Acute lung injury (ALI) is one of the life-threatening complications of sepsis, and macrophage polarization plays a crucial role in the sepsis-associated ALI. However, the regulatory mechanisms of macrophage polarization in ALI and in the development of inflammation are largely unknown. In this study, we demonstrated that macrophage polarization occurs in sepsis-associated ALI and is accompanied by mitochondrial dysfunction and inflammation, and a decrease of PRDX3 promotes the initiation of macrophage polarization and mitochondrial dysfunction. Mechanistically, PRDX3 overexpression promotes M1 macrophages to differentiate into M2 macrophages, and enhances mitochondrial functional recovery after injury by reducing the level of glycolysis and increasing TCA cycle activity. In conclusion, we identified PRDX3 as a critical hub integrating oxidative stress, inflammation, and metabolic reprogramming in macrophage polarization. The findings illustrate an adaptive mechanism underlying the link between macrophage polarization and sepsis-associated ALI.

BACKGROUND: Myocardial ischemia/reperfusion injury (MIRI) seriously threatens the health of people. The mitochondrial dysfunction in cardiomyocytes can promote the progression of MIRI. Dexmedetomidine (Dex) could alleviate the myocardial injury, which was known to reverse mitochondrial dysfunction in lung injury. However, the function of Dex in mitochondrial dysfunction during MIRI remains unclear.
OBJECTIVE: To assess the function of Dex in mitochondrial dysfunction during MIRI.
METHODS: To investigate the function of Dex in MIRI, H9C2 cells were placed in condition of hypoxia/reoxygenation (H/R). CCK8 assay was performed to test the cell viability, and the mitochondrial membrane potential was evaluated by JC-1 staining. In addition, the binding relationship between Sirt3 and Prdx3 was explored by Co-IP assay. Furthermore, the protein expressions were examined using western blot.
RESULTS: Dex could abolish H/R-induced mitochondrial dysfunction in H9C2 cells. In addition, H/R treatment significantly inhibited the expression of Sirt3, while Dex partially restored this phenomenon. Knockdown of Sirt3 or Prdx3 obviously reduced the protective effect of Dex on H/R-induced mitochondrial injury. Meanwhile, Sirt3 could enhance the function of Prdx3 via deacetylation of Prdx3.
CONCLUSIONS: Dex was found to attenuate H/R-induced mitochondrial dysfunction in cardiomyocytes via activation of Sirt3/Prdx3 pathway. Thus, this study might shed new lights on exploring new strategies for the treatment of MIRI.

Nonsteroidal anti-inflammatory drug (NSAID) use is associated with adverse consequences, including hepatic injury. The detrimental hepatotoxicity of diclofenac, a widely used NSAID, is primarily connected to oxidative damage in mitochondria, which are the primary source of reactive oxygen species (ROS). The primary ROS responsible for inducing diclofenac-related hepatocellular toxicity and the principal antioxidant that mitigates these ROS remain unknown. Peroxiredoxin III (PrxIII) is the most abundant and potent H2O2-eliminating enzyme in the mitochondria of mammalian cells. Here, we investigated the role of mitochondrial H2O2 and the protective function of PrxIII in diclofenac-induced mitochondrial dysfunction and apoptosis in hepatocytes. Mitochondrial H2O2 levels were differentiated from other types of ROS using a fluorescent H2O2 indicator. Upon diclofenac treatment, PrxIII-knockdown HepG2 human hepatoma cells showed higher levels of mitochondrial H2O2 than PrxIII-expressing controls. PrxIII-depleted cells exhibited higher mitochondrial dysfunction as measured by a lower oxygen consumption rate, loss of mitochondrial membrane potential, cardiolipin oxidation, and caspase activation, and were more sensitive to apoptosis. Ectopic expression of mitochondrially targeted catalase in PrxIII-knockdown HepG2 cells or in primary hepatocytes derived from PrxIII-knockout mice suppressed the diclofenac-induced accumulation of mitochondrial H2O2 and decreased apoptosis. Thus, we demonstrated that mitochondrial H2O2 is a key mediator of diclofenac-induced hepatocellular damage driven by mitochondrial dysfunction and apoptosis. We showed that PrxIII loss results in the critical accumulation of mitochondrial H2O2 and increases the harmful effects of diclofenac. PrxIII or other antioxidants targeting mitochondrial H2O2 could be explored as potential therapeutic agents to protect against the hepatotoxicity associated with NSAID use.

Ferroptosis, a regulated cell death pathway driven by accumulation of phospholipid peroxides, has been challenging to identify in physiological conditions owing to the lack of a specific marker. Here, we identify hyperoxidized peroxiredoxin 3 (PRDX3) as a marker for ferroptosis both in vitro and in vivo. During ferroptosis, mitochondrial lipid peroxides trigger PRDX3 hyperoxidation, a posttranslational modification that converts a Cys thiol to sulfinic or sulfonic acid. Once hyperoxidized, PRDX3 translocates from mitochondria to plasma membranes, where it inhibits cystine uptake, thereby causing ferroptosis. Applying hyperoxidized PRDX3 as a marker, we determined that ferroptosis is responsible for death of hepatocytes in mouse models of both alcoholic and nonalcoholic fatty liver diseases, the most prevalent chronic liver disorders. Our study highlights the importance of ferroptosis in pathophysiological conditions and opens the possibility to treat these liver diseases with drugs that inhibit ferroptosis.

Bi-allelic variants in peroxiredoxin 3 (PRDX3) have only recently been associated with autosomal recessive spinocerebellar ataxia characterized by early onset slowly progressive cerebellar ataxia, variably associated with hyperkinetic and hypokinetic features, accompanied by cerebellar atrophy and occasional olivary and brainstem involvement. Herein, we describe a further simplex case carrying a reported PRDX3 variant as well as two additional cases with novel variants. We report the first Brazilian patient with SCAR32, replicating the pathogenic status of a known variant. All presented cases from the Brazilian and Indian populations expand the phenotypic spectrum of the disease by displaying prominent neuroradiological findings. SCAR32, although rare, should be included in the differential diagnosis of sporadic or recessive childhood and adolescent-onset pure and complex cerebellar ataxia.

BACKGROUND: Although the implications of circular RNAs (circRNAs) with the progression of diverse pathological conditions have been reported, the circRNA players in osteoarthritis (OA) are barely studied.
METHODS: In this study, twenty-five OA patients who received arthroplasty were recruited for cartilage tissue collection. Public circRNA microarray data from Gene Expression Omnibus was retrieved for circRNA identification. An in vitro cell model of OA-related damages was constructed by treating human chondrocytes (CHON-001 cell line) with IL-1β, and circSOD2 siRNA was used to silence circSOD2 expression to study its functional role in apoptosis, inflammatory responses, and extracellular matrix (ECM) degradation. Besides, we investigated the functional interactions among circSOD2, miR-224-5p, and peroxiredoxin 3 (PRDX3) by luciferase reporter assay, RNA-immunoprecipitation assay, and quantitative reverse transcription polymerase chain reaction.
RESULTS: Our findings revealed the overexpression of circSOD2 in the OA cartilage and cell samples, and circSOD2 knockdown alleviated ECM degradation, inflammation, and apoptosis in CHON-001 cell model. In addition, our findings suggested the regulatory function of circSOD2 knockdown on miR-224-5p expression, while miR-224-5p was capable of downregulating PRDX3 expression. The co-transfection of miR-224-5p inhibitor or pcDNA-PRDX3 could prevent the effect of circSOD2 knockdown.
CONCLUSIONS: Hence, our results demonstrated that knockdown of circSOD2 may serve as an intervention strategy to alleviate OA progression through modulating miR-224-5p/PRDX3 signaling axis.

Trypanosoma cruzi, the causal agent of Chagas disease, has peroxiredoxins (PRXs) expressed in all stages of the parasite and whose function is to detoxify oxidizing agents, such as reactive oxygen species (ROS). These proteins are central for the survival and replication of the parasite and have been proposed as virulence factors. Because of their importance, they have also been considered as possible therapeutic targets, although there is no specific drug against them. One of them, the mitochondrial PRX (TcMPX), is important in the detoxification of ROS in this organelle and has a role in the infectivity of T. cruzi. However, their structural characteristics are unknown, and possible inhibitors have not been proposed. The aim was to describe in detail some structural characteristics of TcMPX and compare it with several PRXs to find possible similarities and repositioning the antibiotic Thiostrepton as a potential inhibitor molecule. It was found that, in addition to the characteristic active site of a 2-cys PRX, this protein has a possible transmembrane motif and motifs involved in resistance to hyper oxidation. The homology model suggests a high structural similarity with human PRX3. This similarity was corroborated by cross-recognition using an anti-human PRX antibody. In addition, molecular docking showed that Thiostrepton, a potent inhibitor of human PRX3, could bind to TcMPX and affect its function. Our results show that Thiostrepton reduces the proliferation of T. cruzi epimastigotes, cell-derived trypomastigotes, and blood trypomastigotes with low cytotoxicity on Vero cells. We also demonstrated a synergic effect of Thriostepton and Beznidazol. The convenience of seeking treatment alternatives against T. cruzi by repositioning compounds as Thiostrepton is discussed.

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Nonalcoholic fatty liver disease (NAFLD) is the leading liver chronic disease featuring hepatic steatosis. Mitochondrial β-oxidation participates in the derangement of lipid metabolism at the basis of NAFLD, and mitochondrial oxidative stress contributes to the onset of the disease. We evaluated the presence and effects of mitochondrial oxidative stress in the liver from rats fed a high-fat plus fructose (HF-F) diet inducing NAFLD. Supplementation with dehydroepiandrosterone (DHEA), a multitarget antioxidant, was tested for efficacy in delaying NAFLD. A marked mitochondrial oxidative stress was originated by all diets, as demonstrated by the decrease in Superoxide Dismutase 2 (SOD2) and Peroxiredoxin III (PrxIII) amounts. All diets induced a decrease in mitochondrial DNA content and an increase in its oxidative damage. The diets negatively affected mitochondrial biogenesis as shown by decreased peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α), mitochondrial transcription factor A (TFAM), and the COX-IV subunit from the cytochrome c oxidase complex. The reduced amounts of Beclin-1 and lipidated LC3 II form of the microtubule-associated protein 1 light chain 3 (LC3) unveiled the diet-related autophagy\'s decrease. The DHEA supplementation did not prevent the diet-induced changes. These results demonstrate the relevance of mitochondrial oxidative stress and the sequential dysfunction of the organelles in an obesogenic diet animal model of NAFLD.

OBJECTIVE: The aim of this study was to report the results of screening peroxiredoxin 3 (PRDX3) and PDZ domain-containing protein 8 (PDZD8) in a previously unreported pedigree with punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) to confirm that the PRDX3 mutation c.568G>C is the genetic basis of PPPCD.
METHODS: Ophthalmologic examination of the proband and her affected father was performed with slit lamp biomicroscopy. Saliva was collected from the proband as a source of DNA, after which screening for PRDX3 and PDZD8 was performed.
RESULTS: Slit lamp examination of the proband revealed polychromatic deposits diffusely distributed at the pre-Descemet level in both corneas and anterior subcapsular in the crystalline lens of both eyes. The proband\'s father also demonstrated diffuse pre-Descemetic polychromatic deposits in both eyes but no lenticular deposits. Screening of PRDX3 in the proband demonstrated the c.568G>C (p.Asp190His) variant previously associated with PPPCD and failed to identify any variants in PDZD8.
CONCLUSIONS: We report the initial confirmation of PRDX3 as the genetic basis of PPPCD in a previously unreported pedigree and expand the phenotype of PPPCD to include polychromatic lenticular deposits.