Investigating relationships between the host genome, rumen microbiome, and dairy cow feed efficiency using mediation analysis with structural equation modeling.

The rumen microbiome is crucial for converting feed into absorbable nutrients used for milk synthesis, and the efficiency of this process directly impacts the profitability and sustainability of the dairy industry. Recent studies have found that the rumen microbial composition explains part of the variation in feed efficiency traits, including dry matter intake, milk energy, and residual feed intake. The main goal of this study was to reveal relationships between the host genome, rumen microbiome, and dairy cow feed efficiency using structural equation models. Our specific objectives were to (i) infer the mediation effects of the rumen microbiome on feed efficiency traits, (ii) estimate the direct and total heritability of feed efficiency traits, and (iii) calculate the direct and total breeding values of feed efficiency traits. Data consisted of dry matter intake, milk energy, and residual feed intake records, SNP genotype data, and 16S rRNA rumen microbial abundances from 448 mid-lactation Holstein cows from 2 research farms. We implemented structural equation models such that the host genome directly affects the phenotype (GP → P) and the rumen microbiome (GM → P), while the microbiome affects the phenotype (M → P), partially mediating the effect of the host genome on the phenotype (G → M → P). We found that 7 to 30% of microbes within the rumen microbial community had structural coefficients different from zero. We classified these microbes into 3 groups that could have different uses in dairy farming. Microbes with heritability <0.10 but significant causal effects on feed efficiency are attractive for external interventions. On the other hand, 2 groups of microbes with heritability ≥0.10, significant causal effects, and genetic covariances and causal effects with the same or opposite sign to feed efficiency are attractive for selective breeding, improving or decreasing the trait heritability and response to selection, respectively. In general, the inclusion of the different microbes in genomic models tends to decrease the trait heritability rather than increase it, ranging from -15% to +5%, depending on the microbial group and phenotypic trait. Our findings provide more understanding to target rumen microbes that can be manipulated, either through selection or management interventions, to improve feed efficiency traits.

Characterization of the equine placental microbial population during nocardioform placentitis.

Nocardioform placentitis is a poorly understood disease of equine late gestation. The presence of nocardioform, filamentous branching gram-positive bacteria, has been linked to the disease, with Crossiella equi, Amycolatopsis spp., and Streptomyces spp. being the most frequently identified bacteria. However, these bacteria are not found in all clinical cases in addition to being isolated from healthy, normal postpartum placentas. To better understand this form of placentitis, we analyzed the microbial composition in the equine placenta (chorioallantois) of both healthy postpartum (control; n = 11) and nocardioform-affected samples (n = 22) using 16S rDNA sequencing. We found a lower Shannon index in nocardioform samples, a higher Chao1 index in nocardioform samples, and a difference in beta diversity between control and nocardioform samples (p < 0.05), suggesting the presence of dysbiosis during the disease. In the majority of the NP samples (77 %), one of the following genera-Amycolatopsis, Crossiella, Lentzea, an unidentified member of the Pseudonocardiaceae family, Mycobacterium, or Enterococcus -represented over 70 % of the relative abundance. Overall, the data suggest that a broader spectrum of potential opportunistic pathogens could be involved in nocardioform placentitis, extending beyond the traditionally recognized bacteria, resulting in a similar histomorphological profile.

Shifts in uterine microbiome associated with pregnancy outcomes at first insemination and clinical cure in dairy cows with metritis.

Objectives were to assess differences in uterine microbiome associated with clinical cure and pregnancy outcomes in dairy cows treated for metritis. Cows with metritis (reddish-brownish, watery, and fetid vaginal discharge) were paired with cows without metritis based on parity and days postpartum. Uterine contents were collected through transcervical lavage at diagnosis, five days later following antimicrobial therapy (day 5), and at 40 days postpartum. Uterine microbiome was assessed by sequencing the V4 hypervariable region of the 16S rRNA gene. Although alpha-diversity based on Chao1, Shannon, and inverse Simpson indexes at diagnosis did not differ between cows with and without metritis, disease was associated with differences in beta-diversity. Prevalence of Porphyromonas, Bacteroides, and Veillonella was greater in cows with metritis. Streptococcus, Sphingomonas, and Ureaplasma were more prevalent in cows without metritis. Differences in beta-diversity between cows with and without metritis persisted on day 5. Uterine microbiome was not associated with clinical cure. Richness and alpha-diversity, but not beta-diversity, of uterine microbiome 40 days postpartum were associated with metritis and pregnancy. No relationship between uterine microbiome and pregnancy outcomes was observed. Results indicate that factors other than changes in intrauterine bacterial community underlie fertility loss and clinical cure in cows with metritis.

AF-React study: Prevalence of thrombotic events in patients with atrial fibrillation receiving NOACs - real-world data analysis from northern Portugal primary healthcare.

Introduction: Anticoagulation is recommended for stroke prevention in patients with atrial fibrillation (AF). The guidelines suggest non-vitamin K antagonist anticoagulants (NOACs) as the primary therapy for anticoagulation in AF. Several patient-related factors increase the risk of thrombotic events: elderly individuals, a previous history of stroke, and chronic kidney disease. This study aims to determine the association between NOACs and other patient variables in AF and the occurrence of thrombotic events. Methods: The database included all adults with the code K78 (ICPC-2 code for AF) who received clinical care in Northern Portugal's Primary Health Care between January 2016 and December 2018 and were dispensed the same NOAC at the pharmacy. Results: The results indicate that 10.2% of AF patients on NOAC anticoagulation experienced a stroke. Furthermore, patients treated with apixaban and dabigatran had higher odds of experiencing a stroke compared to those treated with rivaroxaban. Among patients with the same age, gender, and CHA2DS2Vasc Score, apixaban was significantly associated with a higher likelihood of thrombotic events than rivaroxaban. Discussion: These results have not been previously reported in studies with real-world data; therefore, a more detailed analysis should be conducted to enhance the validity of these findings.

Macrophages, IL-10, and nitric oxide increase, induced by hyperglycemic conditions, impact the development of murine melanoma B16F10-Nex2.

Epidemiological studies show a strong correlation between diabetes and the increased risk of developing different cancers, including melanoma. In the present study, we investigated the impact of a streptozotocin (STZ)-induced hyperglycemic environment on B16F10-Nex2 murine melanoma development. Hyperglycemic male C57Bl/6 mice showed increased subcutaneous tumor development, partially inhibited by metformin. Tumors showed increased infiltrating macrophages, and augmented IL-10 and nitric oxide (NO) concentrations. In vivo neutralization of IL-10, NO synthase inhibition, and depletion of macrophages reduced tumor development. STZ-treated TLR4 KO animals showed delayed tumor development; the transfer of hyperglycemic C57Bl/6 macrophages to TLR4 KO reversed this effect. Increased concentrations of IL-10 present in tumor homogenates of hyperglycemic mice induced a higher number of pre-angiogenic structures in vitro, and B16F10-Nex2 cells incubated with different glucose concentrations in vitro produced increased levels of IL-10. In summary, our findings show that a hyperglycemic environment stimulates murine melanoma B16F10-Nex2 primary tumor growth, and this effect is dependent on tumor cell stimulation, increased numbers of macrophages, and augmented IL-10 and NO concentrations. These findings show the involvement of tumor cells and other components of the tumor microenvironment in the development of subcutaneous melanoma under hyperglycemic conditions, defining novel targets for melanoma control in diabetic patients.

Appropriateness of prescribing profiles and intake adherence to non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: analysis of a retrospective longitudinal study using real-world data from Northern Portugal (AF-React Study).

OBJECTIVES: This study aimed to assess the appropriateness of prescribing profiles and intake adherence to non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF). DESIGN: Retrospective longitudinal study. SETTING: The study was conducted in the Regional Health Administration of Northern Portugal. PARTICIPANTS: The authors selected a database of 21 854 patients with prescriptions for NOACs between January 2016 and December 2018 and were classified with AF until December 2018. OUTCOME MEASURES: The appropriate dosage of NOAC for patients with AF divided into three categories: contraindicated, inconsistent and consistent, based on the 2020 European Society of Cardiology guidelines for AF. RESULTS: Dabigatran had a lower percentage of guideline-consistent doses (n=1657, 50.1%) than other drugs such as rivaroxaban (n=4737, 81.6%), apixaban (n=3830, 78.7%) and edoxaban (n=436, 82.1%). Most patients with an inconsistent dose were prescribed a lower dose than recommended based on their glomerular filtration rate (GFR). Among patients younger than 75 years with GFR >60 mL/min, 59.8% (n=10 028) had an adequate GFR range, while 27.8% (n=7166) of GFR measurements from patients older than 75 years old and 29.4% (n=913) of GFR measurements from patients younger than 75 years with GFR <60 mL/min were within an adequate time range. Adherence to NOACs varied across different drugs, with 59.1% (n=540) adhering to edoxaban, 56.3% (n=5443) to rivaroxaban, 55.3% (n=3143) to dabigatran and 53.3% (n=4211) to apixaban. CONCLUSIONS: Dabigatran had the lowest percentage of guideline-consistent doses. Patients younger than 75 years with GFR >60 mL/min had the highest percentage with an adequate GFR range, while other groups who require closer GFR monitoring had lower percentages within an adequate GFR range. Adherence to NOACs differed among different drugs, with greater adherence to treatment with edoxaban and less adherence to apixaban.

An artificial intelligence approach of feature engineering and ensemble methods depicts the rumen microbiome contribution to feed efficiency in dairy cows.

Genetic selection has remarkably helped U.S. dairy farms to decrease their carbon footprint by more than doubling milk production per cow over time. Despite the environmental and economic benefits of improved feed and milk production efficiency, there is a critical need to explore phenotypical variance for feed utilization to advance the long-term sustainability of dairy farms. Feed is a major expense in dairy operations, and their enteric fermentation is a major source of greenhouse gases in agriculture. The challenges to expanding the phenotypic database, especially for feed efficiency predictions, and the lack of understanding of its drivers limit its utilization. Herein, we leveraged an artificial intelligence approach with feature engineering and ensemble methods to explore the predictive power of the rumen microbiome for feed and milk production efficiency traits, as rumen microbes play a central role in physiological responses in dairy cows. The novel ensemble method allowed to further identify key microbes linked to the efficiency measures. We used a population of 454 genotyped Holstein cows in the U.S. and Canada with individually measured feed and milk production efficiency phenotypes. The study underscored that the rumen microbiome is a major driver of residual feed intake (RFI), the most robust feed efficiency measure evaluated in the study, accounting for 36% of its variation. Further analyses showed that several alpha-diversity metrics were lower in more feed-efficient cows. For RFI, [Ruminococcus] gauvreauii group was the only genus positively associated with an improved feed efficiency status while seven other taxa were associated with inefficiency. The study also highlights that the rumen microbiome is pivotal for the unexplained variance in milk fat and protein production efficiency. Estimation of the carbon footprint of these cows shows that selection for better RFI could reduce up to 5 kg of diet consumed per cow daily, potentially reducing up to 37.5% of CH4. These findings shed light that the integration of artificial intelligence approaches, microbiology, and ruminant nutrition can be a path to further advance our understanding of the rumen microbiome on nutrient requirements and lactation performance of dairy cows to support the long-term sustainability of the dairy community.

The pathogen-encoded signalling receptor Tir exploits host-like intrinsic disorder for infection.

The translocated intimin receptor (Tir) is an essential type III secretion system (T3SS) effector of attaching and effacing pathogens contributing to the global foodborne disease burden. Tir acts as a cell-surface receptor in host cells, rewiring intracellular processes by targeting multiple host proteins. We investigated the molecular basis for Tir's binding diversity in signalling, finding that Tir is a disordered protein with host-like binding motifs. Unexpectedly, also are several other T3SS effectors. By an integrative approach, we reveal that Tir dimerises via an antiparallel OB-fold within a highly disordered N-terminal cytosolic domain. Also, it has a long disordered C-terminal cytosolic domain partially structured at host-like motifs that bind lipids. Membrane affinity depends on lipid composition and phosphorylation, highlighting a previously unrecognised host interaction impacting Tir-induced actin polymerisation and cell death. Furthermore, multi-site tyrosine phosphorylation enables Tir to engage host SH2 domains in a multivalent fuzzy complex, consistent with Tir's scaffolding role and binding promiscuity. Our findings provide insights into the intracellular Tir domains, highlighting the ability of T3SS effectors to exploit host-like protein disorder as a strategy for host evasion.

Host and rumen microbiome contributions to feed efficiency traits in Holstein cows.

It is now widely accepted that dairy cow performance is influenced by both the host genome and rumen microbiome composition. The contributions of the genome and the microbiome to the phenotypes of interest are quantified by heritability (h2) and microbiability (m2), respectively. However, if the genome and microbiome are included in the model, then the h2 reflects only the contribution of the direct genetic effects quantified as direct heritability (hd2), and the holobiont effect reflects the joint action of the genome and the microbiome, quantified as the holobiability (ho2). The objectives of this study were to estimate h2, hd2,m2, and ho2 for dry matter intake, milk energy, and residual feed intake; and to evaluate the predictive ability of different models, including genome, microbiome, and their interaction. Data consisted of feed efficiency records, SNP genotype data, and 16S rRNA rumen microbial abundances from 448 mid-lactation Holstein cows from 2 research farms. Three kernel models were fit to each trait: one with only the genomic effect (model G), one with the genomic and microbiome effects (model GM), and one with the genomic, microbiome, and interaction effects (model GMO). The model GMO, or holobiont model, showed the best goodness-of-fit. The hd2 estimates were always 10% to 15% lower than h2 estimates for all traits, suggesting a mediated genetic effect through the rumen microbiome, and m2 estimates were moderate for all traits, and up to 26% for milk energy. The ho2 was greater than the sum of hd2 and m2, suggesting that the genome-by-microbiome interaction had a sizable effect on feed efficiency. Kernel models fitting the rumen microbiome (i.e., models GM and GMO) showed larger predictive correlations and smaller prediction bias than the model G. These findings reveal a moderate contribution of the rumen microbiome to feed efficiency traits in lactating Holstein cows and strongly suggest that the rumen microbiome mediates part of the host genetic effect.

The expression of endothelial and inducible nitric oxide synthase and apoptosis in intestinal ischemia and reperfusion injury under the action of ischemic preconditioning and pentoxifylline

Abstract Purpose: To investigate the expression of nitric oxide synthase (NOS) and apoptosis associated with ischemic preconditioning (IPC) and pentoxifylline (PTX) in intestinal ischemia (I) and reperfusion (R) injury. Methods: Thirty male rats were assigned to 5 groups: (CG), no clamping of the superior mesenteric artery (90 minutes); (IR-SS) saline + ischemia (30 minutes) + reperfusion (60 minutes); (IR-PTX) PTX + ischemia (30 minutes) + reperfusion (60 minutes); (IPC-IR-SS) 5 minutes of ischemia + 5 minutes of reperfusion (IPC) + saline + I(30 minutes)+R(60 minutes); and (IPC-IR-PTX) IPC + PTX + I(30 minutes)+ R(60 minutes). Results: The application of IPC and PTX showed a significantly lower immunohistochemistry reaction for active caspase-3 (P<0.05) compared to IR+SS. The number of cells immunoreactive to BCL-2 was higher in the IR-PTX group (P>0.05). The NOS-2 expression (qRTPCR) in the IR-PTX group (P<0.05) was higher than the values for the IPC+IR-SS and IPC-IR-PTX groups. The NOS-3 expression was significantly upper in the IPC-IR-PTX group than in the CG (P<0.05), the IR-SS (P<0.05) and the IR-PTX (P<0.05) groups. Conclusions: The BCL-2 and active caspase-3 showed beneficial effects on PTX and IPC. The expression of NOS-2 and NOS-3 in the IPC and IPC-PTX groups showed no synergistic effect.

The role of ischemic preconditioning and pentoxifylline in intestinal ischemia/reperfusion injury of rats

Abstract Purpose: To investigate the role of ischemic preconditioning (IPC) and pentoxifylline (PTX) in intestinal mucosa ischemia/reperfusion injury (IR). Methods: Thirty rats were assigned to 5 groups (N=6): (CG): no clamping of the superior mesenteric artery (90 min.); (IR-SS): saline + ischemia (30 min.) + reperfusion (60 min.); (IR-PTX): PTX + ischemia (30min.) + reperfusion (60 min.); (IPC-IR-SS): 5 min. of ischemia + 5 minutes of reperfusion (IPC) + saline + ischemia (30 min.) + reperfusion (60 min.); (IPC-IR-PTX ): 5 min. of ischemia + 5 min. of reperfusion (IPC) + PTX + 30 min. of I + 60 minutes of R. Results: The IR-PTX, IPC-IR-SS and IPC-IR-PTX groups had significantly lower scores of mucosa damage than the IR-SS group. IR-PTX group showed higher scores than the IPC-IR-PTX group, in accordance with the hypothesis of a favorable effect of IPC alone or in association with PTX. Additionally, IPC-IR-SS had a higher damage score than the IPC-IR-PTX. The villi height and crypt depth were similar in all groups. The villi height in the IR-SS was significantly lower. Conclusion: Ischemic preconditioning or pentoxifylline alone protect the intestinal mucosa from ischemia/reperfusion injury. However, they do not have a synergistic effect when applied together.

Heparin modulates the expression of genes encoding pro and anti-apoptotic proteins in endothelial cells exposed to intestinal ischemia and reperfusion in rats

PURPOSE: To investigate if expression of genes encoding pro and anti-apoptotic proteins in the rat enteric endothelial cells stimulated by intestinal ischemia followed by reperfusion (IR) can be modified by treatment with heparin (HP). METHODS: Eighteen adult Wistar rats were divided in three groups: sham group submitted to laparotomy only (SG), ischemia followed by reperfusion group (IRG); ischemia followed by reperfusion plus pretreatment with HP 100 mg.kg-1 (IRG+HP). Ischemia was performed by clamping of the superior mesenteric artery. After 60 min of ischemia, metal clamps were removed for reperfusion for 120 min. Gene expression of encoding pro (Casp1, Casp6, Casp3, Cflar, Fas and Pgl) and anti-apoptotic (Bcl2, Bcl2l1 and Naip2) proteins in rat enteric endothelial cells was evaluated by PCR microarray method. RESULTS: Compared to rat endothelial cells of SG, the expression of pro-apoptotic genes was up-regulated in IRG while anti-apoptotic genes were down-regulated. In contrast, the expression of anti-apoptotic genes in IRG+HP was up-regulated while pro-apoptotic genes was down-regulated compared to SG. CONCLUSION: The attenuation by heparin of intestinal ischemia-reperfusion previously demonstrated in rodents could be related with ability of this drug to stimulate and reduce gene expression of encoding anti and pro-apoptotic proteins, respectively. .

Ischemic preconditioning and the gene expression of enteric endothelial cell biology of rats submitted to intestinal ischemia and reperfusion

PURPOSE: To investigate the effects of ischemic preconditioning (IPC) on the expression of pro and anti-apoptotic genes in rat endothelial cells undergoing enteric ischemia (I) and reperfusion (R). METHODS: Thirty rats underwent clamping of the superior mesenteric vessels. Sham group (GS) laparotomy only; Ischemia (GI): intestinal ischemia (60 min); Ischemia and Reperfusion (GIR): ischemia (60 min) and reperfusion (120 min); Ischemia and intestinal ischemic preconditioning (GI + IPC) : 5 minutes of ischemia followed by 10 min of reperfusion before sustained ischemia (60 min) ischemia and reperfusion and IPC (GIR + IPC): 5 min ischemia followed by 10 min of reperfusion before sustained ischemia (60min) and reperfusion (120 min). Rat Endothelial Cell Biology (PCR array) to determine the expression of genes related to endothelial cell biology. RESULTS: Gene expression of pro-apoptotic markers (Casp1, Casp6, Cflar, Fas, and Pgl) was down regulated in GI+IPC and in GIR + IPC. In contrast, the expression of anti-apoptotic genes (Bcl2 and Naip2), was up-regulated in GI + IPC and in GIR + IPC. CONCLUSION: Ischemic preconditioning may protect against cell death caused by ischemia and reperfusion.

L-arginine in the ischemic phase protects against liver ischemia-reperfusion injury / A L-arginina durante a fase isquêmica protege o fígado das lesões de isquemia e reperfusão

PURPOSE: To investigate the effects of intravenous L-arginine (LG) infusion on liver morphology, function and proinflammatory response of cytokines during the early phase of ischemia-reperfusion injury (IRI). METHODS: Thirty rabbits were subjected to 60 minutes of hepatic ischemia and 120 minutes of reperfusion. An intravenous injection of saline or L-arginine was administered five minutes before the ischemia and five minutes before initiating the reperfusion and at the 55th and 115th minutes after the ischemia. Samples were collected for histological analysis of the liver and measurements of the serum AST, ALT and LDH and the cytokines IL-6 and TNF-alpha. RESULTS: It was observed a significant reduction of sinusoidal congestion, cytoplasmic vacuolization, infiltration of polymorphonuclear leukocyte, nuclear pyknosis, necrosis and steatosis in liver tissue, as well as AST, ALT and LDH after injection of LG in the ischemia (p <0.001). Lower levels of IL-6 and TNF-alpha were associated with LG infusion during ischemia. Higher levels these proteins were observed in animals receiving LG during reperfusion. CONCLUSION: L-arginine protects the liver against ischemia/reperfusion injury, mainly when is administered during the ischemic phase.

OBJETIVO: Investigar os efeitos da infusão endovenosa da L-arginina (LG) na morfologia, função e resposta de citocinas pró-inflamatórias do fígado durante a fase precoce da lesão de isquemia e reperfusão (IRI). MÉTODOS: Trinta coelhos foram submetidos a 60 minutos de isquemia hepática e 120 minutos de reperfusão. Foi administrada injecção intravenosa de solução salina ou L-arginina aos cinco minutos antes de iniciar a isquemia e cinco minutos antes de iniciar a reperfusão e aos 55 e 115 minutos após o início da isquemia. Realizou-se análise histológica do fígado e dosagens séricas de AST, ALT, LDH, citocinas IL-6 e TNF-alfa. RESULTADOS: Ocorreu redução significante da congestão sinusoidal, vacuolização citoplasmática, infiltração de leucócitos polimorfonucleares, picnose nuclear, necrose e esteatose no tecido hepático, assim como nos níveis de AST, ALT e LDH após a injeção da LG na isquemia (p<0,001). Níveis mais baixos de IL-6 e TNF-alfa foram associados com a infusão LG durante a isquemia. Níveis mais elevados dessas proteínas foram observados nos animais que receberam LG durante a reperfusão. CONCLUSÃO: A L-arginina protegeu o fígado contra a lesão de isquemia e reperfusão principalmente quando administrada durante a fase de isquemia.

Interaction of [3H]8-methoxypsoralen with cultured normal human epidermal melanocytes

FUNDAMENTOS - O tratamento normalmente usado para o vitiligo envolve a combinaçäo de 8-metoxipsoraleno (8-MOP) e radiaçäo ultravioleta A, conhecida como PUVA-terapia. Embora a estimulaçäo da proliferaçäo e diferenciaçäo de melanócitos possa explicar a eficiência da PUVA-terapia no tratamento do vitiligo, até a presente data, näo se demonstrou nenhuma interaçäo direta desse composto com melanócitos humanos normais em cultura. OBJETIVOS - Estudar a interaçäo de [3H]8-metoxipsoraleno com melanócitos humanos normais em cultura obtidos de indivíduos de cor branca e negra. MÉTODOS - Melanócitos humanos normais isolados de prepúcios de crianças e mantidos em meio MCDB-153 na ausência de soro, éster de forbol (PMA) e toxina da cólera, foram incubados com [3H]8-metoxipsoraleno para determinaçäo da ligaçäo específica a essas células. RESULTADOS - Melanócitos isolados de ambos os tipos de pele, mostraram ligaçäo com 8-MOP, embora uma maior porcentagem de ligaçäo tenha sido observada em melanócitos isolados de pessoas de cor negra. CONCLUSÖES - A capacidade proliferativa de melanócitos humanos normais varia de acordo com a cor racial. É possível que as diferenças observadas na ligaçäo do psoraleno, estejam relacionadas com diferenças quanto ao número de receptores de psoralenos entre melanócitos isolados de pele clara e escura

The effects of oxidative stress inducing agents on cell signallin

Reversibie phosphorylation of protein tyrosine residues by protein tyrosine kinases (PTK) mediated by polypeptide growth factor receptors (e.g. epidermal growth factor receptor, platelet derived growth factor receptor, insulin receptor) is a signalling process implicated in a variety of processes such as cellular proliferation, differentiation and transformation. On the other hand, many reports converged to the idea that cellular phosphotyrosine levels are regulated by a family of enzymes referred to as protein tyrosine phosphatases (PTP). An essential cysteine residue located in the conserved catalytic domain is responsible for PTP activity. Furthermore, inhibition of PTP activities by oxidative stress inducing agents has been recently documented. It is well known that free radicais and other oxidants at high concentrations are toxic to cells. However, at low concentrations these species may act as modulators/mediators of signal transduction processes in the presence and absence of polypeptide growth factors. Thus, in this article we reviewed our contribution in the general context of the redox modulation of PTK and PTP mediated signal transduction pathways.

Enolizable carbonyl and imino metabolites may act as endogenous sources of reactive oxygen species

Highly reactive oxyradicals and electronically excited triplet carbonyls can be generated in vitro by iron complexes and heme enzyme-catalyzed aerobic oxidation of synthetic or naturally occurring substances capable of enolization in aqueous medium. Monoenols and enamines, obtained by (alpha-methyne-carbonyl and -imine enolization, undergo dioxygen insertion and ultimately originate triplet species; e.g., isobutanal, 3-methylacetoacetone, Schiff bases. In turn, (alpha-hydroxy- and (alpha-aminocarbonyls (e.g., carbohydrates, 5-aminolevulinic acid) tautomerize to enediols and enolamines and yield oxyradicals, initiated by electron transfer to dioxygen, as polyphenols (e.g., 6-hydroxydopamine) and polyphenolamines do. Free radicals and excited species have been implicated in several normal and pathological processes. We here briefly review our contributions to this research area, emphasizing a possible in vivo prooxidant role for 5-aminolevulinic acid, the heme precursor accumulated in several porphyric disorders (e.g., lead poisoning, acut intermittent porphyria, tyrosinosis).