-
International Journal of Dermatology Mar 2024Antibiotics have constituted the mainstay of acne therapy despite acne being classified as an inflammatory disorder. The indiscriminate usage of antibiotics over the... (Review)
Review
Antibiotics have constituted the mainstay of acne therapy despite acne being classified as an inflammatory disorder. The indiscriminate usage of antibiotics over the years has thus fueled the issue of antimicrobial resistance. Cutibacterium acnes (C. acnes) can acquire resistance due to chromosomal mutation or genetic acquisition. C. acnes can transfer resistance to other resident flora, complicating the management of skin and soft tissue infections. It can also transfer resistant strains to other body sites and to immunocompromised and elderly patients thus putting them at risk of serious infections. Recent studies have highlighted the physiologic role of C. acnes in maintaining the normal homeostasis of the skin microbiome. The role of Malassezia in causation of acne has piqued interest in recent times. The efficacy of antibiotics in acne is attributed to their para-antibiotic, anti-inflammatory action rather than antimicrobial action. Thus, usage of low-dose antibiotics and alternatives to antibiotics has been advocated. Some alternative therapies showing efficacy in acne are probiotics, oral zinc, precision therapy using succinic acid, bacteriophages, and anti-biofilm therapy like myrtacin, topical azelaic acid, and salicylic acid. Using isotretinoin in early stages of acne can reduce the incidence of scarring and alleviate the need for antibiotics. Thus, a gradual shift from antibiotics to alternative therapies in acne is the need of the hour.
Topics: Humans; Aged; Anti-Bacterial Agents; Acne Vulgaris; Isotretinoin; Skin; Salicylic Acid; Propionibacterium acnes
PubMed: 37743606
DOI: 10.1111/ijd.16854 -
Redox Biology Apr 2024Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more...
Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more protective phenotype and reducing the occurrence of clinical events is thought to be a promising method of treating atherosclerotic patients. In the current study, we investigate the immunomodulatory properties of itaconate, an immunometabolite derived from the TCA cycle intermediate cis-aconitate and synthesised by the enzyme Aconitate Decarboxylase 1 (ACOD1, also known as IRG1), in the context of atherosclerosis. Ldlr atherogenic mice transplanted with Acod1 bone marrow displayed a more stable plaque phenotype with smaller necrotic cores and showed increased recruitment of monocytes to the vessel intima. Macrophages from Acod1 mice contained more lipids whilst also displaying reduced induction of apoptosis. Using multi-omics approaches, we identify a metabolic shift towards purine metabolism, in addition to an altered glycolytic flux towards production of glycerol for triglyceride synthesis. Overall, our data highlight the potential of therapeutically blocking ACOD1 with the aim of stabilizing atherosclerotic plaques.
Topics: Humans; Animals; Mice; Plaque, Atherosclerotic; Atherosclerosis; Succinates; Macrophages
PubMed: 38309122
DOI: 10.1016/j.redox.2024.103054 -
Biomaterials Oct 2023Succinate is an important metabolite that modulates metabolism of immune cells and cancer cells in the tumor microenvironment (TME). Herein, we report that polyethylene...
Succinate is an important metabolite that modulates metabolism of immune cells and cancer cells in the tumor microenvironment (TME). Herein, we report that polyethylene succinate (PES) microparticles (MPs) biomaterial mediated controlled delivery of succinate in the TME modulates macrophage responses. Administering PES MPs locally with or without a BRAF inhibitor systemically in an immune-defective aging mice with clinically relevant BRAF mutated YUMM1.1 melanoma decreased tumor volume three-fold. PES MPs in the TME also led to maintenance of M1 macrophages with up-regulation of TSLP and type 1 interferon pathway. Impressively, this led to generation of pro-inflammatory adaptive immune responses in the form of increased T helper type 1 and T helper type 17 cells in the TME. Overall, our findings from this challenging tumor model suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.
Topics: Animals; Mice; Succinic Acid; Tumor-Associated Macrophages; Tumor Microenvironment; Proto-Oncogene Proteins B-raf; Succinates; Melanoma
PubMed: 37643489
DOI: 10.1016/j.biomaterials.2023.122292 -
Science Advances Jun 2023P23, historically known as a heat shock protein 90 (HSP90) co-chaperone, exerts some of its critical functions in an HSP90-independent manner, particularly when it...
P23, historically known as a heat shock protein 90 (HSP90) co-chaperone, exerts some of its critical functions in an HSP90-independent manner, particularly when it translocates into the nucleus. The molecular nature underlying how this HSP90-independent p23 function is achieved remains as a biological mystery. Here, we found that p23 is a previously unidentified transcription factor of COX-2, and its nuclear localization predicts the poor clinical outcomes. Intratumor succinate promotes p23 succinylation at K7, K33, and K79, which drives its nuclear translocation for COX-2 transcription and consequently fascinates tumor growth. We then identified M16 as a potent p23 succinylation inhibitor from 1.6 million compounds through a combined virtual and biological screening. M16 inhibited p23 succinylation and nuclear translocation, attenuated COX-2 transcription in a p23-dependent manner, and markedly suppressed tumor growth. Therefore, our study defines p23 as a succinate-activated transcription factor in tumor progression and provides a rationale for inhibiting p23 succinylation as an anticancer chemotherapy.
Topics: Humans; Succinic Acid; Transcription Factors; Cyclooxygenase 2; Pyridinolcarbamate; Carcinogenesis; Cell Transformation, Neoplastic; Succinates; Adenocarcinoma of Lung; Molecular Chaperones; HSP90 Heat-Shock Proteins; Lung Neoplasms
PubMed: 37390202
DOI: 10.1126/sciadv.ade0387 -
Molecular Cell Mar 2024SUCNR1 is an auto- and paracrine sensor of the metabolic stress signal succinate. Using unsupervised molecular dynamics (MD) simulations (170.400 ns) and mutagenesis...
SUCNR1 is an auto- and paracrine sensor of the metabolic stress signal succinate. Using unsupervised molecular dynamics (MD) simulations (170.400 ns) and mutagenesis across human, mouse, and rat SUCNR1, we characterize how a five-arginine motif around the extracellular pole of TM-VI determines the initial capture of succinate in the extracellular vestibule (ECV) to either stay or move down to the orthosteric site. Metadynamics demonstrate low-energy succinate binding in both sites, with an energy barrier corresponding to an intermediate stage during which succinate, with an associated water cluster, unlocks the hydrogen-bond-stabilized conformationally constrained extracellular loop (ECL)-2b. Importantly, simultaneous binding of two succinate molecules through either a "sequential" or "bypassing" mode is a frequent endpoint. The mono-carboxylate NF-56-EJ40 antagonist enters SUCNR1 between TM-I and -II and does not unlock ECL-2b. It is proposed that occupancy of both high-affinity sites is required for selective activation of SUCNR1 by high local succinate concentrations.
Topics: Mice; Rats; Animals; Humans; Succinic Acid; Receptors, G-Protein-Coupled; Molecular Dynamics Simulation; Succinates; Stress, Physiological
PubMed: 38325379
DOI: 10.1016/j.molcel.2024.01.011 -
International Immunopharmacology Jul 2023Intestinal ischemia-reperfusion (I/R) injury is a common pathophysiological process in various diseases, and the disruption of the intestinal barrier composed of tight...
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.
Topics: Animals; Mice; Rats; Inflammation; Intestines; Necroptosis; Reperfusion Injury; Succinates; Succinic Acid; Kruppel-Like Factor 4
PubMed: 37285681
DOI: 10.1016/j.intimp.2023.110425 -
JCI Insight Oct 2023Modulation 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...
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.
Topics: Humans; Neutrophils; Succinates; Macrophages; Inflammation
PubMed: 37707952
DOI: 10.1172/jci.insight.169208 -
Phytomedicine : International Journal... Jan 2024Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome...
BACKGROUND
Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury.
PURPOSE
This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved.
METHODS/RESULTS
From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury.
CONCLUSION
These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.
Topics: Humans; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; Tubulin; Metabolic Reprogramming; Macrophages; Succinates; Cardiomyopathies; Sepsis; Succinic Acid; Lipopolysaccharides; Caffeic Acids
PubMed: 37951150
DOI: 10.1016/j.phymed.2023.155175 -
Inflammation Feb 2024Itaconate is an unsaturated dicarboxylic acid that is derived from the decarboxylation of the Krebs cycle intermediate cis-aconitate and has been shown to exhibit...
Itaconate is an unsaturated dicarboxylic acid that is derived from the decarboxylation of the Krebs cycle intermediate cis-aconitate and has been shown to exhibit anti-inflammatory and anti-bacterial/viral properties. But the mechanisms underlying itaconate's anti-inflammatory activities are not fully understood. Necroptosis, a lytic form of regulated cell death (RCD), is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) signaling. It has been involved in the pathogenesis of organ injury in many inflammatory diseases. In this study, we aimed to explore whether itaconate and its derivatives can inhibit necroptosis in murine macrophages, a mouse MPC-5 cell line and a human HT-29 cell line in response to different necroptotic activators. Our results showed that itaconate and its derivatives dose-dependently inhibited necroptosis, among which dimethyl itaconate (DMI) was the most effective one. Mechanistically, itaconate and its derivatives inhibited necroptosis by suppressing the RIPK1/RIPK3/MLKL signaling and the oligomerization of MLKL. Furthermore, DMI promoted the nuclear translocation of Nrf2 that is a critical regulator of intracellular redox homeostasis, and reduced the levels of intracellular reactive oxygen species (ROS) and mitochondrial superoxide (mtROS) that were induced by necroptotic activators. Consistently, DMI prevented the loss of mitochondrial membrane potential induced by the necroptotic activators. In addition, DMI mitigated caerulein-induced acute pancreatitis in mice accompanied by reduced activation of the necroptotic signaling in vivo. Collectively, our study demonstrates that itaconate and its derivatives can inhibit necroptosis by suppressing the RIPK1/RIPK3/MLKL signaling, highlighting their potential applications for treating necroptosis-associated diseases.
Topics: Mice; Humans; Animals; Protein Kinases; Acute Disease; Pancreatitis; Anti-Inflammatory Agents; Apoptosis; Succinates
PubMed: 37759136
DOI: 10.1007/s10753-023-01909-z -
The American Journal of Emergency... Sep 2023Succinylcholine and rocuronium are the most commonly utilized neuromuscular blocker agents (NMBAs) for rapid sequence intubation (RSI) in the emergency department (ED)....
BACKGROUND
Succinylcholine and rocuronium are the most commonly utilized neuromuscular blocker agents (NMBAs) for rapid sequence intubation (RSI) in the emergency department (ED). The duration of action of rocuronium is significantly longer (∼30 min) compared to succinylcholine (∼10 min) and previous studies have shown that patients receiving rocuronium are more likely to have longer time to sedation initiation following RSI. Furthermore, patients receiving rocuronium may be more likely to experience awareness with paralysis than those receiving succinylcholine. The primary goal for this study was to evaluate the association between NMBA use during RSI and post-intubation sedation and analgesia practices in the ED.
METHODS
This was a retrospective, multicenter cohort study including patients 18 years and older that received succinylcholine or rocuronium during RSI in the ED between September 1, 2020 and August 31, 2021. Patients were excluded if they were intubated prior to ED arrival, experienced an out-of-hospital or in ED cardiac arrest, or received sugammadex within 60 min of rocuronium administration. Patients were screened in reverse chronological order until the targeted sample size was achieved and all data was abstracted from the electronic health record. The primary outcome was the time to initiation of analgesia or sedation. Secondary outcomes included dose of sedatives or analgesia administered at 30- and 60 min, and medications administered for post-intubation sedation or analgesia.
FINDINGS
A total of 200 ED patients were included of which 100 received succinylcholine and 100 received rocuronium. There was no difference in the median time to initiation of analgesia or sedation between the succinylcholine and rocuronium groups (10 vs 8.5 min, p = 0.82) or in Kaplan-Meier cumulative probabilities (p = 0.17). At 60 min post-RSI, those receiving succinylcholine received significantly higher median doses of propofol (20 μg/kg/min vs. 10 μg/kg/min; p = 0.02) and fentanyl [100 μg vs. 84.2 μg; p = 0.02].
CONCLUSION
While no differences were observed in the time to initiation of post-intubation sedation or analgesia in ED patients receiving succinylcholine compared to rocuronium, differences in the intensity of post-intubation regimens was observed. Further investigation is needed to evaluate the adequacy of sedation following RSI in the ED.
Topics: Humans; Succinylcholine; Rocuronium; Neuromuscular Depolarizing Agents; Retrospective Studies; Cohort Studies; Androstanols; Neuromuscular Nondepolarizing Agents; Intubation, Intratracheal; Analgesia; Emergency Service, Hospital
PubMed: 37356339
DOI: 10.1016/j.ajem.2023.06.017