Powering prescription: Mitochondria as "Living Drugs" - Definition, clinical applications, and industry advancements.

Mitochondria's role as engines and beacons of metabolism and determinants of cellular health is being redefined through their therapeutic application as "Living Drugs" (LDs). Artificial mitochondrial transfer/transplant (AMT/T), encompassing various techniques to modify, enrich, or restore mitochondria in cells and tissues, is revolutionizing acellular therapies and the future of medicine. This article proposes a necessary definition for LDs within the Advanced Therapeutic Medicinal Products (ATMPs) framework. While recognizing different types of LDs as ATMPs, such as mesenchymal stem cells (MSCs) and chimeric antigen receptor T (CAR T) cells, we focus on mitochondria due to their unique attributes that distinguish them from traditional cell therapies. These attributes include their inherent living nature, diverse sources, industry applicability, validation, customizability for therapeutic needs, and their capability to adapt and respond within recipient cells. We trace the journey from initial breakthroughs in AMT/T to the current state-of-the-art applications by emerging innovative companies, highlighting the need for manufacturing standards to navigate the transition of mitochondrial therapies from concept to clinical practice. By providing a comprehensive overview of the scientific, clinical, and commercial landscape of mitochondria as LDs, this article contributes to the essential dialogue among regulatory agencies, academia, and industry to shape their future in medicine.

An updated examination of the perception of barriers for pharmacogenomics implementation and the usefulness of drug/gene pairs in Latin America and the Caribbean.

Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region's continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the "need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics". Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%-99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC.

Exploring the role of mitochondria transfer/transplant and their long-non-coding RNAs in regenerative therapies for skin aging.

Advancing age and environmental stressors lead to mitochondrial dysfunction in the skin, inducing premature aging, impaired regeneration, and greater risk of cancer. Cells rely on the communication between the mitochondria and the nucleus by tight regulation of long non-coding RNAs (lncRNAs) to avoid premature aging and maintain healthy skin. LncRNAs act as key regulators of cell proliferation, differentiation, survival, and maintenance of skin structure. However, research on how the lncRNAs are dysregulated during aging and due to stressors is needed to develop therapies to regenerate skin's function and structure. In this article, we discuss how age and environmental stressors may alter lncRNA homeodynamics, compromising cell survival and skin health, and how these factors may become inducers of skin aging. We describe skin cell types and how they depend on mitochondrial function and lncRNAs. We also provide a list of mitochondria localized and nuclear lncRNAs that can serve to better understand skin aging. Using bioinformatic prediction tools, we predict possible functions of lncRNAs based on their subcellular localization. We also search for experimentally determined protein interactions and the biological processes involved. Finally, we provide therapeutic strategies based on gene editing and mitochondria transfer/transplant (AMT/T) to restore lncRNA regulation and skin health. This article offers a unique perspective in understanding and defining the therapeutic potential of mitochondria localized lncRNAs (mt-lncRNAs) and AMT/T to treat skin aging and related diseases.

Use of food and food-derived products in the treatment of gastritis: A systematic review.

Gastritis is the acute or chronic inflammation of gastric mucosa and is triggered by diverse factors. Treatments used for non-bacterial gastritis include proton pump inhibitors, histamine H2 receptor inhibitors, and antacids, and their use is linked to various side effects. Research on alternative therapeutics using food or food-based products is extensive, mostly in preclinical research. We aimed at documenting the clinical advances in food-based therapies as alternative therapeutics for gastritis. Articles with information on the treatment of gastritis with food or food-based products published until December 1, 2020 were identified through a systematic search in PubMed Medline Database. Additionally, references of retrieved articles were screened for relevant reviews and meta-analyses. Two investigators independently selected and reviewed the titles and abstracts of articles and extracted the study characteristics (PICO framework) and key findings. Dual quality assessment and data extraction were performed. We found 28 clinical studies evaluating garlic, turmeric, red peppers, broccoli sprouts, cranberry juice, honey, oils, and probiotics contained in different foods, such as juices, yogurt, and cheese. The existing literature presents a high risk of bias, and results of the same should be evaluated and replicated with precaution; more rigorous clinical studies are lacking.

Impact of single-nucleotide variants and nutritional status on population pharmacokinetics of Doxorubicin, and its effect on cardiotoxicity in children with leukemia.

PURPOSE:  Doxorubicin is an important antineoplastic agent with wide interindividual variability in response to treatment and in its cardiotoxic effects. To determine the effect of genotypic status of three single-nucleotide variants in ABCC1, NCF4, and CBR3 genes and nutritional status assessed by body mass index, on the population pharmacokinetics of Doxorubicin and its cardiotoxic effects in pediatric patients with leukemia. PATIENTS AND METHODS: Seventy pediatric patients treated with Doxorubicin were studied, in which 189 biological samples were obtained to determine Doxorubicin concentrations (1 to 3 samples per patient) at different times, for 20 h. RESULTS: Low body mass index and age ≤ 7 years were associated with decreased clearance of Doxorubicin, and female gender was associated with increased clearance of Doxorubicin. Low BMI and low height were associated with a decrease and increase, respectively, in the intercompartmental clearance (Q) of Doxorubicin. TT homozygosity of the single-nucleotide variant rs3743527 of the ABCC1 gene was associated with an increase in clearance and decreased area under the curve, AA homozygosity of the single-nucleotide variant rs1883112 of the NCF4 gene was associated with a decrease in the volume of distribution in the peripheral compartment (V2), and GG homozygosity of CBR3 rs1056892 with increasing area under the curve. CONCLUSION: Some covariates studied are directly related to the increase or decrease of the pharmacokinetic parameters of Doxorubicin. Decreased clearance, V2, and increased area under the curve were associated with systolic dysfunction, and decreased Q and V2 were associated with diastolic dysfunction. These results may contribute to the effective and safe use of Doxorubicin in pediatric patients with leukemia.

Evaluation of the Efficacy and Safety of Silver Nanoparticles in the Treatment of Non-Neurological and Neurological Distemper in Dogs: A Randomized Clinical Trial.

Canine distemper is caused by canine distemper virus (CDV), a multisystemic infectious disease with a high morbidity and mortality rate in dogs. Nanotechnology represents a development opportunity for new molecules with antiviral effects that may become effective treatments in veterinary medicine. This study evaluated the efficacy and safety of silver nanoparticles (AgNPs) in 207 CDV, naturally infected, mixed-breed dogs exhibiting clinical signs of the non-neurological and neurological phases of the disease. Group 1a included 52 dogs (experimental group) diagnosed with non-neurologic distemper treated with 3% oral and nasal AgNPs in addition to supportive therapy. Group 1b included 46 dogs (control group) diagnosed with non-neurological distemper treated with supportive therapy only. Group 2a included 58 dogs with clinical signs of neurological distemper treated with 3% oral and nasal AgNPs in addition to supportive therapy. Group 2b included 51 dogs (control group) diagnosed with clinical signs of neurological distemper treated with supportive therapy only. Efficacy was measured by the difference in survival rates: in Group 1a, the survival rate was 44/52 (84.6%), versus 7/46 in Group 1b (15.2%), while both showed clinical signs of non-neurological distemper. The survival rate of dogs with clinical signs of neurological distemper in Group 2a (38/58; 65.6%) was significantly higher than those in Control Group 2b (0/51; 0%). No adverse reactions were detected in experimental groups treated with AgNPs. AgNPs significantly improved survival in dogs with clinical signs of neurological and non-neurological distemper. The use of AgNPs in the treatment of neurological distemper led to a drastic increase in the proportion of dogs recovered without sequels compared to dogs treated without AgNPs. The evidence demonstrates that AgNP therapy can be considered as a targeted treatment in dogs severely affected by canine distemper virus.

Key points for translating wound regenerative agents from in vivo assays in mice to clinical validation.

Skin wound healing leads to the recovery of tissue structure and homeostasis after injury. Numerous factors can hamper wound healing and complete recovery of the harmed tissue, causing the formation of scars or chronic wounds. Therapeutic options to improve wound regeneration are limited, possibly due to failure during pre-clinical validation toward clinical trials. In this article, the authors aim to convey key points and provide recommendations for the development of regenerative agents that improve wound healing using mouse models.First, the authors highlight the differences in the wound healing processes of mice and humans. Later, the authors apply a quasi-systematic research approach based on a search algorithm of 32 terms that focuses on in vivomouse model assays of regenerative factors. The authors analyze the top 20 most cited articles of 2241 hits produced by Scopus. The authors focus the search on a period covering the last 10 years (January 2011 to October 2021). The authors synthesize information from the top 20 articles and present the most common type of mouse model used, mouse characteristics (strain, sex, age, weight), surgical wounding technique employed (size, location, equipment), agents tested, methods of wound monitoring, regeneration assessment and key points to consider for the translational potential of these agents. This knowledge will help the scientific community design better in vivo assays and translate their results to further research and clinical validation.

The MitoAging Project: Single nucleotide polymorphisms (SNPs) in mitochondrial genes and their association to longevity.

Mitochondrial dysfunction is a major hallmark of aging. Mitochondrial DNA (mtDNA) mutations (inherited or acquired) may cause a malfunction of the respiratory chain (RC), and thus negatively affect cell metabolism and function. In contrast, certain mtDNA single nucleotide polymorphisms (SNPs) may be beneficial to mitochondrial electron transport chain function and the extension of cellular health as well as lifespan. The goal of the MitoAging project is to detect key physiological characteristics and mechanisms that improve mitochondrial function and use them to develop therapies to increase longevity and a healthy lifespan. We chose to perform a systematic literature review (SLR) as a tool to collect key mtDNA SNPs associated with an increase in lifespan. Then validated our results by comparing them to the MitoMap database. Next, we assessed the effect of relevant SNPs on protein stability. A total of 28 SNPs were found in protein coding regions. These SNPs were reported in Japan, China, Turkey, and India. Among the studied SNPs, the C5178A mutation in the ND2 gene of Complex I of the RC was detected in all the reviewed reports except in Uygur Chinese centenarians. Then, we found that G9055A (ATP6 gene) and A10398G (ND3 gene) polymorphisms have been associated with a protective effect against Parkinson's disease (PD). Additionally, C8414T in ATP8 was significantly associated with longevity in three Japanese reports. Interestingly, using MitoMap we found that G9055A (ATP6 gene) was the only SNP promoting longevity not associated with any pathology. The identification of SNPs associated with an increase in lifespan opens the possibility to better understand individual differences regarding a decrease in illness susceptibility and find strategies that contribute to healthy aging.

Early evidence of the artificial transfer/transplant of mitochondria to oocytes and zygotes by MitoCeption.

Oocytes may carry mutations in their mitochondrial DNA (mtDNA) which affect fertility and embryo development leading to hereditary diseases or rejection. Mitochondrial replacement therapies (MRTs) such as polar body transfer, spindle transfer and pronuclear transfer, aim to change dysfunctional to normal mitochondria inside oocytes and zygotes resulting in healthier offspring. Even with promising results, MRTs techniques are invasive to oocytes and may negatively affect their viability and the success of the procedure. This article shows early evidence of the use of MitoCeption, a mitochondria transfer/transplant (AMT/T) technique to possibly induce the internalization of exogenous mitochondria in a dose-dependent manner to recipient oocytes in comparison to coincubation. By using human isolated mitochondria in a mix obtained from different donors we were able to identify their mtDNA in murine oocytes by qPCR. Fluorescence microscopy showed that exogenous and transferred mitochondria (MitoTracker ® Red) by MitoCeption were internalized in oocytes and zygotes (CellTracker® Green). After maintaining mitocepted zygotes to two-cell embryos, we transferred them to subrogate female mice and obtained healthy mice pups; however, without clear evidence of the maintenance of human mtDNA in the tissues of mice pups. These early results are puzzling, and they open the path to generate more research regarding the use of MitoCeption in comparison to coincubation in order to transfer mitochondria to oocytes using less invasive procedures.

Association of genetic polymorphisms NCF4 rs1883112, CBR3 rs1056892, and ABCC1 rs3743527 with the cardiotoxic effects of doxorubicin in children with acute lymphoblastic leukemia.

OBJECTIVES: Cardiotoxicity is a frequent complication secondary to the use of anthracyclines for cancer chemotherapy. Evidence suggests that certain polymorphic genetic variants modify the risk for anthracycline-related cardiotoxicity. Reports documenting the impact of genetic polymorphisms on anthracycline-cardiotoxicity risk in pediatric patients with cancers from Latin American countries are scarce. The objective of this study was to evaluate associations between NCF4 rs1883112, CBR3 rs1056892 and ABCC1 rs3743527 genotype status and echocardiographic parameters indicative of anthracycline-cardiotoxicity in a group of Mexican children with acute lymphoblastic leukemia (ALL). METHODS: Sixty-seven children (2-18 years old) with ALL were treated at the State Cancer Center in Durango, Mexico. NCF4, CBR3, and ABCC1 genotypes were examined by real-time PCR. Left ventricular ejection fraction and diastolic filling ratio were examined as markers of systolic and diastolic anthracycline-toxicity. RESULTS: NCF4 rs1883112 genotype status was significantly associated with the risk of doxorubicin cardiotoxicity [odds ratio (OR) = 10.80, 95% confidence interval (CI) 1.69-68.98, P = 0.01]. There was a significant association between heterozygous CBR3 rs1056892 genotype status and anthracycline-cardiotoxicity risk (OR = 9.91, 95% CI 1.07-91.47, P = 0.04). Heterozygosis for the ABCC1 rs3743527 allele was associated with protection from anthracycline-cardiotoxicity (OR = 0.30, 95% CI 0.09-0.91, P = 0.03). CONCLUSION: This pilot study suggests that selected polymorphic variants may impact the risk for anthracycline-cardiotoxicity in pediatric patients with ALL treated with a contemporary chemotherapeutic regimen in Mexico.

Strategies to Apply Water-Deficit Stress: Similarities and Disparities at the Whole Plant Metabolism Level in Medicago truncatula.

Water-deficit stresses such as drought and salinity are the most important factors limiting crop productivity. Hence, understanding the plant responses to these stresses is key for the improvement of their tolerance and yield. In this study M. truncatula plants were subjected to 250 mM NaCl as well as reduced irrigation (No-W) and 250 g/L polyethylene glycol (PEG)-6000 to induce salinity and drought stress, respectively, provoking a drop to -1.7 MPa in leaf water potential. The whole plant physiology and metabolism was explored by characterizing the stress responses at root, phloem sap and leaf organ level. PEG treatment led to some typical responses of plants to drought stress, but in addition to PEG uptake, an important impairment of nutrient uptake and a different regulation of carbon metabolism could be observed compared to No-W plants. No-W plants showed an important redistribution of antioxidants and assimilates to the root tissue, with a distinctive increase in root proline degradation and alkaline invertase activity. On the contrary, salinity provoked an increase in leaf starch and isocitrate dehydrogenase activity, suggesting key roles in the plant response to this stress. Overall, results suggest higher protection of salt-stressed shoots and non-irrigated roots through different mechanisms, including the regulation of proline and carbon metabolism, while discarding PEG as safe mimicker of drought. This raises the need to understand the effect at the whole plant level of the different strategies employed to apply water-deficit stress.

Phloem Sap Proteins Are Part of a Core Stress Responsive Proteome Involved in Drought Stress Adjustment.

During moderate drought stress, plants can adjust by changes in the protein profiles of the different organs. Plants transport and modulate extracellular stimuli local and systemically through commonly induced inter- and intracellular reactions. However, most proteins are frequently considered, cell and organelle specific. Hence, while signaling molecules and peptides can travel systemically throughout the whole plant, it is not clear, whether protein isoforms may exist ubiquitously across organs, and what function those may have during drought regulation. By applying shotgun proteomics, we extracted a core proteome of 92 identical protein isoforms, shared ubiquitously amongst several Medicago truncatula tissues, including roots, phloem sap, petioles, and leaves. We investigated their relative distribution across the different tissues and their response to moderate drought stress. In addition, we functionally compared this plant core stress responsive proteome with the organ-specific proteomes. Our study revealed plant ubiquitous protein isoforms, mainly related to redox homeostasis and signaling and involved in protein interaction networks across the whole plant. Furthermore, about 90% of these identified core protein isoforms were significantly involved in drought stress response, indicating a crucial role of the core stress responsive proteome (CSRP) in the plant organ cross-communication, important for a long-distance stress-responsive network. Besides, the data allowed for a comprehensive characterization of the phloem proteome, revealing new insights into its function. For instance, CSRP protein levels involved in stress and redox are relatively more abundant in the phloem compared to the other tissues already under control conditions. This suggests a major role of the phloem in stress protection and antioxidant activity enabling the plants metabolic maintenance and rapid response upon moderate stress. We anticipate our study to be a starting point for future investigations of the role of the core plant proteome. Under an evolutionary perspective, CSRP would enable communication of different cells with each other and the environment being crucial for coordinated stress response of multicellular organisms.

Moringa oleifera Lam. leaf powder antioxidant activity and cytotoxicity in human primary fibroblasts.

Moringa oleifera Lam. (MO) leaf powder has been well studied, however, understanding how extraction methods of antioxidant compounds affect human primary fibroblasts still needs to be determined. The antioxidant capacity was analyzed through a copper reduction capacity method and primary human skin fibroblasts were evaluated for cytotoxicity using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Antioxidant activity under the influence of methanolic solvents (Trolox equivalents of 160.18 nmol/µL) was 17 times higher than under aqueous solvents. Interestingly, the aqueous extract showed less toxicity in comparison to the methanolic, as cells resulted more susceptible to concentrations ranging from 0.05 to 5 mg/L. Although, MO methanol solvent showed a higher antioxidant capacity in comparison to the aqueous solvent, it presented greater cytotoxicity. Thus, it is concluded that the aqueous extract could be suitable for downstream processing and applications.

Pro12Ala PPAR-γ2 and +294T/C PPAR-δ Polymorphisms and Association with Metabolic Traits in Teenagers from Northern Mexico.

Peroxisome proliferator-activated receptors (PPARs) play roles in glucose and lipid metabolism regulation. Pro12Ala PPAR-γ2 and +294T/C PPAR-δ have been associated with dyslipidemia, hyperglycemia and high body mass index (BMI). We compared metabolic traits and determined associations with Pro12Ala PPAR-γ2 or +294T/C PPAR-δ polymorphism among teenagers from different ethnicity. Four hundred and twelve samples with previous biochemical and biometric measurements were used. Genomic DNA from peripheral blood was extracted and analyzed by end-point PCR for Pro12Ala PPAR-γ2. The +294T/C PPAR-δ PCR product was also digested with Bsl I. Two genotype groups were formed: major allele homozygous and minor allele carriers. Pro12Ala PPAR-γ2 G minor allele frequencies were: 10% in Mestizo-1, 19% in Mestizo-2, 23% in Tarahumara, 12% in Mennonite, and 17% in the total studied population. The +294T/C PPAR-δ C minor allele frequencies were: 18% in Mestizo-1, 20% in Mestizo-2, 6% in Tarahumara, 13% in Mennonite, and 12% in the total studied population. Teenagers with PPAR-γ2 G allele showed a greater risk for either high waist/height ratio or low high-density lipoprotein; and, also had lower total cholesterol. Whereas, PPAR-γ2 G allele showed lower overweight/obesity phenotype (BMI Z-score) frequency, PPAR-δ C allele was a risk factor for it. Metabolic traits were associated with both PPAR polymorphisms.

Use of Human Umbilical Cord and Its Byproducts in Tissue Regeneration.

The fresh or cryopreserved human umbilical cord (HUC) and its byproducts, such as cells and extracts, have different uses in tissue regeneration. Defining what HUC byproduct is more effective in a particular application is a challenge. Furthermore, the methods of isolation, culture and preservation, may affect cell viability and regenerative properties. In this article, we review the HUC and its byproducts' applications in research and clinical practice. We present our results of successful use of HUC as a patch to treat gastroschisis and its potential to be applied in other conditions. Our in vitro results show an increase in proliferation and migration of human fibroblasts by using an acellular HUC extract. Our goal is to promote standardization of procedures and point out that applications of HUC and its byproducts, as well as the resulting advances in regenerative medicine, will depend on rigorous quality control and on more research in this area.

Genotype Analysis of ABCC1, NCF4 and CBR3 Polymorphism and the Association With Childhood Acute Lymphoblastic Leukemia in Mexican Childhood Population.

Background: The identification of genetic risk factors for Acute Lymphoblastic Leukemia (ALL), are increasingly urgent and necessary. Objective: The purpose of this study is to determine the association of the genetic polymorphisms ABCC1 rs3743527, NCF4 rs1883112 and CBR3 rs1056892 with ALL. Methods: DNA samples were obtained in 71 children with ALL (from 2 to 18 years) and in 71 controls without ALL, to determine the polymorphisms by real-time polymerase chain reaction (qPCR), using specific TaqMan probes in a StepOne® thermal cycler (Applied Biosystems, United States). Results: The results of the Odds Ratio analysis show that in the rs1883112 polymorphism of the NCF4 gene, the heterozygous allele has a risk effect for ALL (OR = 3.1870, CI = 1.8880-7.9383 and p = 0.0002), in turn the mutated genotype (AA) is associated with a protective effect (OR = 0.26, 0.1248 to 0.5434 and p = 0.0003). On the other hand, the CBR3 rs1056892 polymorphism shows a significant association of risk to ALL, in the presence of the HT genotype (OR = 2.77, IC = 1.3837 to 5.5651 and p = 0.004) and the mutated genotype of this polymorphism has a significant association with protection to ALL in the HM genotype (OR = 0.52, IC = 0.2639 to 1.0304 and p = 0.05). While the inheritance models of the polymorphisms let us see that of the rs1883112 polymorphism of the NCF4 polymorphism; the HT genotype of the codominant model shows a protective effect against ALL (OR = 0.4117, IC = 0.1718 to 0.9866 and p = 0.04), the recessive model shows us and confirms what we already saw in table number 3, being that there is an association with protective effect in the HM genotype (OR = 0.2604, IC = 0.1248 to 0.5434 and p = 0.0003). In the polymorphism rs1056892 of the CBR3 gene, a protection association was found in the heterozygous allele of the codominant model (OR = 0.3448, IC = 0.1375 to 0.8896 and p = 0.0274). In addition, the recessive inheritance model for the HM genotype shows a protective effect to ALL, (OR = 0.52, CI = 0.9919 to 3.8638 and p = 0.05). Conclusion: There is an evident impact of the NCF4 rs1883112 and CBR3 rs1056892 polymorphisms with an increased risk of susceptibility to ALL; Likewise, through the codominant inheritance model, the effect of the variation of the CBR3 rs1056892 gene as a protective factor against ALL was evaluated.

Milk intake and IGF-1 rs6214 polymorphism as protective factors to obesity.

Mexico ranks 2nd in adult obesity and 4th in milk intake worldwide. Low levels of IGF-1 have been related to obesity and can be reverted by milk intake. The rs6214 polymorphism has been associated with an increase in the expression of IGF-1. Therefore, the aim of the study was to evaluate the association between both, rs6214 polymorphism and milk intake, and obesity. We analysed 99 adult volunteers, with and without a history of milk intake, for the presence of this polymorphism through qPCR and body composition by electro-bioimpedance. Univariate logistic regression analyses showed that TT genotype is inversely associated with obesity and body fat mass. Besides, milk intake is also related to low obesity, body fat mass and visceral fat, and high percentage of lean mass. Multivariate logistic regression analyses confirm the univariate relationships, showing a clear inverted association between TT genotype, milk intake and obesity.

Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children.

Acute lymphoblastic leukemia (ALL) is a frequent neoplasia occurring in children. The most commonly used drug for the treatment of ALL is methotrexate (MTX), an anti-folate agent. Previous studies suggest that folate transporters play a role in ALL prognosis and that genetic polymorphism of genes encoding folate transporters may increase the risk of ALL. Therefore, the main goal of this study was to determine the associations among six genetic polymorphisms in four genes related with the folate transporter pathway to determine a relationship with the occurrence of ALL in Mexican children. A case-control study was performed in 73 ALL children and 133 healthy children from Northern and Northwestern Mexico. COL18A1 (rs2274808), SLC19A1 (rs2838956), ABCB1 (rs1045642 and rs1128503), and ABCC5 (rs9838667 and rs3792585). Polymorphisms were assayed through qPCR. Our results showed an increased ALL risk in children carrying CT genotype (OR = 2.55, CI 95% 1.11-5.83, p = 0.0001) and TT genotype (OR = 21.05, CI 95% 5.62-78.87, p < 0.0001) of COL18A1 rs2274808; in SLC19A1 rs2838956 AG carriers (OR = 44.69, CI 95% 10.42-191.63, p = 0.0001); in ABCB1 rs1045642 TT carriers (OR = 13.76, CI 95% 5.94-31.88, p = 0.0001); in ABCC5 rs9838667 AC carriers (OR = 2.61, CI 95% 1.05-6.48, p < 0.05); and in ABCC5 rs3792585 CC carriers (OR = 9.99, CI 95% 3.19-31.28, p = 0.004). Moreover, several combinations of genetic polymorphisms were found to be significantly associated with a risk for ALL. Finally, two combinations of ABCC5 polymorphisms resulted in protection from this neoplasia. In conclusion, certain genetic polymorphisms related to the folate transport pathway, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642, and ABCC5 rs3792585, were associated with an increased risk for ALL in Mexican children.

Association of ABCB1, ABCC5 and xanthine oxidase genetic polymorphisms with methotrexate adverse reactions in Mexican pediatric patients with ALL.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is one of the most frequent oncological disorders in pediatric populations. To date, the drug of choice for the treatment of ALL is methotrexate, a drug associated with a high risk of adverse reactions (ADRs). The xanthine oxidase (XO) polymorphisms, 1936A>G and 2107A>G, as well as the polymorphic variants derived from ATP-binding cassette transporter gene subfamilies, ABCB1 and ABCC5, of drug resistant codifying genes, are implicated as precursors of drug-related neurologic, hepatic, and renal toxicities. Our aim was to determine whether the mentioned polymorphisms are risk or protective factors for the development of adverse reactions by methotrexate in our pediatric population with ALL. METHODS: A total of 35 Mexican children from Centro Estatal de Cancerología-Durango, Mexico, with ALL and the previously noted polymorphisms as determined qPCR were studied. At the same time, a 12-month drug monitoring program was conducted in accordance with WHO-PAHO guidelines for pharmacovigilance. RESULTS: The ABCB11936A>G and 2107A>G and ABCC5 3414+434A>C polymorphisms were not associated with methotrexate ADRs. Single nucleotide polymorphisms (SNPs) of ABCB1 1236C>T (OR 0.19, 95% CI: 0.03-0.9, p<0.05) and ABCC5 3933+313T>C (OR 0.12, 95% CI: 0.027-0.58, p<0.05) were associated with methotrexate ADRs. CONCLUSIONS: SNPs 1236C>T of ABCB1 and ABCC5 3933+313T>C are not associated with the development of typical ADRs by methotrexate, rather, they showed a protective factor for myelosuppression in the studied sick population.

Ecophysiological roles of abaxial anthocyanins in a perennial understorey herb from temperate deciduous forests.

Accumulation of abaxial anthocyanins is an intriguing leaf trait particularly common among deeply shaded understorey plants of tropical and temperate forests whose ecological significance is still not properly understood. To shed light on it, possible ecophysiological roles of abaxial anthocyanins were tested in the perennial understorey herb of temperate deciduous forests Saxifraga hirsuta, chosen as a model species due to the coexistence of green and anthocyanic leaves and the presence of an easily removable lower anthocyanic epidermis. Anthocyanins accumulated during autumn, which temporally matched the overstorey leaf fall. Patterns of development of abaxial anthocyanins and direct measurements of photochemical efficiency under monochromatic light were not consistent with a photoprotective hypothesis. Enhancement of light capture also seemed unlikely since the back-scattering of red light towards the lower mesophyll was negligible. Seed germination was similar under acyanic and anthocyanic leaves. A relevant consequence of abaxial anthocyanins was the dramatic reduction of light transmission through the leaf. The dark environment generated underneath the Saxifraga canopy was enhanced by the horizontal repositioning of leaves, which occurs in parallel with reddening. This might play a role in biotic interactions by inhibiting vital processes of competitors, which may be of especial importance in spring before the overstorey leaves sprout.