Cobalt protoporphyrin modulates antioxidant enzyme activity in the hypothalamus and motor cortex of female rats.

Cobalt protoporphyrin (CoPP) is a synthetic heme analog that has been observed to reduce food intake and promote sustained weight loss. While the precise mechanisms responsible for these effects remain elusive, earlier research has hinted at the potential involvement of nitric oxide synthase in the hypothalamus. This study aimed to delve into CoPP's impact on the activities of crucial antioxidant enzymes: superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) across seven distinct brain regions (hippocampus, hypothalamus, prefrontal cortex, motor cortex, striatum, midbrain, and cerebellum), as well as in the liver and kidneys. Female Wistar rats weighing 180 to 200 grams received a single subcutaneous dose of 25 µmol/kg CoPP. After six days, brain tissue was extracted to assess the activities of antioxidant enzymes and quantify malondialdehyde levels. Our findings confirm that CoPP administration triggers the characteristic effects of decreased food intake and reduced body weight. Moreover, it led to an increase in SOD activity in the hypothalamus, a pivotal brain region associated with food intake regulation. Notably, CoPP-treated rats exhibited elevated enzymatic activity of catalase, GR, and GST in the motor cortex without concurrent signs of heightened oxidative stress. These results underscore a strong connection between the antioxidant system and food intake regulation. They also emphasize the need for further investigation into the roles of antioxidant enzymes in modulating food intake and the ensuing weight loss, using CoPP as a valuable research tool.

Selenium in combination with a tomato lipid extract as a therapy for benign prostatic hyperplasia and its alterations in rats with induced BPH.

Benign prostatic hyperplasia (BPH) is the most common adenoma in old men. Tomatoes are a rich source of bioactive compounds that, as well as selenium (Se), possess antioxidant and antiproliferative activity. The aim was to evaluate the therapeutic effect of Se in combination with a tomato extract in aged rats with BPH. Aged male Wistar rats were divided in the following groups (n = 10 rats/group): Control (C), BPH, BPH + Finasteride (BPH + F), BPH + Tomato Lipidic Extract (BPH + E), BPH + Selenium (BPH + S) and BPH plus E plus S (BPH + E + S). After 4 weeks of treatment, prostate weight, diuresis, antioxidants enzymes, prooxidants and inflammatory markers, growth factors and androgens were determined. BPH + E + S reduced prostate weight by 59.29% and inhibited growth by 99.35% compared to BPH + F which only decreased weight and inhibited growth by 15.31% and 57.54%, respectively. Prooxidant markers were higher with BPH + F (49.4% higher vs. BPH), but BPH + E + S decreased these markers (94.27% vs. BPH) and increased antioxidant activity. Finally, diuresis was higher with the BPH + E + S combination and markers of inflammation and growth factors were significantly lower with respect to BPH + F. Our findings provide a beneficial and protective therapeutic option of E + S directed against androgens, oxidative stress and inflammation that regulates cell proliferation in the prostate gland.

Magnesium (Mg2+) Deficiency, Not Well-Recognized Non-Infectious Pandemic: Origin and Consequence of Chronic Inflammatory and Oxidative Stress-Associated Diseases.

Magnesium (Mg2+) is an essential mineral nutrient, necessary for many biochemical reactions in the human body, including energy metabolism, protein and DNA synthesis, maintenance of the electrical potential of nervous and cardiac tissues, control of blood glucose, and regulation of blood pressure. However, currently, the world population suffers from a severe problem because the consumption of Mg2+ in the diet is deficient and generalized in the populations. Mg2+ deficiency causes oxidative stress (OS) due to the increase in reactive oxygen species (ROS) that originate from mitochondrial dysfunction, activation of the renin-angiotensin-aldosterone system (RAAS), and abnormal regulation of calcium homeostasis. In addition, Mg2+ deficiency also causes inflammation by increasing the production of proinflammatory molecules such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-α), which in turn can exacerbate the production of ROS. The combination of inflammation and OS induced by Mg2+ deficiency increases the risk of developing chronic diseases. This review describes Mg2+ deficiency, its complications, and its relationship with OS and chronic inflammatory diseases. In addition, the importance of increasing the intake of Mg2+ throughout the world is highlighted.

Tomato lipidic extract plus selenium decrease prostatic hyperplasia, dihydrotestosterone and androgen receptor expression versus finasteride in rats.

PURPOSE: Evaluate the therapeutic effect of a tomato lipidic extract (STE) in combination with selenium (Se) on rats with prostatic hyperplasia (PH) and to observe its possible mechanisms of action and synergism versus finasteride. MATERIALS AND METHODS: 54 male Wistar rats of nine weeks old were divided in Control (C), PH, Finasteride (F), STE, Se, F + STE, F + Se, STE + Se and F + STE + Se with testosterone enanthate (except C). After 4 weeks of treatment administration, prostate weight, bladder weight, diuresis, prooxidant and antioxidant activity, dihydrotestosterone (DHT), androgen receptor (AR) expression and anatomopathological analysis were determined. RESULTS: STE + Se decreased prostate weight 53.8% versus 28% in F group, also STE + Se decreased significatively glandular hyperplasia, prooxidant activity, DHT and AR expression and increased diuresis and antioxidant activity versus finasteride which increased MDA in prostate. CONCLUSIONS: These results demonstrate a greater therapeutic and beneficial effect of tomato lipidic extract in combination with Se in young rats with PH with respect to finasteride without increase prooxidant activity.

Mechanistic Insights on Pd-Catalyzed Three-Component Reactions of Alkynols, Methyl Orthoformate, and Salicylaldehyde Derivatives. Application to the Synthesis of Steroid Chroman Ketals and Spiroketals with Antioxidant Activity.

Contrary to our previous report in which a Pd-catalyzed three-component reaction of a steroid alkynol, trimethyl orthoformate, and salicylaldehyde exclusively produced chroman ketals, the same reaction employing 2,5-dihydroxysalicylaldehyde led to a mixture of a chroman ketal and a spiroketal. Provided that both courses of the reaction imply a 4 + 2 inverse demand cycloaddition between an o-quinone methide and an enol ether, density functional theory calculations revealed that the chroman ketal/spiroketal selectivity is governed by both, the rate of the formation of the o-quinone methide and the isomerization of the initially produced exocyclic enol ether─that led to the spiroketal─to its endocyclic partner that produces the chroman ketal. Remarkably, Lewis catalysis is central to the observed reactivity, and the availability of plausible catalytic species controls the overall chemoselectivity. The methodology herein applied and scrutinized enriches the palette of reactions, leading to increased molecular complexity, as demonstrated in the obtained products, whose antioxidant activity and detailed NMR characterization are presented.

Nuclear factor erythroid 2-related factor 2 in human papillomavirus-related cancers.

High-risk human papillomavirus (HR-HPV) infection is a necessary cause for the development of cervical cancer. Moreover, HR-HPV is also associated with cancers in the anus, vagina, vulva, penis and oropharynx. HR-HPVs target and modify the function of different cell biomolecules, such as glucose, amino acids, lipids and transcription factors (TF), such as p53, nuclear factor erythroid 2-related factor 2 (Nrf2), among others. The latter is a master TF that maintains redox homeostasis. Nrf2 also induces the transcription of genes associated with cell detoxification. Since both processes are critical for cell physiology, Nrf2 deregulation is associated with cancer development. Nrf2 is a crucial molecule in HPV-related cancer development but underexplored. Moreover, Nrf2 activation is also associated with resistance to chemotherapy and radiotherapy in these cancers. This review focusses on the importance of Nrf2 during HPV-related cancer development, resistance to therapy and potential therapies associated with Nrf2 as a molecular target.

Antioxidant/anti-inflammatory effect of Mg2+ in coronavirus disease 2019 (COVID-19).

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), characterised by high levels of inflammation and oxidative stress (OS). Oxidative stress induces oxidative damage to lipids, proteins, and DNA, causing tissue damage. Both inflammation and OS contribute to multi-organ failure in severe cases. Magnesium (Mg2+ ) regulates many processes, including antioxidant and anti-inflammatory responses, as well as the proper functioning of other micronutrients such as vitamin D. In addition, Mg2+ participates as a second signalling messenger in the activation of T cells. Therefore, Mg2+ deficiency can cause immunodeficiency, exaggerated acute inflammatory response, decreased antioxidant response, and OS. Supplementation with Mg2+ has an anti-inflammatory response by reducing the levels of nuclear factor kappa B (NF-κB), interleukin (IL) -6, and tumor necrosis factor alpha. Furthermore, Mg2+ supplementation improves mitochondrial function and increases the antioxidant glutathione (GSH) content, reducing OS. Therefore, Mg2+ supplementation is a potential way to reduce inflammation and OS, strengthening the immune system to manage COVID-19. This narrative review will address Mg2+ deficiency associated with a worse disease prognosis, Mg2+ supplementation as a potent antioxidant and anti-inflammatory therapy during and after COVID-19 disease, and suggest that randomised controlled trials are indicated.

Isoliquiritigenin pretreatment regulates ER stress and attenuates cisplatin-induced nephrotoxicity in male Wistar rats.

Cisplatin (CP) is a chemotherapeutic drug used to treat solid tumors. However, studies have revealed its nephrotoxic effect. Oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction are involved in CP-induced renal damage. Thus, preconditioning (hormetic effect) of ER stress is a strategy to prevent CP-induced renal damage. On the other hand, isoliquiritigenin (IsoLQ) is recognized as a flavonoid with antioxidant properties and an inducer of ER stress. Therefore, we evaluated the ER stress-inducing capacity of IsoLQ and its possible protective effect against CP-induced nephrotoxicity in adult male Wistar rats. The findings reflected that IsoLQ pretreatment might decrease renal damage by reducing plasma creatinine and blood urea nitrogen levels in animals with CP-induced nephrotoxicity. These may be associated with IsoLQ activating ER stress and unfolded protein response (UPR). We found increased messenger RNA levels of the ER stress marker glucose-related protein 78 kDa (GRP78). In addition, we also found that pretreatment with IsoLQ reduced the levels of CCAAT/enhancer-binding protein-homologous protein (CHOP) and X-box-binding protein 1 (XBP1) in the renal cortex, reflecting that IsoLQ can regulate the UPR and activation of the apoptotic pathway. Moreover, this preconditioning with IsoLQ of ER stress had oxidative stress-regulatory effects, as it restored the activity of glutathione peroxidase and glutathione reductase enzymes. Finally, IsoLQ modifies the protein expression of mitofusin 2 (Mfn-2) and voltage-dependent anion channel (VDAC). In conclusion, these data suggest that IsoLQ pretreatment has a nephroprotective effect; it could functionally regulate the ER and mitochondria and reduce CP-induced renal damage by attenuating hormesis-mediated ER stress.

α-Mangostin induces oxidative damage, mitochondrial dysfunction, and apoptosis in a triple-negative breast cancer model.

Triple-negative breast cancer (TNBC) does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor; therefore, TNBC lacks targeted therapy, and chemotherapy is the only available treatment for this illness but causes side effects. A putative strategy for the treatment of TNBC could be the use of the polyphenols such as α-Mangostin (α-M), which has shown anticancerogenic effects in different cancer models and can modulate the inflammatory and prooxidant state in several pathological models. The redox state, oxidative stress (OS), and oxidative damage are highly related to cancer development and its treatment. Thus, this study aimed to evaluate the effects of α-M on redox state, mitochondrial metabolism, and apoptosis in 4T1 mammary carcinoma cells. We found that α-M decreases both protein levels and enzymatic activity of catalase, and increases reactive oxygen species, oxidized proteins and glutathione disulfide, which demonstrates that α-M induces oxidative damage. We also found that α-M promotes mitochondrial dysfunction by abating basal respiration, the respiration ligated to oxidative phosphorylation (OXPHOS), and the rate control of whole 4T1 cells. Additionally, α-M also decreases the levels of OXPHOS subunits of mitochondrial complexes I, II, III, and adenosine triphosphate synthase, the activity of mitochondrial complex I as well as the levels of peroxisome proliferator-activated receptor-gamma co-activator 1α, showing a mitochondrial mass reduction. Then, oxidative damage and mitochondrial dysfunction induced by α-M induce apoptosis of 4T1 cells, which is evidenced by B cell lymphoma 2 decrease and caspase 3 cleavage. Taken together, our results suggest that α-M induces OS and mitochondrial dysfunction, resulting in 4T1 cell death through apoptotic mechanisms.

Effect of Resveratrol on Markers of Oxidative Stress and Sirtuin 1 in Elderly Adults with Type 2 Diabetes.

Type 2 diabetes (T2D) affects a large part of the adult population and impairs its quality of life. Because of this, natural compounds with antioxidant, anti-inflammatory and hypoglycemic properties have been used as adjuvants. Among these compounds, resveratrol (RV) stands out, a polyphenol that has been studied in several clinical trials, the results of which are controversial. We conducted a randomized clinical trial on 97 older adults with T2D to evaluate the effect of RV on oxidative stress markers and sirtuin 1, using doses of 1000 mg/day (EG1000, n = 37) and 500 mg/day (EG500, n = 32) compared with a placebo (PG, n = 28). Biochemical markers, oxidative stress and sirtuin 1 levels were measured at baseline and after six months. We observed a statistically significant increase (p < 0.05) in total antioxidant capacity, antioxidant gap, the percentage of subjects without oxidant stress and sirtuin 1 levels in EG1000. In the PG, we observed a significant increase (p < 0.05) in lipoperoxides, isoprostanes and C-reactive protein levels. An increase in the oxidative stress score and in the percentage of subjects with mild and moderate oxidative stress was observed too. Our findings suggest that 1000 mg/day of RV exerts a more efficient antioxidant effect than 500 mg/day.

Mitochondrial Impairment: A Link for Inflammatory Responses Activation in the Cardiorenal Syndrome Type 4.

Cardiorenal syndrome type 4 (CRS type 4) occurs when chronic kidney disease (CKD) leads to cardiovascular damage, resulting in high morbidity and mortality rates. Mitochondria, vital organelles responsible for essential cellular functions, can become dysfunctional in CKD. This dysfunction can trigger inflammatory responses in distant organs by releasing Damage-associated molecular patterns (DAMPs). These DAMPs are recognized by immune receptors within cells, including Toll-like receptors (TLR) like TLR2, TLR4, and TLR9, the nucleotide-binding domain, leucine-rich-containing family pyrin domain-containing-3 (NLRP3) inflammasome, and the cyclic guanosine monophosphate (cGMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (cGAS-STING) pathway. Activation of these immune receptors leads to the increased expression of cytokines and chemokines. Excessive chemokine stimulation results in the recruitment of inflammatory cells into tissues, causing chronic damage. Experimental studies have demonstrated that chemokines are upregulated in the heart during CKD, contributing to CRS type 4. Conversely, chemokine inhibitors have been shown to reduce chronic inflammation and prevent cardiorenal impairment. However, the molecular connection between mitochondrial DAMPs and inflammatory pathways responsible for chemokine overactivation in CRS type 4 has not been explored. In this review, we delve into mechanistic insights and discuss how various mitochondrial DAMPs released by the kidney during CKD can activate TLRs, NLRP3, and cGAS-STING immune pathways in the heart. This activation leads to the upregulation of chemokines, ultimately culminating in the establishment of CRS type 4. Furthermore, we propose using chemokine inhibitors as potential strategies for preventing CRS type 4.

How Micronutrients Fuel Immune System At the Molecular Level: An Approach to the Immune Response Against Respiratory Viruses.

Viral respiratory infections could range from a common cold to severe pneumonia, and their resolution mainly relies on appropriate immune system function. The widespread popular knowledge that nutritional habits influence immune system function has been demonstrated over the past decades in which increasing scientific evidence unveils certain nutrients as critical drivers of immunity. Micronutrients encompass minerals and vitamins necessary for a broad range of biological processes; since their deficiency could cause several clinical manifestations, such as weakness, growth retardation, and susceptibility to infections; hence, micronutrients represent one of the multiple factors that modulate immune function. Among micronutrients are those that act mainly as antioxidants, regulating gene expression and as a structural part of proteins for their proper function. Here, we review how some of the most recognized micronutrients are participating at the molecular level in each step of the innate and adaptive immune response against viruses focusing on viral respiratory tract infections, such as those caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).

Redox state associated with antitumor and immunomodulatory peptides in cancer.

Cancer, a major public health problem, is the fourth cause of death in the world. While cancer mortality has decreased in recent decades due to more effective treatments, mostly based on improving antitumor immunity, some forms of cancer are resistant to these immunotherapies. A promising approach for cancer treatment involves the administration of antitumor and immunomodulatory peptides. Immunomodulatory peptides have been proved to exert antitumor and immunomodulatory effects by activating immune cells such as cytotoxic T cells, with fewer side-effects. A process closely related to the regulation of the immune system by immunomodulatory antitumor peptides is the modulation of the redox state, which has been poorly studied. This review focuses on the redox state regulated by antitumor and immunomodulatory peptides in cancer development, and on the potential of redox state as a therapy associated with these peptides in cancer treatment.

Protein degradation-associated mechanisms that are affected in Alzheimer´s disease.

Alzheimer's disease (AD) is the most common type of dementia associated with age-related neurodegeneration. Alteration of several molecular mechanisms has been correlated with the progression of AD. In recent years, dysregulation of proteostasis-associated pathways has emerged as a potential risk factor for neurodegenerative diseases. This review investigated the ubiquitin-proteasome system, lysosome-associated degradation, endoplasmic-reticulum-associated degradation, and the formation of advanced glycation end products. These pathways involved in proteostasis have been reported to be altered in AD, suggesting that their study may be critical for identifying new biomarkers and target molecules for AD.

Regulation of autophagy by high- and low-risk human papillomaviruses.

While high-risk human papillomavirus (HR-HPV) infection is related to the development of cervical, vulvar, anal, penile and oropharyngeal cancer, low-risk human papillomavirus (LR-HPV) infection is implicated in about 90% of genital warts, which rarely progress to cancer. The carcinogenic role of HR-HPV is due to the overexpression of HPV E5, E6 and E7 oncoproteins which target and modify cellular proteins implicated in cell proliferation, apoptosis and immortalization. LR-HPV proteins also target and modify some of these processes; however, their oncogenic potential is lower than that of HR-HPV. HR-HPVs have substantial differences with LR-HPVs such as viral integration into the cell genome, induction of p53 and retinoblastoma protein degradation, alternative splicing in HR-HPV E6-E7 open reading frames, among others. In addition, LR-HPV can activate the autophagy process in infected cells while HR-HPV infection deactivates it. However, in cancer HR-HPV might reactivate autophagy in advance stages. Autophagy is a catabolic process that maintains cell homoeostasis by lysosomal degradation and recycling of damaged macromolecules and organelles; nevertheless, depending upon cellular context autophagy may also induce cell death. Therefore, autophagy can contribute either as a promotor or as a suppressor of tumours. In this review, we focus on the role of HR-HPV and LR-HPV in autophagy during viral infection and cancer development. Additionally, we review key regulatory molecules such as microRNAs in HPV present during autophagy, and we emphasize the potential use of cancer treatments associated with autophagy in HPV-related cancers.

Effect of mycobacterial proteins that target mitochondria on the alveolar macrophages activation during Mycobacterium tuberculosis infection.

Purpose of the study: During the early and progressive (late) stages of murine experimental pulmonary tuberculosis, the differential activation of macrophages contributes to disease development by controlling bacterial growth and immune regulation. Mycobacterial proteins P27 and PE_PGRS33 can target the mitochondria of macrophages. This study aims to evaluate the effect of both proteins on macrophage activation during mycobacterial infection. Materials and methods: We assess both proteins for mitochondrial oxygen consumption, and morphological changes, as well as bactericide activity, production of metabolites, cytokines, and activation markers in infected MQs. The cell line MH-S was used for all the experiments. Results: We show that P27 and PE_PGRS33 proteins modified mitochondrial dynamics, oxygen consumption, bacilli growth, cytokine production, and some genes that contribute to macrophage alternative activation and mycobacterial intracellular survival. Conclusions: Our findings showed that these bacterial proteins partially contribute to promoting M2 differentiation by altering mitochondrial metabolic activity.

Food-grade titanium dioxide decreases hematocrit and hemoglobin and increases compulsive-like behavior in male mice.

Food-grade titanium dioxide (E171) is widely used as a food additive, and it is known that after oral consumption, E171 is translocated into the bloodstream reaching the highest titanium level at 6 h. E171 is accumulated in some organs triggering toxicity, but the effects on the blood parameters after oral consumption have been less studied. Recently, evidence shows that oral exposure to E171 induces behavioral signs of anxiety and depression. The relation between blood alterations and psychiatric disorders has been previously demonstrated. However, the oral exposure to E171 effects on alterations in blood parameters and effects linked to alterations in animal behavior has not been explored. In this short communication, we aimed to investigate the effects of E171 on specific blood parameters (hematocrit, hemoglobin, number of erythrocytes, and leukocytes) and anxiety and compulsive-like behavior in males and females orally exposed to ~5 mg/kg for 4 weeks. The results showed that E171 decreased hematocrit and hemoglobin in male but not in female mice while leukocyte and erythrocyte count remained unaltered. Oral consumption of E171 decreased the levels of anxiety-like behavior in females but not in male mice, while compulsive-like behavior was increased in both male and female mice.

Influence of Age and Dose on the Effect of Resveratrol for Glycemic Control in Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis.

Background: Several clinical trials have suggested that resveratrol has hypoglycemic properties; however, there are other studies in which such an effect has not been observed. Methods: We carried out a systematic search in several databases; seventeen studies were selected for the systematic review and fifteen were included in the meta-analysis. Results: Resveratrol decreases glucose levels in subjects aged 45−59 years at doses <250 mg/day (−8.64 mg/dL, p < 0.00001), 250−500 mg/day (−22.24 mg/dL, p = 0.0003), and 500−1000 mg/day (−28.40 mg/dL, p = 0.0008), while in subjects older than 60 years, it only decreases with doses of 250−500 mg/day. Likewise, HbA1c improved in subjects aged 45−59 years with doses of 250−500 mg (−0.60%, p < 0.00001), but not in subjects older than 60 years. Insulin levels improved in subjects aged 45−59 years with doses < 250 mg/day (−0.80 mIU/L, p = 0.0003) and doses of 250−500 mg/day (−5.0 mIU/L, p = 0.0003), although in subjects older than 60 years, they only improved with doses of 250−500 mg/day (−1.79 mIU/L, p = 0.01). On the other hand, HOMA-IR only improved in subjects older than 60 years with doses of 250−500 mg/day (−0.40, p = 0.01). Conclusions: Resveratrol has a statistically significant dose−response effect on glucose concentrations, HbA1c, and insulin levels; however, there is not enough scientific evidence to propose a therapeutic dose.

Electrophilic Modulation of the Superoxide Anion Radical Scavenging Ability of Copper(II) Complexes with 4-Methyl Imidazole.

Three Cu(II) coordination compounds with 4-methyl imidazole were obtained, such as [Cu(C4H6N2)4(NO3)2], [Cu(C4H6N2)4Br2], and [Cu(C4H6N2)4Cl2]. Crystallographic studies confirmed their structural similarity with Cu(II) in the active site of endogenous copper-zinc superoxide dismutase (CuZn-SOD). The superoxide anion radical (O2•-) scavenging activity was evaluated by the non-enzymatic experimental assay and followed the trend [Cu(C4H6N2)4(NO3)2] > [Cu(C4H6N2)4Br2] > [Cu(C4H6N2)4Cl2]. The density functional theory and the hard and soft acids and bases principle showed the importance of the electron-deficient character of Cu(II) in the chemical reactivity of the coordination compounds; Cu(II) is the softest site in the molecule and it is preferred for the nucleophilic and radical attacks of the soft O2•-. A simple rule was obtained: "the electron-deficient character of Cu(II) is the key index for the O2•- scavenging activity and is modulated by the electron-releasing counteranion effect on the coordination compound".

Mitochondrial Dysfunction and Alterations in Mitochondrial Permeability Transition Pore (mPTP) Contribute to Apoptosis Resistance in Idiopathic Pulmonary Fibrosis Fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by increased activation of fibroblasts/myofibroblasts. Previous reports have shown that IPF fibroblasts are resistant to apoptosis, but the mechanisms remain unclear. Since inhibition of the mitochondrial permeability transition pore (mPTP) has been implicated in the resistance to apoptosis, in this study, we analyzed the role of mitochondrial function and the mPTP on the apoptosis resistance of IPF fibroblasts under basal conditions and after mitomycin C-induced apoptosis. We measured the release of cytochrome c, mPTP opening, mitochondrial calcium release, oxygen consumption, mitochondrial membrane potential, ADP/ATP ratio, ATP concentration, and mitochondrial morphology. We found that IPF fibroblasts were resistant to mitomycin C-induced apoptosis and that calcium, a well-established activator of mPTP, is decreased as well as the release of pro-apoptotic proteins such as cytochrome c. Likewise, IPF fibroblasts showed decreased mitochondrial function, while mPTP was less sensitive to ionomycin-induced opening. Although IPF fibroblasts did not present changes in the mitochondrial membrane potential, we found a fragmented mitochondrial network with scarce, thinned, and disordered mitochondria with reduced ATP levels. Our findings demonstrate that IPF fibroblasts are resistant to mitomycin C-induced apoptosis and that altered mPTP opening contributes to this resistance. In addition, IPF fibroblasts show mitochondrial dysfunction evidenced by a decrease in respiratory parameters.