Sulforaphane protects from kidney damage during the release of unilateral ureteral obstruction (RUUO) by activating nuclear factor erythroid 2-related factor 2 (Nrf2): Role of antioxidant, anti-inflammatory, and antiapoptotic mechanisms.

Releasing unilateral ureteral obstruction (RUUO) is the gold standard for decreasing renal damage induced during unilateral ureteral obstruction (UUO); however, the complete recovery after RUUO depends on factors such as the time and severity of obstruction and kidney contralateral compensatory mechanisms. Interestingly, previous studies have shown that kidney damage markers such as oxidative stress, inflammation, and apoptosis are present and even increase after removal obstruction. To date, previous therapeutic strategies have been used to potentiate the recovery of renal function after RUUO; however, the mechanisms involving renal damage reduction are poorly described and sometimes focus on the recovery of renal functionality. Furthermore, using natural antioxidants has not been completely studied in the RUUO model. In this study, we selected sulforaphane (SFN) because it activates the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that induces an antioxidant response, decreasing oxidative stress and inflammation, preventing apoptosis. Thus, we pre-administrated SFN on the second day after UUO until day five, where we released the obstruction on the three days after UUO. Then, we assessed oxidative stress, inflammation, and apoptosis markers. Interestingly, we found that SFN administration in the RUUO model activated Nrf2, inducing its translocation to the nucleus to activate its target proteins. Thus, the Nrf2 activation upregulated glutathione (GSH) content and the antioxidant enzymes catalase, glutathione peroxidase (GPx), and glutathione reductase (GR), which reduced the oxidative stress markers. Moreover, the improvement of antioxidant response by SFN restored S-glutathionylation in the mitochondrial fraction. Activated Nrf2 also reduced inflammation by lessening the nucleotide-binding domain-like receptor family pyrin domain containing 3 and interleukin 1ß (IL-1ß) production. Reducing oxidative stress and inflammation prevented apoptosis by avoiding caspase 3 cleavage and increasing B-cell lymphoma 2 (Bcl2) levels. Taken together, the obtained results in our study showed that the upregulation of Nrf2 by SFN decreases oxidative stress, preventing inflammation and apoptosis cell death during the release of UUO.

Human Papilloma Virus-Infected Cells.

Human papillomavirus (HPV) is associated with infection of different tissues, such as the cervix, anus, vagina, penis, vulva, oropharynx, throat, tonsils, back of the tongue, skin, the lungs, among other tissues. HPV infection may or may not be associated with the development of cancer, where HPVs not related to cancer are defined as low-risk HPVs and are associated with papillomatosis disease. In contrast, high-risk HPVs (HR-HPVs) are associated with developing cancers in areas that HR-HPV infects, such as the cervix. In general, infection of HPV target cells is regulated by specific molecules and receptors that induce various conformational changes of HPV capsid proteins, allowing activation of HPV endocytosis mechanisms and the arrival of the HPV genome to the human cell nucleus. After the transcription of the HPV genome, the HPV genome duplicates exponentially to lodge in a new HPV capsid, inducing the process of exocytosis of HPV virions and thus releasing a new HPV viral particle with a high potential of infection. This infection process allows the HPV viral life cycle to conclude and enables the growth of HPV virions. Understanding the entire infection process has been a topic that researchers have studied and developed for decades; however, there are many things to still understand about HPV infection. A thorough understanding of these HPV infection processes will allow new potential treatments for HPV-associated cancer and papillomatosis. This chapter focuses on HPV infection, the process that will enable HPV to complete its HPV life cycle, emphasizing the critical role of different molecules in allowing this infection and its completion during the HPV viral life cycle.

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.

Mitochondrial transplantation strategies in multifaceted induction of cancer cell death.

Otto Warburg hypothesized that some cancer cells reprogram their metabolism, favoring glucose metabolism by anaerobic glycolysis (Warburg effect) instead of oxidative phosphorylation, mainly because the mitochondria of these cells were damaged or dysfunctional. It should be noted that mitochondrial apoptosis is decreased because of the dysfunctional mitochondria. Strategies like mitochondrial transplantation therapy, where functional mitochondria are transplanted to cancer cells, could increase cell death, such as apoptosis, because the intrinsic apoptosis mechanisms would be reactivated. In addition, mitochondrial transplantation is associated with the redox state, which could promote synergy with common anticancer treatments such as ionizing radiation, chemotherapy, or radiotherapy, increasing cell death due to the presence or decrease of oxidative stress. On the other hand, mitochondrial transfer, a natural process for sharing mitochondrial between cells, induces an increase in chemoresistance and invasiveness in cancer cells that receive mitochondria from cells of the tumor microenvironment (TME), which indicates an antitumor therapeutic target. This review focuses on understanding mitochondrial transplantation as a therapeutic outcome induced by a procedure in aspects including oxidative stress, metabolism shifting, mitochondrial function, auto-/mitophagy, invasiveness, and chemoresistance. It also explores how these mechanisms, such as apoptosis, necroptosis, and parthanatos, impact cell death pathways. Finally, it discusses the chemoresistance and invasiveness in cancer cells associated with mitochondria transfer, indicating an antitumor therapeutic target.

Quercetin and Ferroptosis.

Quercetin is a flavonoid present in apples, onions, tea, red wines, and berries, and it has shown different beneficial effects, such as providing cardiovascular protection, possessing anti-inflammatory properties, and demonstrating anticancer activity, among others. These diseases are related to oxidizing molecules such as ROS because these species react and induce the oxidation of cellular biomolecules, such as proteins, lipids, DNA, or carbohydrates, which alters cellular homeostasis. Regarding lipids, the oxidation of these molecules induces lipid hydroperoxides which, if not decreased, particularly by GPX4, produce highly reactive aldehydes such as 4HNE and MDA. These oxidative conditions induce ferroptosis, a type of cell death associated with oxidation that differs from other types of cell death, such as apoptosis, necrosis, or autophagy. The induction of ferroptosis is desired in some diseases, such as cancer, but in others, such as cardiovascular diseases, this type of cell death is not wanted. The possible effects of quercetin associated with reducing or inducing ferroptosis have not been reviewed. Thus, this review focuses on the ability of quercetin to produce ferroptosis in diseases such as cancer as a treatment option and, conversely, on its role in deactivating ferroptosis to alleviate diseases such as cardiovascular diseases.

Assessment of Kidney Mitochondrial Function by High-Resolution Respirometry, Transmission Electron Microscopy, and Histological Techniques.

Proper kidney function depends highly on mitochondria homeostasis. This organelle is the primary source of ATP production in the kidney and regulates other cellular processes such as redox and calcium homeostasis. Although the mitochondria's primary recognized function is cellular energy production, through the function of the Krebs cycle, electron transport system (ETS), as well as oxygen and electrochemical gradient consumption, this function is interconnected with multiple signaling and metabolic pathways, making bioenergetics a central hub in renal metabolism. Furthermore, mitochondrial biogenesis, dynamics, and mass are also strongly related to bioenergetics. This central role is not surprising given that mitochondrial impairment, including functional and structural alterations, has been recently reported in several kidney diseases. Here, we describe assessment of mitochondrial mass, structure, and bioenergetics in kidney tissue and renal-derived cell lines. These methods allow investigation of mitochondrial alterations in kidney tissue and renal cells under different experimental conditions.

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.

The Development of Dyslipidemia in Chronic Kidney Disease and Associated Cardiovascular Damage, and the Protective Effects of Curcuminoids.

Chronic kidney disease (CKD) is a health problem that is constantly growing. This disease presents a diverse symptomatology that implies complex therapeutic management. One of its characteristic symptoms is dyslipidemia, which becomes a risk factor for developing cardiovascular diseases and increases the mortality of CKD patients. Various drugs, particularly those used for dyslipidemia, consumed in the course of CKD lead to side effects that delay the patient's recovery. Therefore, it is necessary to implement new therapies with natural compounds, such as curcuminoids (derived from the Curcuma longa plant), which can cushion the damage caused by the excessive use of medications. This manuscript aims to review the current evidence on the use of curcuminoids on dyslipidemia in CKD and CKD-induced cardiovascular disease (CVD). We first described oxidative stress, inflammation, fibrosis, and metabolic reprogramming as factors that induce dyslipidemia in CKD and their association with CVD development. We proposed the potential use of curcuminoids in CKD and their utilization in clinics to treat CKD-dyslipidemia.

Targeting Mitochondrial Therapy in the Regulation of HPV Infection and HPV-Related Cancers.

It has been previously proposed that some types of cancer cells reprogram their metabolic pathways, favoring the metabolism of glucose by aerobic glycolysis (Warburg effect) instead of oxidative phosphorylation, mainly because the mitochondria of these cells are damaged, thus displaying mitochondrial dysfunction. However, in several cancers, the mitochondria do not exhibit any dysfunction and are also necessary for the tumor's growth and maintenance. Remarkably, if the mitochondria are dysfunctional, specific processes associated with the release of cytochrome c (cyt c), such as apoptosis, are significantly impaired. In these cases, cellular biotherapies such as mitochondrial transplantation could restore the intrinsic apoptotic processes necessary for the elimination of cancers. On the other hand, if the mitochondria are in good shape, drugs that target the mitochondria are a valid option for treating the related cancers. Famously, the mitochondria are targeted by the human papillomavirus (HPV), and HPV-related cancers depend on the host's mitochondria for their development and progression. On the other hand, the mitochondria are also important during treatment, such as chemotherapy, since they are key organelles for the increase in reactive oxygen species (ROS), which significantly increases cell death due to the presence of oxidative stress (OS). In this way, the mitochondria in HPV infection and in the development of HPV-related cancer could be targeted to reduce or eliminate HPV infections or HPV-related cancers. To our knowledge, there was no previous review specifically focusing on this topic, so this work aimed to summarize for the first time the potential use of mitochondria-targeting drugs, providing molecular insights on the main therapeutics developed so far in HPV infection and HPV-related cancer. Thus, we reviewed the mechanisms associated with HPV-related cancers, with their early proteins and mitochondrial apoptosis specifically induced by different compounds or drugs, in which these molecules induce the production of ROS, the activation of proapoptotic proteins, the deactivation of antiapoptotic proteins, the loss of mitochondrial membrane potential (Δψm), cyt c release, and the activation of caspases, which are all events which lead to the activation of mitochondrial apoptosis pathways. This makes these compounds and drugs potential anticancer therapeutics that target the mitochondria and could be exploited in future biomedical strategies.

Therapeutic Effect of Curcumin on 5/6Nx Hypertriglyceridemia: Association with the Improvement of Renal Mitochondrial ß-Oxidation and Lipid Metabolism in Kidney and Liver.

Chronic kidney disease (CKD) prevalence is constantly increasing, and dyslipidemia in this disease is characteristic, favoring cardiovascular events. However, the mechanisms of CKD dyslipidemia are not fully understood. The use of curcumin (CUR) in CKD models such as 5/6 nephrectomy (5/6Nx) has shown multiple beneficial effects, so it has been proposed to correct dyslipidemia without side effects. This work aimed to characterize CUR's potential therapeutic effect on dyslipidemia and alterations in lipid metabolism and mitochondrial ß-oxidation in the liver and kidney in 5/6Nx. Male Wistar rats were subjected to 5/6Nx and progressed by 4 weeks; meanwhile, CUR (120 mg/kg) was administered for weeks 5 to 8. Our results showed that CUR reversed the increase in liver and kidney damage and hypertriglyceridemia induced by 5/6Nx. CUR also reversed mitochondrial membrane depolarization and ß-oxidation disorders in the kidney and the increased lipid uptake and the high levels of proteins involved in fatty acid synthesis in the liver and kidney. CUR also decreased lipogenesis and increased mitochondrial biogenesis markers in the liver. Therefore, we concluded that the therapeutic effect of curcumin on 5/6Nx hypertriglyceridemia is associated with the restoration of renal mitochondrial ß-oxidation and the reduction in lipid synthesis and uptake in the kidneys and liver.

Sulforaphane Protects against Unilateral Ureteral Obstruction-Induced Renal Damage in Rats by Alleviating Mitochondrial and Lipid Metabolism Impairment.

Unilateral ureteral obstruction (UUO) is an animal rodent model that allows the study of obstructive nephropathy in an accelerated manner. During UUO, tubular damage is induced, and alterations such as oxidative stress, inflammation, lipid metabolism, and mitochondrial impairment favor fibrosis development, leading to chronic kidney disease progression. Sulforaphane (SFN), an isothiocyanate derived from green cruciferous vegetables, might improve mitochondrial functions and lipid metabolism; however, its role in UUO has been poorly explored. Therefore, we aimed to determine the protective effect of SFN related to mitochondria and lipid metabolism in UUO. Our results showed that in UUO SFN decreased renal damage, attributed to increased mitochondrial biogenesis. We showed that SFN augmented peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and nuclear respiratory factor 1 (NRF1). The increase in biogenesis augmented the mitochondrial mass marker voltage-dependent anion channel (VDAC) and improved mitochondrial structure, as well as complex III (CIII), aconitase 2 (ACO2) and citrate synthase activities in UUO. In addition, lipid metabolism was improved, observed by the downregulation of cluster of differentiation 36 (CD36), sterol regulatory-element binding protein 1 (SREBP1), fatty acid synthase (FASN), and diacylglycerol O-acyltransferase 1 (DGAT1), which reduces triglyceride (TG) accumulation. Finally, restoring the mitochondrial structure reduced excessive fission by decreasing the fission protein dynamin-related protein-1 (DRP1). Autophagy flux was further restored by reducing beclin and sequestosome (p62) and increasing B-cell lymphoma 2 (Bcl2) and the ratio of microtubule-associated proteins 1A/1B light chain 3 II and I (LC3II/LC3I). These results reveal that SFN confers protection against UUO-induced kidney injury by targeting mitochondrial biogenesis, which also improves lipid metabolism.

Expression Profiles of Kidney Mitochondrial Proteome during the Progression of the Unilateral Ureteral Obstruction: Focus on Energy Metabolism Adaptions.

Kidney diseases encompass many pathologies, including obstructive nephropathy (ON), a common clinical condition caused by different etiologies such as urolithiasis, prostatic hyperplasia in males, tumors, congenital stenosis, and others. Unilateral ureteral obstruction (UUO) in rodents is an experimental model widely used to explore the pathophysiology of ON, replicating vascular alterations, tubular atrophy, inflammation, and fibrosis development. In addition, due to the kidney's high energetic demand, mitochondrial function has gained great attention, as morphological and functional alterations have been demonstrated in kidney diseases. Here we explore the kidney mitochondrial proteome differences during a time course of 7, 14, and 21 days after the UUO in rats, revealing changes in proteins involved in three main metabolic pathways, oxidative phosphorylation (OXPHOS), the tricarboxylic acid cycle (TCA), and the fatty acid (FA) metabolism, all of them related to bioenergetics. Our results provide new insight into the mechanisms involved in metabolic adaptations triggered by the alterations in kidney mitochondrial proteome during the ON.

Pathological Similarities in the Development of Papillomavirus-Associated Cancer in Humans, Dogs, and Cats.

Canis familiaris, Felis catus, and human papillomavirus are nonenveloped viruses that share similarities in the initiation and development of cancer. For instance, the three species overexpress the oncoproteins E6 and E7, and Canis familiaris and human papillomavirus overexpress the E5 oncoprotein. These similarities in the pathophysiology of cancer among the three species are beneficial for treating cancer in dogs, cats, and humans. To our knowledge, this topic has not been reviewed so far. This review focuses on the information on cancer research in cats and dogs comparable to that being conducted in humans in the context of comparative pathology and biomarkers in canine, feline, and human cancer. We also focus on the possible benefit of treatment associated with the E5, E6, and E7 oncoproteins for cancer in dogs, cats, and humans.

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.

Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls.

The nuclear factor erythroid 2-related factor 2 (Nrf2) protects the cell against oxidative damage. The Nrf2 system comprises a complex network that functions to ensure adequate responses to redox perturbations, but also metabolic demands and cellular stresses. It must be kept within a physiologic activity range. Oxidative stress and alterations in Nrf2-system activity are central for chronic-kidney-disease (CKD) progression and CKD-related morbidity. Activation of the Nrf2 system in CKD is in multiple ways related to inflammation, kidney fibrosis, and mitochondrial and metabolic effects. In human CKD, both endogenous Nrf2 activation and repression exist. The state of the Nrf2 system varies with the cause of kidney disease, comorbidities, stage of CKD, and severity of uremic toxin accumulation and inflammation. An earlier CKD stage, rapid progression of kidney disease, and inflammatory processes are associated with more robust Nrf2-system activation. Advanced CKD is associated with stronger Nrf2-system repression. Nrf2 activation is related to oxidative stress and moderate uremic toxin and nuclear factor kappa B (NF-κB) elevations. Nrf2 repression relates to high uremic toxin and NF-κB concentrations, and may be related to Kelch-like ECH-associated protein 1 (Keap1)-independent Nrf2 degradation. Furthermore, we review the effects of pharmacological Nrf2 activation by bardoxolone methyl, curcumin, and resveratrol in human CKD and outline strategies for how to adapt future Nrf2-targeted therapies to the requirements of patients with CKD.

Renal damage induced by cadmium and its possible therapy by mitochondrial transplantation.

Cadmium (Cd) is one of the most toxic metals without biological function, and its accumulation in living organisms has been reported. The kidney is a target organ in Cd toxicity; it has been observed that Cd causes kidney damage even at low concentrations, and Cd damage can quickly progress to chronic kidney disease. The mitochondria play a fundamental role in the nephrotoxicity of Cd; Cd enters the mitochondria and affects the electron transport system (ETS), increases the production of reactive oxygen species (ROS), decreases the mitochondrial membrane potential (Δψm), alters mitochondrial dynamics, induces mutations in mitochondrial deoxyribonucleic acid (mtDNA) and decreased biogenesis leading to increased mitophagy, autophagy, and inevitably apoptosis. Existing therapies to treat Cd nephrotoxicity are currently based on antioxidant and chelating compounds, but despite their promising effects, they have some limitations; therefore, Cd nephrotoxicity continues to represent a global health problem. Mitochondrial transplantation is a new experimental approach with positive results by reversing mitochondrial alterations in cardiac and kidney dysfunction mainly caused by oxidative stress. Hence, the current review discusses the role of mitochondria in Cd-induced toxicity in the kidney and proposes mitochondrial transference as a novel therapy based on transplanting healthy mitochondria to cells with Cd-compromised mitochondria. This review is the first to propose mitochondrial transplantation as a treatment for heavy metal-induced kidney damage.

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.

Involvement of Inflammasome Components in Kidney Disease.

Inflammasomes are multiprotein complexes with an important role in the innate immune response. Canonical activation of inflammasomes results in caspase-1 activation and maturation of cytokines interleukin-1ß and -18. These cytokines can elicit their effects through receptor activation, both locally within a certain tissue and systemically. Animal models of kidney diseases have shown inflammasome involvement in inflammation, pyroptosis and fibrosis. In particular, the inflammasome component nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) and related canonical mechanisms have been investigated. However, it has become increasingly clear that other inflammasome components are also of importance in kidney disease. Moreover, it is becoming obvious that the range of molecular interaction partners of inflammasome components in kidney diseases is wide. This review provides insights into these current areas of research, with special emphasis on the interaction of inflammasome components and redox signalling, endoplasmic reticulum stress, and mitochondrial function. We present our findings separately for acute kidney injury and chronic kidney disease. As we strictly divided the results into preclinical and clinical data, this review enables comparison of results from those complementary research specialities. However, it also reveals that knowledge gaps exist, especially in clinical acute kidney injury inflammasome research. Furthermore, patient comorbidities and treatments seem important drivers of inflammasome component alterations in human kidney disease.

Extracellular Vesicles in Redox Signaling and Metabolic Regulation in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a world health problem increasing dramatically. The onset of CKD is driven by several mechanisms; among them, metabolic reprogramming and changes in redox signaling play critical roles in the advancement of inflammation and the subsequent fibrosis, common pathologies observed in all forms of CKD. Extracellular vesicles (EVs) are cell-derived membrane packages strongly associated with cell-cell communication since they transfer several biomolecules that serve as mediators in redox signaling and metabolic reprogramming in the recipient cells. Recent studies suggest that EVs, especially exosomes, the smallest subtype of EVs, play a fundamental role in spreading renal injury in CKD. Therefore, this review summarizes the current information about EVs and their cargos' participation in metabolic reprogramming and mitochondrial impairment in CKD and their role in redox signaling changes. Finally, we analyze the effects of these EV-induced changes in the amplification of inflammatory and fibrotic processes in the progression of CKD. Furthermore, the data suggest that the identification of the signaling pathways involved in the release of EVs and their cargo under pathological renal conditions can allow the identification of new possible targets of injury spread, with the goal of preventing CKD progression.

GK-1 Induces Oxidative Stress, Mitochondrial Dysfunction, Decreased Membrane Potential, and Impaired Autophagy Flux in a Mouse Model of Breast Cancer.

Breast cancer (BC) is the second most common cancer worldwide in women. During the last decades, the mortality due to breast cancer has progressively decreased due to early diagnosis and the emergence of more effective new treatments. However, human epidermal growth factor receptor 2 (HER2) and triple-negative breast cancer (TNBC) remain with poor prognoses. In our research group, we are proposing the GK-1 immunomodulatory peptide as a new alternative for immunotherapy of these aggressive tumors. GK-1 reduced the growth rate of established tumors and effectively reduced lung metastasis in the 4T1 experimental murine model of breast cancer. Herein, the effect of GK-1 on the redox state, mitochondrial metabolism, and autophagy of triple-negative tumors that can be linked to cancer evolution was studied. GK-1 decreased catalase activity, reduced glutathione (GSH) content and GSH/oxidized glutathione (GSSG) ratio while increased hydrogen peroxide (H2O2) production, GSSG, and protein carbonyl content, inducing oxidative stress (OS) in tumoral tissues. This imbalance between reactive oxygen species (ROS) and antioxidants was related to mitochondrial dysfunction and uncoupling, characterized by reduced mitochondrial respiratory parameters and dissipation of mitochondrial membrane potential (ΔΨm), respectively. Furthermore, GK-1 likely affected autophagy flux, confirmed by elevated levels of p62, a marker of autophagy flux. Overall, the induction of OS, dysfunction, and uncoupling of the mitochondria and the reduction of autophagy could be molecular mechanisms that underlie the reduction of the 4T1 breast cancer induced by GK-1.