic reprogramming of macrophages in mice.

Macrophages exhibited different phenotypes in response to environmental cues. To meet the needs of rapid response to stimuli, M1-activated macrophages preferred glycolysis to oxidative phosphorylation (OXPHOS) in mitochondria to quickly produce energy and obtain ample raw materials to support cell activation at the same time. Activated macrophages produced free radicals and cytokines to eradicate pathogens but also induced oxidative damage and enhanced inflammation. Grossamide (GSE), a lignanamide from Polygonum multiflorum Thunb., exhibited notable anti-inflammatory effects. In this study, the potential of GSE on macrophage polarization was explored. GSE significantly down-regulated the levels of M1 macrophage biomarkers (Cd32a, Cd80 and Cd86) while increased the levels of M2 indicators (Cd163, Mrc1 and Socs1), showing its potential to inhibit LPS-induced M1 polarization of macrophages. This ability has close a link to its effect on metabolic reprogramming of macrophage. GSE shunted nitric oxide (NO) production from arginine by up-regulation of arginase and down-regulation of inducible nitric oxide synthase, thus attenuated the inhibition of NO on OXPHOS. LPS created three breakpoints in the tricarboxylic acid cycle (TCA) cycle of macrophage as evidenced by down-regulated isocitrate dehydrogenase, accumulation of succinate and the inhibited SDH activity, significantly decreased level of oxoglutarate dehydrogenase expression and its substrate α-ketoglutarate. Thus GSE reduced oxidative stress and amended fragmented TCA cycle. As a result, GSE maintained redox (NAD+/NADH) and energy (ATP/ADP) state, reduced extracellular acidification rate and enhanced the oxygen consumption rate. In addition, GSE decreased the release of inflammatory cytokines by inhibiting the activation of the LPS/TLR4/NF-κB pathway. These findings highlighted the central role of immunometabolism of macrophages in its functional plasticity, which invited future study of mode of action of anti-inflammatory drugs from viewpoint of metabolic reprogramming.

Aging Relevant Metabolite Itaconate Inhibits Inflammatory Bone Loss.

Progressive bone loss during aging makes osteoporosis one of the most common and life impacting conditions in geriatric populations. The bone homeostasis is maintained through persistent remodeling mediated by bone-forming osteoblast and bone-resorbing osteoclast. Inflammaging, a condition characterized by increased pro-inflammatory markers in the blood and other tissues during aging, has been reported to be associated with skeletal stem/progenitor cell dysfunction, which will result in impaired bone formation. However, the role of age-related inflammation and metabolites in regulation of osteoclast remains largely unknown. In the present study, we observed dichotomous phenotypes of anti-inflammatory metabolite itaconate in responding to inflammaging. Itaconate is upregulated in macrophages during aging but has less reactivity in responding to RANKL stimulation in aged macrophages. We confirmed the inhibitory effect of itaconate in regulating osteoclast differentiation and activation, and further verified the rescue role of itaconate in lipopolysaccharides induced inflammatory bone loss animal model. Our findings revealed that itaconate is a crucial regulatory metabolite during inflammaging that inhibits osteoclast to maintain bone homeostasis.

Adipose-Derived Mesenchymal Stem Cells Reprogram M1 Macrophage Metabolism via PHD2/HIF-1α Pathway in Colitis Mice.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease worldwide. Infiltration of pro-inflammatory macrophages (M1 macrophages) contributes to the occurrence of bowel inflammation. Transplantation of mesenchymal stem cells (MSCs) is a promising therapeutic strategy for UC, but the exact mechanism remains unknow yet. Here, we treated DSS-induced colitis mice with adipose-derived mesenchymal stem cells (ADMSCs) and revealed that ADMSCs alleviated colon inflammation by reducing the infiltration of M1 macrophages. Moreover, ADMSCs exerted this therapeutic effect by inhibiting succinate accumulation, increasing PHD2 to prevent M1 macrophages from overexpressing HIF-1α and thereby reprogramming the glycolytic pathway of M1 macrophages. Meanwhile, the succinate secreted by M1 macrophages triggered ADMSCs to secrete PGE2 in return, which could also shift macrophages from M1 phenotype to M2. Our work demonstrated an immunomodulatory effect of ADMSCs and provided a novel perspective on UC therapy.

Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo.

A Krebs cycle intermediate metabolite, itaconate, has gained attention as a potential antimicrobial and autoimmune disease treatment due to its anti-inflammatory effects. While itaconate and its derivatives pose an attractive therapeutic option for the treatment of inflammatory diseases, the effects outside the immune system still remain limited, particularly in the muscle. Therefore, we endeavored to determine if itaconate signaling impacts muscle differentiation. Utilizing the well-established C2C12 model of in vitro myogenesis, we evaluated the effects of itaconate and its derivatives on transcriptional and protein markers of muscle differentiation as well as mitochondrial function. We found itaconate and the derivatives dimethyl itaconate and 4-octyl itaconate disrupt differentiation media-induced myogenesis. A primary biological effect of itaconate is a succinate dehydrogenase (SDH) inhibitor. We find the SDH inhibitors dimethyl malonate and harzianopyridone phenocopie the anti-myogenic effects of itaconate. Furthermore, we find treatment with exogenous succinate results in blunted myogenesis. Together our data indicate itaconate and its derivatives interfere with in vitro myogenesis, potentially through inhibition of SDH and subsequent succinate accumulation. We also show 4-octyl itaconate suppresses injury-induced MYOG expression in vivo. More importantly, our findings suggest the therapeutic potential of itaconate, and its derivatives could be limited due to deleterious effects on myogenesis.

Preclinical evaluation of targeted therapies in Sdhb-mutated tumors.

Therapies for metastatic SDHB-dependent pheochromocytoma and paraganglioma (PPGL) are limited and poorly efficient. New targeted therapies and identification of early non-invasive biomarkers of response are thus urgently needed for these patients. We characterized an in vivo allograft model of spontaneously immortalized murine chromaffin cells (imCC) with inactivation of the Sdhb gene by dynamic contrast-enhanced MRI (DCE-MRI) and 18FDG-PET. We evaluated the response to several therapies: IACS-010759 (mitochondrial respiratory chain complex I inhibitor), sunitinib (tyrosine kinase inhibitor with anti-angiogenic activity), talazoparib (poly ADP ribose polymerase (PARP) inhibitor) combined or not to temozolomide (alkylating agent), pharmacological inhibitors of HIF2a (PT2385 and PT2977 (belzutifan)) and molecular inactivation of HIF2a (imCC Sdhb-/- shHIF2a). Multimodal imaging was performed, including magnetic resonance spectroscopy (1H-MRS) to monitor the level of succinate in vivo. The allografted model of Sdhb-/- imCC reflected SDHB-deficient tumors, with increased angiogenesis and a particular avidity for 18FDG. After 14 days of treatment, IACS-010759, sunitinib and talazoparib at high doses allowed a significant reduction of the tumor volumes. In contrast to the tumor growth inhibition observed in Sdhb-/- shHIF2a imCC tumors, pharmacological inhibitors of HIF2a (PT2385 and belzutifan) showed no antitumor action in this model, alone or in combination with sunitinib. 1H-MRS, but not DCE-MRI, enabled the monitoring response to sunitinib, which was the best treatment in this study, promoting a decrease in succinate levels detected in vivo. This study paves the way for new therapeutic options and reveals a potential new early biomarker of response to treatment in SDHB-dependent PPGL.

Hepatoprotective Role of 4-Octyl Itaconate in Concanavalin A-Induced Autoimmune Hepatitis.

4-Octyl itaconate (OI) is a novel anti-inflammatory metabolite that exerts protective effects in many various disease models. However, its function in autoimmune hepatitis- (AIH-) associated hepatic injury has not been investigated. In this study, we successfully used concanavalin A (Con A) to establish an AIH-associated liver injury model. Furthermore, we investigated the effect of OI in Con A-induced liver injury and found that OI mitigated Con A-induced histopathological damage. OI administration reduced serum levels of alanine transaminase and aspartate transaminase in Con A-treated mice and attenuated the infiltration of macrophages induced by Con A. Moreover, OI effectively inhibited the expression of proinflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and IL-1ß induced by Con A. Furthermore, OI decreased hepatocyte apoptosis and malondialdehyde levels and increased the reduced glutathione/oxidized glutathione ratio in the Con A-induced liver injury model. In addition, we found that OI inhibited Con A-induced hepatocyte apoptosis in vitro, while Nrf2 deletion eliminated this effect. Furthermore, we administrated the Nrf2 inhibitor ML385 in OI+Con A-treated mice and found that ML385 eliminated the protective effect of OI in vivo. In addition, OI inhibited Con A-induced activation of nuclear factor-kappa B (NF-𝜅B) and the expression of proinflammatory cytokines in macrophages. Therefore, OI protected mice from Con A-induced liver damage and may be associated with Nrf2 activation and NF-𝜅B inhibition. Finally, our study revealed that OI inhibited TNF-α, or supernatants from Con A-treated RAW264.7 cells induced hepatocyte apoptosis. In conclusion, our study indicated that OI alleviated Con A-induced hepatic damage by reducing inflammatory response, oxidative stress, and apoptosis.