Investigating the Taenia solium Fatty Acid Binding Protein Superfamily for Their Immunological Outlook and Prospect for Therapeutic Targets.

Taenia solium, like other helminthic parasites, lacks key components of cellular machinery required for endogenous lipid biosynthesis. This deficiency compels the parasite to obtain all of its lipid requirements from its host. The passage of lipids across the cell membrane is tightly regulated. To facilitate effective lipid transport, the cestode parasite utilizes certain lipid binding proteins called FABPs. These FABPs bind with the lipid ligands and allow the transport of lipids across the membranes and into the cytosol. Here, by integrating a computational with homology protein prediction tools, we had identified five FABPs in the T. solium proteome. We confirmed their presence by RNA expression analysis of respective genes from the parasite's cysticerci transcript. During the molecular modeling and MD simulation studies, two of them, TsM_000544100 and TsM_001185100, were most stable. Furthermore, they had a robust interaction with the IgG1 molecule, as evidenced by MD simulation. In addition, by employing in silico screening, we had identified potential ligand interacting residues that are present on the probable druggable site. In combination with in vitro cysticidal assays, enalaprilat dihydrate showed efficacy against cysticerci, which suggests that FABPs play a significant role in the cysticercus life cycle. Together, we provided a detailed distribution of all FABPs expressed by T. solium cysticerci and the critical role of TsM_001185100 in cysticercus viability.

Taenia solium cysticerci's extracellular vesicles Attenuate the AKT/mTORC1 pathway for Alleviating DSS-induced colitis in a murine model.

The excretory-secretory proteome plays a pivotal role in both intercellular communication during disease progression and immune escape mechanisms of various pathogens including cestode parasites like Taenia solium. The cysticerci of T. solium causes infection in the central nervous system known as neurocysticercosis (NCC), which affects a significant population in developing countries. Extracellular vesicles (EVs) are 30-150-nm-sized particles and constitute a significant part of the secretome. However, the role of EV in NCC pathogenesis remains undetermined. Here, for the first time, we report that EV from T. solium larvae is abundant in metabolites that can negatively regulate PI3K/AKT pathway, efficiently internalized by macrophages to induce AKT and mTOR degradation through auto-lysosomal route with a prominent increase in the ubiquitination of both proteins. This results in less ROS production and diminished bacterial killing capability among EV-treated macrophages. Due to this, both macro-autophagy and caspase-linked apoptosis are upregulated, with a reduction of the autophagy substrate sequestome 1. In summary, we report that T. solium EV from viable cysts attenuates the AKT-mTOR pathway thereby promoting apoptosis in macrophages, and this may exert immunosuppression during an early viable stage of the parasite in NCC, which is primarily asymptomatic. Further investigation on EV-mediated immune suppression revealed that the EV can protect the mice from DSS-induced colitis and improve colon architecture. These findings shed light on the previously unknown role of T. solium EV and the therapeutic role of their immune suppression potential.

Proteostasis in neurodegenerative diseases.

Proteostasis is essential for normal function of proteins and vital for cellular health and survival. Proteostasis encompasses all stages in the "life" of a protein, that is, from translation to functional performance and, ultimately, to degradation. Proteins need native conformations for function and in the presence of multiple types of stress, their misfolding and aggregation can occur. A coordinated network of proteins is at the core of proteostasis in cells. Among these, chaperones are required for maintaining the integrity of protein conformations by preventing misfolding and aggregation and guide those with abnormal conformation to degradation. The ubiquitin-proteasome system (UPS) and autophagy are major cellular pathways for degrading proteins. Although failure or decreased functioning of components of this network can lead to proteotoxicity and disease, like neuron degenerative diseases, underlying factors are not completely understood. Accumulating misfolded and aggregated proteins are considered major pathomechanisms of neurodegeneration. In this chapter, we have described the components of three major branches required for proteostasis-chaperones, UPS and autophagy, the mechanistic basis of their function, and their potential for protection against various neurodegenerative conditions, like Alzheimer's, Parkinson's, and Huntington's disease. The modulation of various proteostasis network proteins, like chaperones, E3 ubiquitin ligases, proteasome, and autophagy-associated proteins as therapeutic targets by small molecules as well as new and unconventional approaches, shows promise.

Acetaminophen induces mitochondrial apoptosis through proteasome dysfunctions.

Acetaminophen is a known antipyretic and non-opioid analgesic for mild pain and fever. Numerous studies uncover their hidden chemotherapeutics applications, including chronic cancer pain management. Acetaminophen also represents an anti-proliferative effect in some cancer cells. Few studies also suggest that the use of Acetaminophen can trigger apoptosis and impede cellular growth. However, Acetaminophen's molecular potential and precise mechanism against improper cellular proliferation and use as an effective anti-proliferative agent still need to be better understood. Here, our current findings show that Acetaminophen induces proteasomal dysfunctions, resulting in aberrant protein accumulation and mitochondrial abnormalities, and consequently induces cell apoptosis. We observed that the Acetaminophen treatment leads to improper aggregation of ubiquitylated expanded polyglutamine proteins, which may be due to the dysfunctions of proteasome activities. Our in-silico analysis suggests the interaction of Acetaminophen and proteasome. Furthermore, we demonstrated the accumulation of proteasome substrates and the depletion of proteasome activities after treating Acetaminophen in cells. Acetaminophen induces proteasome dysfunctions and mitochondrial abnormalities, leading to pro-apoptotic morphological changes and apoptosis successively. These results suggest that Acetaminophen can induce cell death and may retain a promising anti-proliferative effect. These observations can open new possible molecular strategies in the near future for developing and designing specific and effective proteasome inhibitors, which can be helpful in conjugation with other anti-tumor drugs for their better efficiency.

Taenia solium excretory secretory proteins (ESPs) suppresses TLR4/AKT mediated ROS formation in human macrophages via hsa-miR-125.

BACKGROUND: Helminth infections are a global health menace affecting 24% of the world population. They continue to increase global disease burden as their unclear pathology imposes serious challenges to patient management. Neurocysticercosis is classified as neglected tropical disease and is caused by larvae of helminthic cestode Taenia solium. The larvae infect humans and localize in central nervous system and cause NCC; a leading etiological agent of acquired epilepsy in the developing world. The parasite has an intricate antigenic make-up and causes active immune suppression in the residing host. It communicates with the host via its secretome which is complex mixture of proteins also called excretory secretory products (ESPs). Understanding the ESPs interaction with host can identify therapeutic intervention hot spots. In our research, we studied the effect of T. solium ESPs on human macrophages and investigated the post-translation switch involved in its immunopathogenesis. METHODOLOGY: T. solium cysts were cultured in vitro to get ESPs and used for treating human macrophages. These macrophages were studied for cellular signaling and miR expression and quantification at transcript and protein level. CONCLUSION: We found that T. solium cyst ESPs treatment to human macrophages leads to activation of Th2 immune response. A complex cytokine expression by macrophages was also observed with both Th1 and Th2 cytokines in milieu. But, at the same time ESPs modulated the macrophage function by altering the host miR expression as seen with altered ROS activity, apoptosis and phagocytosis. This leads to activated yet compromised functional macrophages, which provides a niche to support parasite survival. Thus T. solium secretome induces Th2 phenomenon in macrophages which may promote parasite's survival and delay their recognition by host immune system.

El monitoreo orientado a la equidad en el contexto de la cobertura universal de salud / Equity-oriented monitoring in the context of universal health coverage

El monitoreo de las desigualdades en la salud es fundamental para el logro progresivo y equitativo de la cobertura universal de salud. Para que tenga éxito, el monitoreo global de las desigualdades debe ser lo suficientemente intuitivo a fin de que pueda adoptarse ampliamente y debe mantener al mismo tiempo su credibilidad técnica. En este artículo se analizan algunas consideraciones metodológicas para el monitoreo de la cobertura universal de salud orientado a la equidad y se proponen recomendaciones con respecto al monitoreo y el establecimiento de metas. La desigualdad es multidimensional, de modo que el grado de desigualdad puede variar considerablemente entre distintas dimensiones, como la posición económica, la educación, el sexo y la residencia urbana o rural. Por ello, el monitoreo global debe incluir dimensiones complementarias de la desigualdad (como la posición económica y la residencia urbana o rural) y el sexo. Para una dimensión dada de la desigualdad, deben establecerse subgrupos para el monitoreo considerando la aplicabilidad de los criterios entre los países y la heterogeneidad de los subgrupos. En el caso de la desigualdad asociada a la posición económica, recomendamos formar subgrupos utilizando quintiles y para la desigualdad por residencia urbana o rural, recomendamos una categorización binaria. La desigualdad abarca las poblaciones, por lo que los enfoques apropiados para el monitoreo deben basarse en comparaciones entre dos subgrupos (enfoque de brecha) o entre múltiples subgrupos (enfoque de gradiente o espectro completo). Al medirse la desigualdad, las mediciones absolutas y relativas deben comunicarse al mismo tiempo, junto con los datos desagregados; la desigualdad debe informarse junto con el promedio nacional. Recomendamos establecer metas que se basen en reducciones proporcionales de la desigualdad absoluta en los grupos poblacionales. Crear la capacidad de monitorear las desigualdades en la salud es oportuno, pertinente e importante. El desarrollo de sistemas de información de salud de alta calidad, incluidas la recolección, el análisis y la interpretación de los datos y las prácticas de presentación de informes vinculadas a los ciclos de revisión y evaluación en los sistemas de salud, permitirá realizar un monitoreo eficaz de las desigualdades en la salud a escala mundial y nacional. Estas medidas apoyarán el logro progresivo de la cobertura universal de salud orientado a la equidad.

Monitoring inequalities in health is fundamental to the equitable and progressive realization of universal health coverage (UHC). A successful approach to global inequality monitoring must be intuitive enough for widespread adoption, yet maintain technical credibility. This article discusses methodological considerations for equity-oriented monitoring of UHC, and proposes recommendations for monitoring and target setting. Inequality is multidimensional, such that the extent of inequality may vary considerably across different dimensions such as economic status, education, sex, and urban/rural residence. Hence, global monitoring should include complementary dimensions of inequality (such as economic status and urban/rural residence) as well as sex. For a given dimension of inequality, subgroups for monitoring must be formulated taking into consideration applicability of the criteria across countries and subgroup heterogeneity. For economic-related inequality, we recommend forming subgroups as quintiles, and for urban/rural inequality we recommend a binary categorization. Inequality spans populations, thus appropriate approaches to monitoring should be based on comparisons between two subgroups (gap approach) or across multiple subgroups (whole spectrum approach). When measuring inequality absolute and relative measures should be reported together, along with disaggregated data; inequality should be reported alongside the national average. We recommend targets based on proportional reductions in absolute inequality across populations. Building capacity for health inequality monitoring is timely, relevant, and important. The development of high-quality health information systems, including data collection, analysis, interpretation, and reporting practices that are linked to review and evaluation cycles across health systems, will enable effective global and national health inequality monitoring. These actions will support equity-oriented progressive realization of UHC.

De la evidencia a la acción sobre los determinantes sociales de la salud mediante el instrumento urban heart en la región de Las Américas / From evidence to action on the social determinants of health through the urban heart instrument in the Americas region

Objetivo. Evaluar la experiencia de determinadas ciudades de la Región de las Américas mediante el empleod el instrumento de evaluación y respuesta en materia de equidad en salud en medios urbanos(Urban HEART), introducido por la Organización Mundial de la Salud en el 2010, y determinar suutilidad para apoyar las iniciativas de los gobiernospara incrementar la equidad en salud utilizando el enfoque de los determinantes sociales de la salud(DSS)...

Linking evidence to action on social determinants of health using Urban HEART in the Americas / De la evidencia a la acción sobre los determinantes sociales de la salud mediante el instrumento Urban HEART en la Región de las Américas

OBJECTIVE: To evaluate the experience of select cities in the Americas using the Urban Health Equity Assessment and Response Tool (Urban HEART) launched by the World Health Organization in 2010 and to determine its utility in supporting government efforts to improve health equity using the social determinants of health (SDH) approach METHODS: The Urban HEART experience was evaluated in four cities from 2010-2013: Guarulhos (Brazil), Toronto (Canada), and Bogotá and Medellín (Colombia). Reports were submitted by Urban HEART teams in each city and supplemented by first-hand accounts of key informants. The analysis considered each city's networks and the resources it used to implement Urban HEART; the process by which each city identified equity gaps and prioritized interventions; and finally, the facilitators and barriers encountered, along with next steps RESULTS: In three cities, local governments spearheaded the process, while in the fourth (Toronto), academia initiated and led the process. All cities used Urban HEART as a platform to engage multiple stakeholders. Urban HEART's Matrix and Monitor were used to identify equity gaps within cities. While Bogotá and Medellín prioritized among existing interventions, Guarulhos adopted new interventions focused on deprived districts. Actions were taken on intermediate determinants, e.g., health systems access, and structural SDH, e.g., unemployment and human rights CONCLUSIONS: Urban HEART provides local governments with a simple and systematic method for assessing and responding to health inequity. Through the SDH approach, the tool has provided a platform for intersectoral action and community involvement. While some areas of guidance could be strengthened, Urban HEART is a useful tool for directing local action on health inequities, and should be scaled up within the Region of the Americas, building upon current experience.

OBJETIVO: Evaluar la experiencia de determinadas ciudades de la Región de las Américas mediante el empleo del instrumento de evaluación y respuesta en materia de equidad en salud en medios urbanos (Urban HEART), introducido por la Organización Mundial de la Salud en el 2010, y determinar su utilidad para apoyar las iniciativas de los gobiernos para incrementar la equidad en salud utilizando el enfoque de los determinantes sociales de la salud (DSS). MÉTODOS: Se evaluó la experiencia de Urban HEART en cuatro ciudades: Guarulhos (Brasil), Toronto (Canadá), y Bogotá y Medellín (Colombia). Los equipos de Urban HEART de cada ciudad presentaron informes y estos fueron complementados por las explicaciones directas de informantes clave. El análisis tuvo en cuenta las redes y los recursos de cada ciudad utilizados para implantar el Urban HEART, el proceso mediante el cual cada ciudad determinó las brechas en materia de equidad y las intervenciones prioritarias y, por último, las barreras y los factores favorecedores detectados, así como las medidas a adoptar RESULTADOS: En tres ciudades, los gobiernos locales lideraron el proceso, mientras que en la cuarta (Toronto), este fue iniciado y conducido por la comunidad académica. Todas las ciudades utilizaron Urban HEART como una plataforma para hacer participar a múltiples interesados directos. Se utilizaron las herramientas Matriz y Monitor de Urban HEART para determinar las brechas de equidad en las ciudades. Mientras Bogotá y Medellín establecieron prioridades entre las intervenciones ya existentes, Guarulhos adoptó nuevas intervenciones centradas en los distritos desprotegidos. Se adoptaron medidas en materia de determinantes intermedios, por ejemplo, el acceso a los sistemas de salud, y los DSS estructurales, tales como el desempleo y los derechos humanos CONCLUSIONES: El instrumento Urban HEART proporciona a los gobiernos locales un método sencillo y sistemático para evaluar y responder a la inequidad en salud. Mediante el enfoque de los DSS, esta herramienta ha proporcionado una plataforma para la acción intersectorial y la participación comunitaria. Aunque podrían fortalecerse algunos aspectos relacionados con la provisión de directrices, Urban HEART constituye una herramienta útil para dirigir la acción local sobre las inequidades en salud y debe extenderse a toda la Región de las Américas aprovechando la experiencia actual.