Recent HPV self-sampling use for cervical cancer screening in Latin America and Caribbean: a systematic review.

Objective: Cervical cancer is one of the deadliest cancers among women in Latin America and Caribbean (LAC), where most of the countries have not been successful in implementing population-level cytology-based screening programs. An increasing body of evidence supports the validity of self-sampling as an alternative to clinician collection for primary Human papillomavirus (HPV) screening. Therefore, this work aims to summarize recent HPV self-sampling approaches in LAC. Method: We performed a systematic review to identify studies focused on "Self-sampling", and "Human Papillomavirus DNA test" and "Latin America" in PubMed, Embase, Web of Science, Cochrane library and SCOPUS databases for publications dating between 01 January 2017 and 15 March 2022 based on the Preferred Reporting Items for systematic reviews and meta-analysis (PRISMA) statement. Additionally, the references of the articles were carefully reviewed. Results: Of the 97 records selected, 20 studies including 163,787 participants, with sample sizes for individual studies ranging from 24 to 147,590 were included in this review. Studies were conducted in 10 LAC countries (18.5%), most with upper medium-income economies (70%). The range of age was 18 to ≥65 years. The vast majority of the studies (85%) addressed the HPV self-sampling strategy for primary cervical cancer screening with overall success for all women including under/never screened and those from special populations (rural, indigenous and gender minorities). Women generally found HPV self-sampling highly acceptable regardless of age, setting of collection, target population or country of residence. Conclusions: HPV self-sampling is a promising strategy to overcome the multiple barriers to cervical cancer screening in LAC settings and increasing attendance in underscreened women in countries/territories with well-established screening programs. Furthermore, this strategy is useful even in LAC countries/territories without organized cervical cancer screening and in special populations such as indigenous, rural and transgender women. Therefore, the information generated by the recent initiatives for HPV self-sampling approach in LAC can be beneficial for decision-making in both new and existing programs in the region.

Effects of hypericin encapsulated on Pluronic F127 photodynamic therapy against triple negative breast cancer.

OBJECTIVE: Breast cancer (BC) currently has no effective treatment especially for the highly aggressive and metastatic triple negative breast cancer (TNBC). Here, we investigated the antitumoral and antimigratory effects of hypericin (HYP) encapsulated on Pluronic F127 (F127/HYP) photodynamic therapy (PDT) against TNBC cell line MDA-MB-231 compared to a nontumorigenic human breast ductal cell line (MCF-10A). METHODS: The phototoxicity/cytotoxicity was assessed by MTT assay, long-term cytotoxicity by clonogenic assay, cell uptake, subcellular distribution, and cellular oxidative stress by fluorescence microscopy, cell death with annexin V-FITC/propidium iodide, PDT mechanism using sodium azide and D-mannitol, and cell migration by wound-healing assay. RESULTS: The treatment promoted phototoxic effect on tumor cell line in a dose-dependent and selective manner. Internalization of F127/HYP was efficient and accumulation occurred in the endoplasmic reticulum and mitochondria, resulting in cellular oxidative stress mainly by the type II mechanism, induced by necrosis. Furthermore, F127/HYP decreased colony formation and reduced the cell migration ability in MDA-MB-231 cells. CONCLUSION: Our results suggest a potentially useful role of F127/HYP micelles as a platform for HYP delivery to more specifically and effectively treat TNBC.

Phthalocyanine and Its Formulations: A Promising Photosensitizer for Cervical Cancer Phototherapy.

Cervical cancer is one of the most common causes of cancer-related deaths in women worldwide. Despite advances in current therapies, women with advanced or recurrent disease present poor prognosis. Photodynamic therapy (PDT) has emerged as an effective therapeutic alternative to treat oncological diseases such as cervical cancer. Phthalocyanines (Pcs) are considered good photosensitizers (PS) for PDT, although most of them present high levels of aggregation and are lipophilic. Despite many investigations and encouraging results, Pcs have not been approved as PS for PDT of invasive cervical cancer yet. This review presents an overview on the pathophysiology of cervical cancer and summarizes the most recent developments on the physicochemical properties of Pcs and biological results obtained both in vitro in tumor-bearing mice and in clinical tests reported in the last five years. Current evidence indicates that Pcs have potential as pharmaceutical agents for anti-cervical cancer therapy. The authors firmly believe that Pc-based formulations could emerge as a privileged scaffold for the establishment of lead compounds for PDT against different types of cervical cancer.

COVID-19 Infection in the Human Reproductive Tract of Men and Nonpregnant Women.

SARS-CoV-2 is an enveloped non-segmented positive-sense RNA virus, classified as a beta coronavirus, responsible for the COVID-19 pandemic. Angiotensin-converting enzyme 2 (ACE2), reported as a SARS-CoV-2 receptor, is expressed in different human tissues (lung, intestine, and kidney) and in the testis, ovaries, uterus, and vagina. This suggests a potential risk to the human reproductive tract in COVID-19 patients. In addition, SARS-CoV-2 RNA has been detected in the blood, urine, facial/anal swabs, semen, and vaginal secretion, suggesting other potential means of transmission. However, little has been reported about SARS-CoV-2 infection in the male and nonpregnant female reproductive tracts, which may provide direct evidence on sexual transmission and fertility problems. Therefore, we focused this narrative review mainly on the distribution of ACE2 and SARS-CoV-2 positivity in the male and nonpregnant female reproductive tracts, providing an overview of the potential threat of COVID-19 to reproductive health and sexual transmission.

The high-risk human papillomavirus continuum along the female reproductive tract and its relationship to infertility and endometriosis.

RESEARCH QUESTION: Is there an association between the presence of sexually transmitted pathogens in the lower (LGT) and upper (UGT) female genital tract with endometriosis and infertility? DESIGN: Case-control study with 60 women submitted to gynaecological laparoscopic surgery. Samples from the UGT and LGT were collected and analysed by single polymerase chain reaction (PCR) for human papillomavirus (HPV) and by multiplex PCR for other sexually transmitted infections (STI). Patients were initially divided into two clinical groups: infertile patients (n = 25) with conjugal infertility and fertile control patients (n = 35). After the surgical findings patients were further divided for additional analysis: an endometriosis group (n = 29) and non-endometriosis control group (n = 31). RESULTS: Sixty per cent of patients were positive for DNA-HPV in some of the genital tract sites sampled. Infertile patients were associated with high-risk HPV (hrHPV) positivity in the UGT sites (P = 0.027). The endometriosis group was associated with hrHPV positivity in the LGT and UGT sites (P = 0.0002 and P = 0.03, respectively). Only hrHPV types were detected in the UGT in both groups. It may be that there is a hrHPV infection continuum, from LGT to UGT, in infertile and endometriosis patients. No association was observed among the other seven STI studied. CONCLUSIONS: This study shows both an association between hrHPV infections in the UGT with infertility and endometriosis, and a possible hrHPV infection continuum, from LGT to UGT. Larger studies are needed to fully investigate the role of hrHPV as a cause of endometriosis and infertility.

Persistence and clinical relevance of Zika virus in the male genital tract.

Zika virus (ZIKV) is a re-emerging mosquito-transmitted flavivirus associated with congenital abnormalities in newborns and with Guillain-Barré syndrome in adults. The virus can also be sexually transmitted and can persist in the male genital tract. Studies evaluating the kinetics of ZIKV in seminal shedding of men who have been infected, as well as in animal and cellular models of infection, have shown that, in addition to the testis and epididymis, the prostate and seminal vesicles could also be involved in persistent ZIKV infection. Additionally, some studies have reported that men infected with ZIKV can present with genitourinary symptoms such as haematospermia, prostatitis, painful ejaculation, penile discharge, and oligospermia; however, little is known about the effect of ZIKV on fertility. Understanding the mechanisms that underlie persistent ZIKV infections in men is crucial to developing guidelines, effective vaccines, and therapies.

Participation in Cervical Screening by Self-collection, Pap, or a Choice of Either in Brazil.

Most cervical cancers occur in women who do not participate in cervical-cancer screening. We therefore evaluated adherence to screening for clinic-based Pap testing, self-collected sampling for HPV testing, and choice of the 2 among 483 unscreened/underscreened women in Brazil. Three public Basic Health Units (BHU) were each randomly assigned to three arms: (i) Pap testing at the BHU (N = 160), (ii) "Self&HPV" (self-collection for HPV testing) (N = 161), and (iii) "Choice" between self-collection and HPV testing and Pap test at the local BHU (N = 162). The theory-based (PEN-3 and Health Belief Model) intervention in all three arms was implemented by trained Community Health Workers (CHW) at participants' home. With the first invitation, 60.0% in the Pap arm, 95.1% [154 of 161 (95.7%) who selected Self&HPV and 0 of 1 (0.0%) who selected Pap] in the Choice arm, and 100% in the Self&HPV arm completed screening. By the second invitation to choose a method of screening in the Choice arm, 100% completed screening. After three invitations, 75.0% of women in the Pap arm completed screening. Adherence to screening differed by study arm (P < 0.001). In conclusion, Self&HPV testing is a promising strategy for unscreened/underscreened women who are recalcitrant or unable to undergo clinic-based cervical screening to complement the screening modality used in the general population. In Brazil, where Pap testing is recommended for routine cervical screening, training CHWs in behavior change strategies and offering Self&HPV or Choice could greatly improve screening population coverage by reaching the unscreened/underscreened populations.

Case Reports: Prolonged Detection of Zika Virus RNA in Vaginal and Endocervical Samples from a Brazilian Woman, 2018.

Zika virus (ZIKV) infection is an emerging public health problem, associated with increased risk for Guillain-Barré syndrome and adverse fetal outcomes, including congenital microcephaly. Zika virus sexual transmission is known, but detection of the virus in different parts of the female reproductive tract is not well established. In this case report, we describe prolonged detection of ZIKV RNA in the vaginal secretion and endocervical mucosa from a Brazilian woman convalescent to ZIKV infection. A viral load of 2 × 102 copies/mL was detected up to 31 days after symptom onset in both samples. Other biological fluids, including whole blood, plasma, serum, urine, and saliva samples, were negative for ZIKV RNA. These findings advance the understanding of ZIKV infection and provide data for additional testing strategies.

Male Partners of Infertile Couples With Seminal Positivity for Markers of Bacterial Vaginosis Have Impaired Fertility.

To access the possibility that key markers of bacterial vaginosis (KM-BV) could affect seminal parameters and thus fertility a prospective cohort study was designed (a) to develop rapid and sensitive multiplex polymerase chain reaction (M-PCR) assays to screen 13 key markers of bacterial vaginosis (KM-BV) in semen specimens, (b) to determine the prevalence of KM-BV in semen from randomized male partners of couples seeking fertility evaluation. A total of 229 semen samples were included in the study from males who visited the Sperm Analysis Section of Brazil between October 2015 and March 2016. Eligible men were 18 years or older and had a semen analysis due fertility evaluation (after failing to conceive with their partner after 1 year of unprotected intercourse). Basic seminal parameters were analyzed, and KM-BV was detected by M-PCR assays. M-PCR assays clearly distinguished 13 KM-BV in 146 semen samples (63.8%), mainly Gardnerella vaginalis (50.7%). Some important associations occurred between the presence of KM-BV in semen and changes in seminal parameters. KM-BV is commonly present in the semen of males seeking fertility evaluation and could potentially play significant roles in male subfertility and/or infertility.

Proanthocyanidin Polymer-Rich Fraction of Stryphnodendron adstringens Promotes in Vitro and in Vivo Cancer Cell Death via Oxidative Stress.

Cervical cancer is the fourth most common cancer that affects women, mainly through human papilloma virus (HPV) infection with high-risk HPV16 and HPV18. The present study investigated the in vitro anticancer activity and mechanism of action of a proanthocyanidin polymer-rich fraction of Stryphnodendron adstringens (F2) in cervical cancer cell lines, including HeLa (HPV18-positive), SiHa (HPV16-positive), and C33A (HPV-negative) cells, and also evaluated in vivo anticancer activity. In vitro, cell viability was determined by the MTT assay. Cell migration was determined by the wound healing assay. The mechanism of action was investigated by performing ultrastructural analysis and evaluating reactive oxygen species (ROS) production, mitochondrial metabolism, lipoperoxidation, BCL-2 family expression, caspase expression, and DNA and cell membrane integrity. In vivo activity was evaluated using the murine Ehrlich solid tumor model. F2 time- and dose-dependently reduced cell viability and significantly inhibited the migration of cervical cancer cells. HeLa and SiHa cells treated with F2 (IC50) exhibited intense oxidative stress (i.e., increase in ROS and decrease in antioxidant species) and mitochondrial damage (i.e., mitochondrial membrane potential depolarization and a reduction of intracellular levels of adenosine triphosphate). Increases in the Bax/BCL-2 ratio and caspase 9 and caspase 3 expression, were observed, with DNA damage that was sufficient to trigger mitochondria-dependent apoptosis. Cell membrane disruption was observed in C33A cells (IC50 and IC90) and HeLa and SiHa cells (IC90), indicating progress to late apoptosis/necrosis. The inhibition of ROS production by N-acetylcysteine significantly suppressed oxidative stress in all three cell lines. In vivo, F2 significantly reduced tumor volume and weight of the Ehrlich solid tumor, and significantly increased lipoperoxidation, indicating that F2 also induces oxidative stress in the in vivo model. These findings indicate that the proanthocyanidin polymer-rich fraction of S. adstringens may be a potential chemotherapeutic candidate for cancer treatment.

Artepillin C Induces Selective Oxidative Stress and Inhibits Migration and Invasion in a Comprehensive Panel of Human Cervical Cancer Cell Lines.

BACKGROUND: Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid) is the main bioactive component of Brazilian green propolis, and possesses, among other things, anticancer properties. However, to the best of our knowledge, there are no studies of artepillin C in cervical cancer. METHOD: To explore a new therapeutic candidate for cervical cancer, we have evaluated the effects of artepillin C on cellular viability in a comprehensive panel of human cervical cancer-derived cell lines including HeLa (human papillomavirus/HPV 18-positive), SiHa (HPV 16-positive), CaSki (HPV 16- and 18-positive) and C33A (HPV-negative) cells compared to a spontaneously immortalized human epithelial cell line (HaCaT). RESULTS: Our results demonstrated that artepillin C had a selective effect on cellular viability and could induce apoptosis possibly by intrinsic pathway, likely a result of oxidative stress, in all cancer-derived cell lines but not in HaCaT. Additionally, artepillin C was able to inhibit the migration and invasion of cancer cells. CONCLUSION: Thus, artepillin C appears to be a promising new candidate as an anticancer drug for cervical cancer induced by different HPV types.

Effects of Herpes Simplex Virus Infections on Seminal Parameters in Male Partners of Infertile Couples.

OBJECTIVE: To assess the possibility that herpes simplex virus (HSV) infection could affect seminal parameters, we (1) standardize and validate a multiplex polymerase chain reaction (M-PCR) assay to detect HSV-1 and HSV-2 in semen, and (2) determine the prevalence of HSV-1/-2 in the semen of randomized male partners of couples seeking fertility evaluation. MATERIALS AND METHODS: A total of 279 semen samples were included in the study from men who visited the Sperm Analysis Section of São Camilo Laboratory of Maringá, Brazil, between November 2014 and July 2015. Eligible men were 18 years or older and had a semen analysis due fertility evaluation (after failing to conceive with their partner after 1 year of unprotected intercourse). Basic seminal parameters were analyzed, and HSV-1 and HSV-2 were detected by M-PCR. RESULTS: The M-PCR assay clearly distinguished and identified 2 HSV types in semen samples. HSV in total was detected in 10.7% of samples, of which 7.5% had HSV-1 exclusively and 3.2% had HSV-2 exclusively. We detected a significant association of HSV-2 infection with hematospermia and with a lower mean seminal volume, and between HSV-1 infection and a lower mean sperm count. CONCLUSION: These findings suggest that the male partners of infertile couples with HSV infections may have changes on the 2 equally important components of semen, spermatozoa and seminal fluid, which may influence fertility. Further studies enrolling a larger number of patients are necessary to confirm these data and to elucidate the clinical relevance of HSV presence in semen.

Male Partners of Infertile Couples with Seminal Infections of Human Papillomavirus Have Impaired Fertility Parameters.

Several studies have addressed the impact of viral infections on male infertility. However, it is still unknown whether human papillomavirus (HPV) can alter seminal parameters. The aim of this study was to determine the prevalence of HPV in the semen of male partners of couples seeking fertility evaluation. Additionally, we assessed the possibility that HPV infections affect seminal parameters. A total of 229 semen samples were collected from men in the Sperm Analysis Section of São Camilo Laboratory of Maringá, Brazil, between October 2015 and March 2016. Basic seminal parameters were analyzed, and HPV was detected and genotyped by polymerase chain reaction. HPV DNA was detected in 16.6% of samples. Of these, 10.5% had single type HPV infections, 6.1% had multiple HPV infections, 5.7% had exclusively high-risk HPV, and 6.1% had exclusively low-risk HPV. Samples positive for single and multiple types of HPV were associated with abnormal viscosity, and samples positive for multiple HPV types were also associated with hypospermia, higher pH, and increased leukocyte numbers. These findings suggest that the male partners of infertile couples with seminal HPV infections may have prostate disturbances indicative of glandular dysfunction, which may influence fertility.

Oxidative Stress Triggered by Apigenin Induces Apoptosis in a Comprehensive Panel of Human Cervical Cancer-Derived Cell Lines.

Recently, the cytotoxic effects of apigenin (4',5,7-trihydroxyflavone), particularly its marked inhibition of cancer cell viability both in vitro and in vivo, have attracted the attention of the anticancer drug discovery field. Despite this, there are few studies of apigenin in cervical cancer, and these studies have mostly been conducted using HeLa cells. To evaluate the possibility of apigenin as a new therapeutic candidate for cervical cancer, we evaluated its cytotoxic effects in a comprehensive panel of human cervical cancer-derived cell lines including HeLa (human papillomavirus/HPV 18-positive), SiHa (HPV 16-positive), CaSki (HPV 16 and HPV 18-positive), and C33A (HPV-negative) cells in comparison to a nontumorigenic spontaneously immortalized human epithelial cell line (HaCaT). Our results demonstrated that apigenin had a selective cytotoxic effect and could induce apoptosis in all cervical cancer cell lines which were positively marked with Annexin V, but not in HaCaT (control cells). Additionally, apigenin was able to induce mitochondrial redox impairment, once it increased ROS levels and H2O2, decreased the Δψm, and increased LPO. Still, apigenin was able to inhibit migration and invasion of cancer cells. Thus, apigenin appears to be a promising new candidate as an anticancer drug for cervical cancer induced by different HPV genotypes.

NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1.

The NF-κB pathway is central to the regulation of inflammation. Here, we demonstrate that the low-output nitric oxide (NO) synthase 1 (NOS1 or nNOS) plays a critical role in the inflammatory response by promoting the activity of NF-κB. Specifically, NOS1-derived NO production in macrophages leads to proteolysis of suppressor of cytokine signaling 1 (SOCS1), alleviating its repression of NF-κB transcriptional activity. As a result, NOS1(-/-) mice demonstrate reduced cytokine production, lung injury, and mortality when subjected to two different models of sepsis. Isolated NOS1(-/-) macrophages demonstrate similar defects in proinflammatory transcription on challenge with Gram-negative bacterial LPS. Consistently, we found that activated NOS1(-/-) macrophages contain increased SOCS1 protein and decreased levels of p65 protein compared with wild-type cells. NOS1-dependent S-nitrosation of SOCS1 impairs its binding to p65 and targets SOCS1 for proteolysis. Treatment of NOS1(-/-) cells with exogenous NO rescues both SOCS1 degradation and stabilization of p65 protein. Point mutation analysis demonstrated that both Cys147 and Cys179 on SOCS1 are required for its NO-dependent degradation. These findings demonstrate a fundamental role for NOS1-derived NO in regulating TLR4-mediated inflammatory gene transcription, as well as the intensity and duration of the resulting host immune response.

MMP-9/RECK Imbalance: A Mechanism Associated with High-Grade Cervical Lesions and Genital Infection by Human Papillomavirus and Chlamydia trachomatis.

BACKGROUND: Matrix metalloproteinases (MMP) are important enzymes in the tumor microenvironment associated with progression of cervical intraepithelial neoplasia (CIN) toward squamous cell carcinoma (SCC) of the cervix. However, the role of MMPs in the inflammatory process associated with Chlamydia trachomatis infection concomitant with the carcinogenic process driven by HPV has not yet been addressed. In the present study, we analyzed the state of the MMP-9-RECK axis in cervical carcinogenesis. METHODS: The levels of MMP-9 and RECK expression were analyzed by immunocytochemistry in liquid-based cytology samples from 136 women with high-grade cervical lesions (CIN2/CIN3) and cervical SCC diagnosed by LLETZ, and in 196 women without cervical neoplasia or CIN1. Real-time qPCR was performed to analyze expression of MMP-9 and RECK in 15 cervical samples. The presence of HPV-DNA and other genital pathogens was evaluated by PCR. RESULTS: We found a higher expression of MMP-9 [OR, 4.2; 95% confidence interval (CI), 2.2-7.8] and lower expression of RECK (OR, 0.4; 95% CI, 0.2-0.7) in women with CIN2/CIN3/SCC when compared with women from the control group (no neoplasia/CIN1). A statistically significant association was also found between MMP-9/RECK imbalance and infection by alpha-9 HPV and C. trachomatis. The prevalence of C. trachomatis infection was significantly higher in women with high-grade cervical disease (OR, 3.7; 95% CI, 1.3-11.3). CONCLUSIONS: MMP-9/RECK imbalance in cervical smears is significantly associated with high-grade cervical diseases and infection by alpha-9 HPV and C. trachomatis. IMPACT: MMP-9/RECK imbalance during cervical inflammation induced by C. trachomatis might play a role in HPV-mediated cervical carcinogenesis.

MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer.

Manganese superoxide dismutase (MnSOD/SOD2) is a mitochondria-resident enzyme that governs the types of reactive oxygen species egressing from the organelle to affect cellular signalling. Here we demonstrate that MnSOD upregulation in cancer cells establishes a steady flow of H2O2 originating from mitochondria that sustains AMP-activated kinase (AMPK) activation and the metabolic shift to glycolysis. Restricting MnSOD expression or inhibiting AMPK suppresses the metabolic switch and dampens the viability of transformed cells indicating that the MnSOD/AMPK axis is critical to support cancer cell bioenergetics. Recapitulating in vitro findings, clinical and epidemiologic analyses of MnSOD expression and AMPK activation indicated that the MnSOD/AMPK pathway is most active in advanced stage and aggressive breast cancer subtypes. Taken together, our results indicate that MnSOD serves as a biomarker of cancer progression and acts as critical regulator of tumour cell metabolism.

Male infertility: a public health issue caused by sexually transmitted pathogens.

Sexually transmitted diseases (STDs) are caused by several pathogens, including bacteria, viruses and protozoa, and can induce male infertility through multiple pathophysiological mechanisms. Additionally, horizontal transmission of STD pathogens to sexual partners or vertical transmission to fetuses and neonates is possible. Chlamydia trachomatis, Ureaplasma spp., human papillomavirus, hepatitis B and hepatitis C viruses, HIV-1 and human cytomegalovirus have all been detected in semen from symptomatic and asymptomatic men with testicular, accessory gland and urethral infections. These pathogens are associated with poor sperm quality and decreased sperm concentration and motility. However, the effects of these STD agents on semen quality are unclear, as are the effects of herpes simplex virus type 1 and type 2, Neisseria gonorrhoeae, Mycoplasma spp., Treponema pallidum and Trichomonas vaginalis, because few studies have evaluated the influence of these pathogens on male infertility. Chronic or inadequately treated infections seem to be more relevant to infertility than acute infections are, although in many cases the exact aetiological agents remain unknown.

Redox control of enzymatic functions: The electronics of life's circuitry.

The field of redox biology has changed tremendously over the past 20 years. Formerly regarded as bi-products of the aerobic metabolism exclusively involved in tissue damage, reactive oxygen species (ROS) are now recognized as active participants of cell signaling events in health and in disease. In this sense, ROS and the more recently defined reactive nitrogen species (RNS) are, just like hormones and second messengers, acting as fundamental orchestrators of cell signaling pathways. The chemical modification of enzymes by ROS and RNS (that result in functional enzymatic alterations) accounts for a considerable fraction of the transient and persistent perturbations imposed by variations in oxidant levels. Upregulation of ROS and RNS in response to stress is a common cellular response that foments adaptation to a variety of physiologic alterations (hypoxia, hyperoxia, starvation, and cytokine production). Frequently, these are beneficial and increase the organisms' resistance against subsequent acute stress (preconditioning). Differently, the sustained ROS/RNS-dependent rerouting of signaling produces irreversible alterations in cellular functioning, often leading to pathogenic events. Thus, the duration and reversibility of protein oxidations define whether complex organisms remain "electronically" healthy. Among the 20 essential amino acids, four are particularly susceptible to oxidation: cysteine, methionine, tyrosine, and tryptophan. Here, we will critically review the mechanisms, implications, and repair systems involved in the redox modifications of these residues in proteins while analyzing well-characterized prototypic examples. Occasionally, we will discuss potential consequences of amino acid oxidation and speculate on the biologic necessity for such events in the context of adaptative redox signaling. © 2014 IUBMB Life, 66(3):167-181, 2014.