Doble synergetic anticancer activity through a combined chemo-photodynamic therapy and bioimaging of a novel Cas-ZnONPs all-in-one system.

A strategy for cancer treatment was implemented, based on chemo-photodynamic therapy, utilizing a novel formulation, low-cost system called Cas-ZnONPs. This system consisted of the incorporation of Casiopeina III-ia (CasIII-ia), a hydrophilic copper coordination compound with well-documented anti-neoplastic activity, on Zinc oxide nanoparticles (ZnONPs) with apoptotic activity and lipophilicity, allowing them to permeate biological barriers. Additionally, ZnONPs exhibited fluorescence, with emission at different wavelengths depending on their agglomeration and enabling real-time tracking biodistribution. Also, ZnONPs served as a sensitizer, generating reactive oxygen species (ROS) in situ. In in vitro studies on HeLa and MDA-MB-231 cell lines, a synergistic effect was observed with the impregnated CasIII-ia on ZnONPs. The anticancer activity had an increase in cellular inhibition, depending on the dose of exposure to UV-vis irradiation. In in vivo studies utilized zebrafish models for xenotransplanting stained MDA-MB-231 cells and testing the effectiveness of Cas-ZnONPs treatment. The treatment successfully eliminated cancer cells, both when combined with Photodynamic Therapy (PDT) and when used alone. However, a significantly higher concentration (50 times) of Cas-ZnONPs was required in the absence of PDT. This demonstrates the potential of Cas-ZnONPs in cancer treatment, especially when combined with PDT.

Neoantigen-specific CD4+ tumor-infiltrating lymphocytes are potent effectors identified within adoptive cell therapy products for metastatic melanoma patients.

BACKGROUND: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) is a promising immunotherapeutic approach for patients with advanced solid tumors. While numerous advances have been made, the contribution of neoantigen-specific CD4+T cells within TIL infusion products remains underexplored and therefore offers a significant opportunity for progress. METHODS: We analyzed infused TIL products from metastatic melanoma patients previously treated with ACT for the presence of neoantigen-specific T cells. TILs were enriched on reactivity to neoantigen peptides derived and prioritized from patient sample-directed mutanome analysis. Enriched TILs were further investigated to establish the clonal neoantigen response with respect to function, transcriptomics, and persistence following ACT. RESULTS: We discovered that neoantigen-specific TIL clones were predominantly CD4+ T cells and were present in both therapeutic responders and non-responders. CD4+ TIL demonstrated an effector T cell response with cytotoxicity toward autologous tumor in a major histocompatibility complex class II-dependent manner. These results were validated by paired TCR and single cell RNA sequencing, which elucidated transcriptomic profiles distinct to neoantigen-specific CD4+ TIL. CONCLUSIONS: Despite methods which often focus on CD8+T cells, our study supports the importance of prospective identification of neoantigen-specific CD4+ T cells within TIL products as they are a potent source of tumor-specific effectors. We further advocate for the inclusion of neoantigen-specific CD4+ TIL in future ACT protocols as a strategy to improve antitumor immunity.

Late puberty onset and lack of acne during adolescence reduce high-grade prostate cancer at adulthood.

BACKGROUND: The interplay between pubertal events patterns (PEP) and prostate cancer (PCa) remains poorly understood. Therefore, we investigated the association of PEP with the odds of PCa, and PCa histological differentiation in men residents of Mexico city. METHODS: In this case-control study, we analyzed the information of 371 incident prostate cancer cases and 775 controls matched on age (±5 years). High-grade prostate cancer was classified with Gleason score at diagnosis as ≥8. With information related to beard growth, age at maximum height attainment, and acne severity, the k-medoids algorithm was used to identify three mutually exclusive PEP (early, intermediate, and late). This association was evaluated using multivariable nonconditional logistic regression models. RESULTS: Men with late PEP, characterized by age at maximum height attainment at around 23 years and no history of acne, was inversely associated with incident (odds ratio [OR]: 0.27; 95% confidence interval [CI]: 0.15-0.48, p trend <0.01) and high-grade prostate cancer (OR: 0.24; 95% CI: 0.09-0.59, p trend <0.01). Similar associations were observed even after adjusting by IGF-1 (OR: 0.19; 95% CI: 0.06-0.58) and androgens excretion (OR: 0.21; 95% CI: 0.06-0.66). Only the association between the absence of acne and prostate cancer remained significant after adjustment by these biomarkers. CONCLUSIONS: This study suggests that pubertal characteristics might be helpful in identifying risk groups, among which, secondary prevention strategies could be applied. Also, the results agree with previous work suggesting other potential biological mechanisms involved in the etiology of prostate cancer such as the infectious and inflammatory pathways.

The Antiviral Compound PSP Inhibits HIV-1 Entry via PKR-Dependent Activation in Monocytic Cells.

Actin depolymerization factor (ADF) cofilin-1 is a key cytoskeleton component that serves to lessen cortical actin. HIV-1 manipulates cofilin-1 regulation as a pre- and post-entry requisite. Disruption of ADF signaling is associated with denial of entry. The unfolded protein response (UPR) marker Inositol-Requiring Enzyme-1α (IRE1α) and interferon-induced protein (IFN-IP) double-stranded RNA- activated protein kinase (PKR) are reported to overlap with actin components. In our published findings, Coriolus versicolor bioactive extract polysaccharide peptide (PSP) has demonstrated anti-HIV replicative properties in THP1 monocytic cells. However, its involvement towards viral infectivity has not been elucidated before. In the present study, we examined the roles of PKR and IRE1α in cofilin-1 phosphorylation and its HIV-1 restrictive roles in THP1. HIV-1 p24 antigen was measured through infected supernatant to determine PSP's restrictive potential. Quantitative proteomics was performed to analyze cytoskeletal and UPR regulators. PKR, IRE1α, and cofilin-1 biomarkers were measured through immunoblots. Validation of key proteome markers was done through RT-qPCR. PKR/IRE1α inhibitors were used to validate viral entry and cofilin-1 phosphorylation through Western blots. Our findings show that PSP treatment before infection leads to an overall lower infectivity. Additionally, PKR and IRE1α show to be key regulators in cofilin-1 phosphorylation and viral restriction.

Energy homeostasis genes modify the association between serum concentrations of IGF-1 and IGFBP-3 and breast cancer risk.

Breast cancer is a multifactorial disease in which the interplay among multiple risk factors remains unclear. Energy homeostasis genes play an important role in carcinogenesis and their interactions with the serum concentrations of IGF-1 and IGFBP-3 on the risk of breast cancer have not yet been investigated. The aim of this study was to assess the modifying effect of the genetic variation in some energy homeostasis genes on the association of serum concentrations of IGF-1 and IGFBP-3 with breast cancer risk. We analyzed 78 SNPs from 10 energy homeostasis genes in premenopausal women from the 4-Corner's Breast Cancer Study (61 cases and 155 controls) and the Mexico Breast Cancer Study (204 cases and 282 controls). After data harmonization, 71 SNPs in HWE were included for interaction analysis. Two SNPs in two genes (MBOAT rs13272159 and NPY rs16131) showed an effect modification on the association between IGF-1 serum concentration and breast cancer risk (Pinteraction < 0.05, adjusted Pinteraction < 0.20). In addition, five SNPs in three genes (ADIPOQ rs182052, rs822391 and rs7649121, CARTPT rs3846659, and LEPR rs12059300) had an effect modification on the association between IGFBP-3 serum concentration and breast cancer risk (Pinteraction < 0.05, adjusted Pinteraction < 0.20). Our findings showed that variants of energy homeostasis genes modified the association between the IGF-1 or IGFBP-3 serum concentration and breast cancer risk in premenopausal women. These findings contribute to a better understanding of this multifactorial pathology.

Protective effects of Surfacen® in allergen-induced asthma mice model.

Airway obstruction with increased airway resistance in asthma, commonly caused by smooth muscle constriction, mucosal edema and fluid secretion into the airway lumen, may partly be due to a poor function of pulmonary surfactant. Surfacen®, a clinical pulmonary surfactant, has anti-inflammatory action, but its effect on asthma has not been studied. This work aimed to evaluate the effect of Surfacen® in a murine allergen-induced acute asthma model, using house dust mite allergens. In a therapeutic experimental setting, mice were first sensitized by being administered with two doses (sc) of Dermatophagoides siboney allergen in aluminum hydroxide followed by one intranasal administration of the allergen. Then, sensitized mice were administered with aerosol of hypertonic 3% NaCl, Salbutamol 0.15 mg/kg, or Surfacen® 16 mg in a whole-body chamber on days 22, 23, and 24. Further, mice were subjected to aerosol allergen challenge on day 25. Surfacen® showed bronchial dilation and inhibition of Th2 inflammation (lower levels of IL-5 and IL-13 in broncoalveolar lavage) which increased IFN-γ and unchanged IL-10 in BAL. Moreover, Sufacen® administration was associated with a marked inhibition of the serum specific IgE burst upon allergen exposure, as well as, IgG2a antibody increase, suggesting potential anti-allergy effects with inclination towards Th1. These results support also the effectiveness of the aerosol administration method to deliver the drug into lungs. Surfacen® induced a favorable pharmacological effect, with a bronchodilator outcome comparable to Salbutamol, consistent with its action as a lung surfactant, and with an advantageous anti-inflammatory and anti-allergic immunomodulatory effect.

Children and adolescents with neurodevelopmental disorders show cognitive heterogeneity and require a person-centered approach.

We aimed to identify patterns of cognitive differences and characterize subgroups of Mexican children and adolescents with three neurodevelopmental disorders (NDD): intellectual disability (ID), autism spectrum disorders (ASD) and attention deficit/hyperactivity disorder (ADHD). The sample included 74 children and adolescents 6-15 years; 34% had ID, ASD or ADHD, 47% had ID in comorbidity with ASD, ADHD or both, 11% had ASD + ADHD, 8% were children without NDD. We applied WISC-IV, Autism Diagnostic Interview-Revised, Mini-International Neuropsychiatric Structured Interview, Child Behavior Checklist, and UNICEF Child Functioning Module. We evaluated the normality of the WISC-IV sub-scales using the Shapiro-Francia test, then conducted a latent class analysis and assessed inter-class differences in terms of household, parent and child characteristics. The following four-class solution best fit the data: "Lower Cognitive Profile" (LCP), "Lower Working Memory" (LWM), "Higher Working Memory" (HWM), "Higher Cognitive Profile" (HCP). LCP included most of the children with ID, who had a low Working Memory (WM) index score. LWM included mainly children with ASD or ID + ADHD; their Perceptual Reasoning (PR) and Processing Speed (PS) index scores were much higher than those for Verbal Comprehension (VC) and WM. HWM included children with ASD or ADHD; their scores for PR, PS and VC were high with lower WM (although higher than for LWM). HCP included children without NDD and with ASD or ADHD or both and had the highest scores on all indices. Children with NDD show cognitive heterogeneity and thus require individualized treatment plans.

Brief Report: Delayed Diagnosis of Treatable Inborn Errors of Metabolism in Children with Autism and Other Neurodevelopmental Disorders.

The objective of our study was to evaluate the frequency of treatable inborn errors of metabolism (IEM) in a clinical sample of Mexican children and adolescents with neurodevelopmental disorders (NDD). Amino acids and acylcarnitines in blood samples of 51 unrelated children and adolescents were analyzed by tandem mass spectrometry to detect treatable IEM of small molecules. One patient with isovaleric acidemia and autism spectrum disorder (ASD) and another with beta-ketothiolase deficiency and ASD/intellectual disability/attention-deficit/hyperactivity disorder (ADHD) were diagnosed, indicating an IEM frequency of 3.9% (1:26 subjects). The high frequency of treatable IEM indicates the need to perform a minimum metabolic screening as part of the diagnostic approach for patient with NDD, particularly when newborn screening programs are limited to a few disorders.

Communication patterns in the doctor-patient relationship: evaluating determinants associated with low paternalism in Mexico.

BACKGROUND: Paternalism/overprotection limits communication between healthcare professionals and patients and does not promote shared therapeutic decision-making. In the global north, communication patterns have been regulated to promote autonomy, whereas in the global south, they reflect the physician's personal choices. The goal of this study was to contribute to knowledge on the communication patterns used in clinical practice in Mexico and to identify the determinants that favour a doctor-patient relationship characterized by low paternalism/autonomy. METHODS: A self-report study on communication patterns in a sample of 761 mental healthcare professionals in Central and Western Mexico was conducted. Multiple ordinal logistic regression models were used to analyse paternalism and associated factors. RESULTS: A high prevalence (68.7% [95% CI 60.0-70.5]) of paternalism was observed among mental health professionals in Mexico. The main determinants of low paternalism/autonomy were medical specialty (OR 1.67 [95% CI 1.16-2.40]) and gender, with female physicians being more likely to explicitly share diagnoses and therapeutic strategies with patients and their families (OR 1.57 [95% CI 1.11-2.22]). A pattern of highly explicit communication was strongly associated with low paternalism/autonomy (OR 12.13 [95% CI 7.71-19.05]). Finally, a modifying effect of age strata on the association between communication pattern or specialty and low paternalism/autonomy was observed. CONCLUSIONS: Among mental health professionals in Mexico, high paternalism prevailed. Gender, specialty, and a pattern of open communication were closely associated with low paternalism/autonomy. Strengthening health professionals' competencies and promoting explicit communication could contribute to the transition towards more autonomist communication in clinical practice in Mexico. The ethical implications will need to be resolved in the near future.

[Open communication between mental health professionals and parents of patients with intellectual disabilities]. / Comunicación abierta entre profesionales de la salud mental y padres de pacientes con discapacidad intelectual.

OBJECTIVE: To estimate the factors associated with open communication between mental health professionals and parents of patients with intellectual disabilities and other neurodevelopmental disorders. MATERIALS AND METHODS: Cross-sectional survey in 759 mental health professionals. The association between the pattern of open communication and the attributes of communication was estimated through a logistic, ordinal, multivariate model. RESULTS: The prevalence of the pattern of open communication in mental health professionals was 30.6% (95%CI 27.4-34.0). The associated factors were younger age (RM=2.42, 95% CI 1.57-3.75), specialty (RM= 1.56, 95%CI 1.09-2.23), high value to the truth (RM= 4.95, 95% CI 3.21-7.65), low paternalism (RM= 10.93, 95%CI 7.22-16.52) and courses in bioethics (RM= 1.45, 95%CI 1.01-2.09), adjusted for confusing variables. CONCLUSIONS: Mental health professionals reported low levels of open com-munication with parents of people with neurovelopmental disorders, so prioritizing the value to the truth, promoting less paternalism, and respecting the autonomy of patients, can contribute to changing these patterns of communication in clinical practice in Mexico.

OBJETIVO: Estimar los factores asociados con la comunicación abierta entre profesionales de la salud mental y padres de pacientes con discapacidad intelectual y otros trastornos del neurodesarrollo. MATERIAL Y MÉTODOS: Encuesta transversal en 759 profesionales de la salud mental. Se estimó la asociación entre el patrón de comunicación abierto y los atributos de la comunicación a través de un modelo logísti-co, ordinal y multivariado. RESULTADOS: La prevalencia del patrón de comunicación abierta en profesionales de la salud mental fue de 30.6% (IC95% 27.4-34.0). Los factores asocia-dos fueron menor edad (RM=2.42, IC95% 1.57-3.75), espe-cialidad (RM=1.56, IC95% 1.09-2.23), alto valor a la verdad (RM=4.95, IC95% 3.21-7.65), bajo paternalismo (RM=10.93, IC95% 7.22-16.52) y cursos de bioética (RM=1.45, IC95% 1.01-2.09), ajustando por variables confusoras. CONCLUSIONES: Los profesionales de la salud mental reportaron bajos niveles de comunicación abierta con los padres de personas con trastornos del neurodesarrollo, por lo que priorizar el valor a la verdad, promover un menor paternalismo y el respeto a la autonomía de los pacientes puede contribuir a cambiar estos patrones de comunicación en la práctica clínica en México.

Comunicación abierta entre profesionales de la salud mental y padres de pacientes con discapacidad intelectual / Open communication between mental health professionals and parents of patients with intellectual disabilities

Resumen Objetivo: Estimar los factores asociados con la comunicación abierta entre profesionales de la salud mental y padres de pacientes con discapacidad intelectual y otros trastornos del neurodesarrollo. Material y métodos: Encuesta transversal en 759 profesionales de la salud mental. Se estimó la asociación entre el patrón de comunicación abierto y los atributos de la comunicación a través de un modelo logístico, ordinal y multivariado. Resultados: La prevalencia del patrón de comunicación abierta en profesionales de la salud mental fue de 30.6% (IC95% 27.4-34.0). Los factores asociados fueron menor edad (RM=2.42, IC95% 1.57-3.75), especialidad (RM=1.56, IC95% 1.09-2.23), alto valor a la verdad (RM=4.95, IC95% 3.21-7.65), bajo paternalismo (RM=10.93, IC95% 7.22-16.52) y cursos de bioética (RM=1.45, IC95% 1.01-2.09), ajustando por variables confusoras. Conclusión: Los profesionales de la salud mental reportaron bajos niveles de comunicación abierta con los padres de personas con trastornos del neurodesarrollo, por lo que priorizar el valor a la verdad, promover un menor paternalismo y el respeto a la autonomía de los pacientes puede contribuir a cambiar estos patrones de comunicación en la práctica clínica en México.

Abstract Objective: To estimate the factors associated with open communication between mental health professionals and parents of patients with intellectual disabilities and other neurodevelopmental disorders. Materials and methods: Cross-sectional survey in 759 mental health professionals. The association between the pattern of open communication and the attributes of communication was estimated through a logistic, ordinal, multivariate model. Results: The prevalence of the pattern of open communication in mental health professionals was 30.6% (95%CI 27.4-34.0). The associated factors were younger age (RM=2.42, 95% CI 1.57-3.75), specialty (RM= 1.56, 95%CI 1.09-2.23), high value to the truth (RM= 4.95, 95% CI 3.21-7.65), low paternalism (RM= 10.93, 95%CI 7.22-16.52) and courses in bioethics (RM= 1.45, 95%CI 1.01-2.09), adjusted for confusing variables. Conclusion: Mental health professionals reported low levels of open communication with parents of people with neurovelopmental disorders, so prioritizing the value to the truth, promoting less paternalism, and respecting the autonomy of patients, can contribute to changing these patterns of communication in clinical practice in Mexico.

Biosensors Platform Based on Chitosan/AuNPs/Phthalocyanine Composite Films for the Electrochemical Detection of Catechol. The Role of the Surface Structure.

Biosensor platforms consisting of layer by layer films combining materials with different functionalities have been developed and used to obtain improved catechol biosensors. Tyrosinase (Tyr) or laccase (Lac) were deposited onto LbL films formed by layers of a cationic linker (chitosan, CHI) alternating with layers of anionic electrocatalytic materials (sulfonated copper phthalocyanine, CuPcS or gold nanoparticles, AuNP). Films with different layer structures were successfully formed. Characterization of surface roughness and porosity was carried out using AFM. Electrochemical responses towards catechol showed that the LbL composites efficiently improved the electron transfer path between Tyr or Lac and the electrode surface, producing an increase in the intensity over the response in the absence of the LbL platform. LbL structures with higher roughness and pore size facilitated the diffusion of catechol, resulting in lower LODs. The [(CHI)-(AuNP)-(CHI)-(CuPcS)]2-Tyr showed an LOD of 8.55∙10-4 µM, which was one order of magnitude lower than the 9.55·10-3 µM obtained with [(CHI)-(CuPcS)-(CHI)-(AuNP)]2-Tyr, and two orders of magnitude lower than the obtained with other nanostructured platforms. It can be concluded that the combination of adequate materials with complementary activity and the control of the structure of the platform is an excellent strategy to obtain biosensors with improved performances.

Fasciola hepatica GST downregulates NF-κB pathway effectors and inflammatory cytokines while promoting survival in a mouse septic shock model.

Parasitic helminths and helminth-derived molecules have demonstrated to possess powerful anti-inflammatory properties and confirmed therapeutic effects on inflammatory diseases. The helminth Fasciola hepatica has been reported to suppress specific Th1 specific immune responses induced by concurrent bacterial infections, thus demonstrating its anti-inflammatory ability in vivo. In this study, we demonstrate that native F. hepatica glutathione S-transferase (nFhGST), a major parasite excretory-secretory antigen, majorly comprised of Mu-class GST isoforms, significantly suppresses the LPS-induced TNFα and IL1ß of mouse bone-marrow derived macrophages in vitro and the pro-inflammatory cytokine/chemokine storm within C57BL/6 mice exposed to lethal doses of LPS increasing their survival rate by more than 85%. Using THP1-Blue CD14 cells, a human monocyte cell line, we also demonstrate that nFhGST suppresses NF-κB activation in response to multiple TLR-ligands, including whole bacteria clinical isolates and this suppression was found to be dose-dependent and independent of the timing of exposure. Moreover, the suppressive effect of nFhGST on NF-κB activation was shown to be independent of enzyme activity or secondary structure of protein. As part of its anti-inflammatory effect nFhGST target multiple proteins of the canonic and non-canonic NF-κB signaling pathway as well as also JAK/STAT pathway. Overall, our results demonstrate the potent anti-inflammatory properties of nFhGST and its therapeutic potential as an anti-inflammatory agent.

Frequency of the T307A, N680S, and -29G>A single-nucleotide polymorphisms in the follicle-stimulating hormone receptor in Mexican subjects of Hispanic ancestry.

BACKGROUND: FSHR SNPs may influence the ovarian sensitivity to endogenous and exogenous FSH stimulation. Given the paucity of data on the FSHR c.919A > G, c.2039A > G and - 29G > A SNPs in Hispanic population, we here analyzed their frequency distribution in Mexican mestizo women. METHODS: Samples from 224 Mexican mestizo women enrolled in an IVF program as well as a genotype database from 8182 Mexican mestizo subjects, were analyzed for FSHR SNPs at positions c.919, c.2039 and - 29G > A. Association between the genetic variants and reproductive outcomes was assessed. RESULTS: The c.919 and c.2039 SNPs were in strong linkage disequilibrium and their corresponding genotype frequencies in the IVF group were: AA 46.8%, AG 44.2%, and GG 8.9%, and AA 41.9%, AG 48.2% and GG 9.8%, respectively. For the -29G > A SNP, genotype frequencies were 27% (GG), 50% (GA) and 23% (AA). In normal oocyte donors with the c.2039 GG genotype, the number of oocytes recovered after ovarian stimulation (COS) were significantly (p < 0.01) lower than in those bearing other genotypes in this or the -29G > A SNP. Analysis of the large scale database revealed that both allelic and genotype frequencies for the three SNPs were very similar to those detected in the IVF cohort (p ≥ 0.38) and that female carriers of the c.2039 G allele tended to present lower number of pregnancies than women bearing the AA genotype; this trend was stronger when women with more Native American ancestry was separately analyzed (OR = 2.0, C.I. 95% 1.03-3.90, p = 0.04). There were no differences or trends in the number of pregnancies among the different genotypes of the -29G > A SNP. CONCLUSIONS: The frequency of the GG/GG combination genotype for the c.919 and c.2039 SNPs in Mexican hispanics is among the lowest reported. The GG genotype is associated with decreased number of oocytes recovered in response to COS as well as to lower pregnancy rates in Hispanic women from the general population. The absence of any effect of the -29AA genotype on the response to COS, indicates that there is no need to perform this particular genotype testing in Hispanic women with the purpose of providing an individually-tailored COS protocol.

Naturally Derived Anti-HIV Polysaccharide Peptide (PSP) Triggers a Toll-Like Receptor 4-Dependent Antiviral Immune Response.

AIM: Intense interest remains in the identification of compounds to reduce human immunodeficiency virus type 1 (HIV-1) replication. Coriolus versicolor's polysaccharide peptide (PSP) has been demonstrated to possess immunomodulatory properties with the ability to activate an innate immune response through Toll-like receptor 4 (TLR4) showing insignificant toxicity. This study sought to determine the potential use of PSP as an anti-HIV agent and whether its antiviral immune response was TLR4 dependent. MATERIALS AND METHODS: HIV-1 p24 and anti-HIV chemokine release was assessed in HIV-positive (HIV+) THP1 cells and validated in HIV+ peripheral blood mononuclear cells (PBMCs), to determine PSP antiviral activity. The involvement of TLR4 activation in PSP anti-HIV activity was evaluated by inhibition. RESULTS: PSP showed a promising potential as an anti-HIV agent, by downregulating viral replication and promoting the upregulation of specific antiviral chemokines (RANTES, MIP-1α/ß, and SDF-1α) known to block HIV-1 coreceptors in THP1 cells and human PBMCs. PSP produced a 61% viral inhibition after PSP treatment in HIV-1-infected THP1 cells. Additionally, PSP upregulated the expression of TLR4 and TLR4 inhibition led to countereffects in chemokine expression and HIV-1 replication. CONCLUSION: Taken together, these findings put forward the first evidence that PSP exerts an anti-HIV activity mediated by TLR4 and key antiviral chemokines. Elucidating these new molecular mediators may reveal additional drug targets and open novel therapeutic avenues for HIV-1 infection.

Metabolic screening and metabolomics analysis in the Intellectual Developmental Disorders Mexico Study.

OBJECTIVE: Inborn errors of metabolism (IEM) are genetic conditions that are sometimes associated with intellectual developmental disorders (IDD). The aim of this study is to contribute to the metabolic characterization of IDD of unknown etiology in Mexico. MATERIALS AND METHODS: Metabolic screening using tandem mass spectrometry and fluorometry will be performed to rule out IEM. In addition, target metabolomic analysis will be done to characterize the metabolomic profile of patients with IDD. CONCLUSION: Identification of new metabolomic profiles associated with IDD of unknown etiology and comorbidities will contribute to the development of novel diagnostic and therapeutic schemes for the prevention and treatment of IDD in Mexico.

HIV-1 Gp120 clade B/C induces a GRP78 driven cytoprotective mechanism in astrocytoma.

HIV-1 clades are known to be one of the key factors implicated in modulating HIV-associated neurocognitive disorders. HIV-1 B and C clades account for the majority of HIV-1 infections, clade B being the most neuropathogenic. The mechanisms behind HIV-mediated neuropathogenesis remain the subject of active research. We hypothesized that HIV-1 gp120 clade B and C proteins may exert differential proliferation, cell survival and NeuroAIDS effects in human astrocytoma cells via the Unfolded Protein Response, an endoplasmic reticulum- based cytoprotective mechanism. The differential effect of gp120 clade B and C was evaluated using for the first time a Tandem Mass Tag isobaric labeling quantitative proteomic approach. Flow cytometry analyses were performed for cell cycle and cell death identification. Among the proteins differentiated by HIV-1 gp120 proteins figure cytoskeleton, oxidative stress, UPR markers and numerous glycolytic metabolism enzymes. Our results demonstrate that HIV-1 gp120 B induced migration, proliferative and protective responses granted by the expression of GRP78, while HIV-1 gp120 C induced the expression of key inflammatory and pro-apoptotic markers. These novel findings put forward the first evidence that GRP78 is a key player in HIV-1 clade B and C neuropathogenic discrepancies and can be used as a novel target for immunotherapies.

Metabolic screening and metabolomics analysis in the Intellectual Developmental Disorders Mexico Study / Tamiz bioquímico y metabolómico en el estudio de los trastornos del desarrollo intelectual en México

Abstract: Objective: Inborn errors of metabolism (IEM) are genetic conditions that are sometimes associated with intellectual developmental disorders (IDD). The aim of this study is to contribute to the metabolic characterization of IDD of unknown etiology in Mexico. Materials and methods: Metabolic screening using tandem mass spectrometry and fluorometry will be performed to rule out IEM. In addition, target metabolomic analysis will be done to characterize the metabolomic profile of patients with IDD. Conclusion: Identification of new metabolomic profiles associated with IDD of unknown etiology and comorbidities will contribute to the development of novel diagnostic and therapeutic schemes for the prevention and treatment of IDD in Mexico.

Resumen: Objetivo: Los errores innatos del metabolismo (EIM) son condiciones genéticas que pueden asociarse con trastornos del desarrollo intelectual (TDI). El objetivo de este estudio es contribuir a la caracterización metabólica de los pacientes con TDI de etiología desconocida. Material y métodos: Se realizará un tamiz metabólico mediante espectrometría de masas-tándem y fluorometría para descartar EIM; además, se analizará el perfil metabolómico de los pacientes con TDI. Conclusión: La identificación de perfiles metabolómicos asociados con los TDI de etiología desconocida contribuirá al desarrollo de nuevos esquemas diagnósticos y terapéuticos para la prevención y tratamiento de los TDI en México.

Targeting multiple pro-apoptotic signaling pathways with curcumin in prostate cancer cells.

Curcumin, an extract from the turmeric rhizome (Curcuma longa), is known to exhibit anti-inflammatory, antioxidant, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Accumulative data indicate that curcumin may induce cancer cell death. However, the detailed mechanism underlying its pro-apoptotic and anti-cancer effects remains to be elucidated. In the present study, we examined the signaling pathways triggered by curcumin, specifically, the exact molecular mechanisms of curcumin-induced apoptosis in highly metastatic human prostate cancer cells. The effect of curcumin was evaluated using for the first time in prostate cancer, a gel-free shotgun quantitative proteomic analysis coupled with Tandem Mass Tag isobaric labeling-based-signaling networks. Results were confirmed at the gene expression level by qRT-PCR and at the protein expression level by western blot and flow cytometry. Our findings revealed that curcumin induced an Endoplasmic Reticulum stress-mediated apoptosis in PC3. The mechanisms by which curcumin promoted cell death in these cells were associated with cell cycle arrest, increased reactive oxygen species, autophagy and the Unfolded Protein Response. Furthermore, the upregulation of ER stress was measured using key indicators of ER stress: Glucose-Regulated Protein 78, Inositol-Requiring Enzyme 1 alpha, Protein Disulfide isomerase and Calreticulin. Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12) and Poly (ADP-ribose) polymerase. The downregulated proteins include anti-apoptotic and anti-tumor markers, supporting their curcumin-induced pro-apoptotic role in prostate cancer cells. Taken together, these data suggest that curcumin may serve as a promising anticancer agent by inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses.