The impact of chemotherapy on adipose tissue remodeling: The molecular players involved in this tissue wasting.

The depletion of visceral and subcutaneous adipose tissue (AT) during chemotherapy significantly correlates with diminished overall survival and progression-free survival. Despite its clinical significance, the intricate molecular mechanisms governing this AT loss and its chemotherapy-triggered initiation remain poorly understood. Notably, the evaluation of AT remodeling in most clinical trials has predominantly relied on computerized tomography scans or bioimpedance, with molecular studies often conducted using animal or in vitro models. To address this knowledge gap, a comprehensive narrative review was conducted. The findings underscore that chemotherapy serves as a key factor in inducing AT loss, exacerbating cachexia, a paraneoplastic syndrome that significantly compromises patient quality of life and survival. The mechanism driving AT loss appears intricately linked to alterations in AT metabolic remodeling, marked by heightened lipolysis and fatty acid oxidation, coupled with diminished lipogenesis. However, adipocyte stem cells' lost ability to divide due to chemotherapy also appears to be at the root of the loss of AT. Notably, chemotherapy seems to deactivate the mitochondrial antioxidant system by reducing key regulatory enzymes responsible for neutralizing reactive oxygen species (ROS), thereby impeding lipogenesis. Despite FDG-PET evidence of AT browning, no molecular evidence of thermogenesis was reported. Prospective investigations unraveling the molecular mechanisms modulated in AT by chemotherapy, along with therapeutic strategies aimed at preventing AT loss, promise to refine treatment paradigms and enhance patient outcomes.

In vitro antitumor effects of aqueous extract and protease inhibitors from Sterculia striata st. Hil. et naud and metabolite profiling.

The present study aims to assess the cytotoxic effect of the aqueous and protease inhibitors extracts of Sterculia striata on breast cancer cell lines. The in vitro results showed significant reductions in the highest concentrations from the S. striata seed extract for all cell lines. The aqueous extract reduced the viability by up to 35% in the MCF-7, 25% in the 4T1, and 35% in the MDA-MB-231 cell lines. Regarding the protease inhibitor extract, a 50% reduction in cell viability was observed in the MDA-MB-231 at concentration of 333 µg/mL. The aqueous and the protease inhibitor extracts showed mild reduction in the viability of macrophage cell lines. Chemical characterisation analysis revealed several polyphenols such as flavonoids, tannins, phenolic acids, and other secondary metabolites including terpenes, steroids, fatty acids, and organic acids, which may be related to the promising bioactivity observed. The S. striata showed antitumor activity, emphasising its pharmacological potential.

Chemotherapy-Induced Molecular Changes in Skeletal Muscle.

Paraneoplastic conditions such as cancer cachexia are often exacerbated by chemotherapy, which affects the patient's quality of life as well as the response to therapy. The aim of this narrative review was to overview the body-composition-related changes and molecular effects of different chemotherapy agents used in cancer treatment on skeletal-muscle remodeling. A literature search was performed using the Web of Science, Scopus, and Science Direct databases and a total of 77 papers was retrieved. In general, the literature survey showed that the molecular changes induced by chemotherapy in skeletal muscle have been studied mainly in animal models and mostly in non-tumor-bearing rodents, whereas clinical studies have essentially assessed changes in body composition by computerized tomography. Data from preclinical studies showed that chemotherapy modulates several molecular pathways in skeletal muscle, including the ubiquitin-proteasome pathway, autophagy, IGF-1/PI3K/Akt/mTOR, IL-6/JAK/STAT, and NF-κB pathway; however, the newest chemotherapy agents are underexplored. In conclusion, chemotherapy exacerbates skeletal-muscle wasting in cancer patients; however, the incomplete characterization of the chemotherapy-related molecular effects on skeletal muscle makes the development of new preventive anti-wasting strategies difficult. Therefore, further investigation on molecular mechanisms and clinical studies are necessary.

Impacts of Ca2+ cation and temperature on bovine α-lactalbumin secondary structures and foamability - Insights from computational molecular dynamics.

We used computational molecular dynamics (MD) to assess molecular conformations of apo- and holo-forms (respectively without and with Ca2+) of bovine α-lactalbumin (α-La) at different temperatures, and to correlate them with the protein's foaming properties. At 4 °C and 25 °C no major protein conformation changes occurred. At 75 °C, lots of changes were evidenced: the Ca2+ depletion triggered the complete loss of h2b, h3c helices and S1, S2 and S3 ß-sheets, and partial losses of H1, H2 and H3 α-helices. The absence of Ca2+ in apo-α-La and its leaving from holo-α-La triggered electrostatic repulsion among Asp82, Asp84 and Asp87, leading to the formation of a hydrophobic cluster involving Phe9, Phe31, Ile1, Va42, Ile55, Phe80 and Leu81. These conformational changes were related to an interfacial tension decrease and to a foaming capacity increase, for both apo-α-La and holo-α-La. This study exemplifies how powerful MD is as a tool to provide a better understanding of the molecular origins of food proteins' techno-functionalities.

Intestinal proteases profiling from Anticarsia gemmatalis and their binding to inhibitors.

Although the importance of intestinal hydrolases is recognized, there is little information on the intestinal proteome of lepidopterans such as Anticarsia gemmatalis. Thus, we carried out the proteomic analysis of the A. gemmatalis intestine to characterize the proteases by LC/MS. We examined the interactions of proteins identified with protease inhibitors (PI) using molecular docking. We found 54 expressed antigens for intestinal protease, suggesting multiple important isoforms. The hydrolytic arsenal featured allows for a more comprehensive understanding of insect feeding. The docking analysis showed that the soybean PI (SKTI) could bind efficiently with the trypsin sequences and, therefore, insect resistance does not seem to involve changing the sequences of the PI binding site. In addition, a SERPIN was identified and the interaction analysis showed the inhibitor binding site is in contact with the catalytic site of trypsin, possibly acting as a regulator. In addition, this SERPIN and the identified PI sequences can be targets for the control of proteolytic activity in the caterpillar intestine and serve as a support for the rational design of a molecule with greater stability, less prone to cleavage by proteases and viable for the control of insect pests such as A. gemmatalis.

Small peptides inhibit gut trypsin-like proteases and impair Anticarsia gemmatalis (Lepidoptera: Noctuidae) survival and development.

BACKGROUND: Anticarsia gemmatalis larvae are key defoliating pests of soybean plants. Inorganic insecticides, harmful to the environment and human health, are the main molecules used in the control of this pest. To apply more sustainable management methods, organic molecules with high specificities, such as proteinaceous protease inhibitors, have been sought. Thus, molecular docking studies, kinetics assays, and biological tests were performed to evaluate the inhibitory activity of two peptides (GORE1 and GORE2) rationally designed to inhibit trypsin-like enzymes, which are the main proteases of A. gemmatalis midgut. RESULTS: The molecular docking simulations revealed critical hydrogen bonding patterns of the peptides with key active site residues of trypsin-like proteases of A. gemmatalis and other Lepidopteran insects. The negative values of binding energy indicate that hydrogen bonds potentiate the tight binding of the peptides with trypsin-like proteases, predicting an effective inhibition. The inhibition's rate constants (Ki) were 0.49 and 0.10 mM for GORE1 and GORE2, resulting in effective inhibition of the activity trypsin on the L-BApNA substrate in the in vitro tests, indicating that the peptide GORE2 has higher inhibitory capacity on the A. gemmatalis trypsins. In addition, the two peptides were determined to be reversible competitive inhibitors. The in vivo test demonstrated that the peptides harm the survival and development of A. gemmatalis larvae. CONCLUSION: These results suggest that these peptides are potential candidates in the management of A. gemmatalis larvae and provide baseline information for the design of new trypsin-like inhibitors based on peptidomimetic tools. © 2020 Society of Chemical Industry.

Noncompetitive tight-binding inhibition of Anticarsia gemmatalis trypsins by Adenanthera pavonina protease inhibitor affects larvae survival.

The economic loss in soybean crops caused by the Lepidoptera insects has encouraged the search for new strategies to control this pest, which are currently based on synthetic insecticides. This paper evaluated the ability of ApTI (Adenanthera pavonina trypsin inhibitor) to inhibit trypsin-like proteins from Anticarsia gemmatalis by docking, molecular dynamics, and enzymatic and survival assay. The docking and molecular dynamic simulation between trypsin and ApTI were performed using the program CLUSPRO and NAMD, respectively. The inhibitory constant Ki and the inhibition type were determined through chromogenic assays. The survival assay of neonatal larvae under treatment with artificial diet supplemented with ApTI was also performed. The ApTI binding site was predicted to block substrate access to trypsin due to four interactions with the enzyme, producing a complex with a surface area of 1,183.7 Å2 . The kinetic analysis revealed a noncompetitive tight-binding mechanism. The survival curves obtained using Kaplan-Meier estimators indicated that the highest larvae mortality was 60%, using 1.2 mg of ApTI per 100 ml of artificial diet. The in vitro, in vivo, and in silico studies demonstrated that ApTI is a strong noncompetitive inhibitor of trypsin with biotechnological potential for the control of A. gemmatalis insect.

El modelo médico como generador de discapacidad / The Medical Model as a Disability Generator / O modelo médico como gerador de deficiência

Resumen: La discapacidad ha tenido diferentes conceptualizaciones, incluyendo aportes religiosos, científicos, médicos y sociales. El modelo médico es fundamental en la prevención y la rehabilitación adecuada, sin embargo, es también un gran generador de discapacidad. El objetivo de este trabajo es presentar la relación del modelo médico de discapacidad y el enfoque biomédico como generadores de discapacidad y proponer una aproximación teórica a nuevos modelos y enfoques que permitan un abordaje ético-ontológico. El presente es un artículo de exposición en dos etapas: en la primera se hizo una revisión de literatura sobre discapacidad. En la segunda, se presentan los resultados de la discusión entre los autores para comparar e identificar argumentos y contraargumentos de los modelos tradicionales, con respecto a las nuevas formas de análisis con una visión desde la bioética. Una de las principales conclusiones de este análisis es que el modelo médico ha hecho aportes fundamentales en la conceptualización y clasificación de la discapacidad; sin embargo, el enfoque mono -causal positivista termina favoreciendo la medicalización, la discapacidad y demanda más recursos. La discapacidad es un asunto en evolución en el que interactúan las deficiencias individuales y las barreras personales y ambientales, por lo que es necesario superar el paradigma médico y fortalecer el biopsicosocial.

Abstract: Disability has had different conceptualizations, which have included religious, scientific, medical and social contributions. The medical model is fundamental for appropriate prevention and rehabilitation. The goal of this paper is to show the relationship of the disability medical model and the biomedical approach as generators of disability and to propose a theoretical approach to new models and perspectives that allow for an ethical-ontological approach. This is an expository article presented in two stages: in the first one a literature review on disability was carried out. In the second one, the results of the discussion are presented amongst the authors to compare and identify arguments and counterarguments of the traditional models, with regards to the forms of analysis with a view from bioethics. One of the main conclusions of this analysis is that the medical model has made fundamental contributions to the conceptualization of disability; however, the positivistic monocausal approach ends up favoring medicalization, disability and it demands more resources. Disability is a subject in evolution where the individual deficiencies and the personal and environmental barriers interact, therefore it is necessary to overcome the medical paradigm and to strengthen the biopsychosocial.

Resumo: O conceito de deficiência recebeu diferentes contribuições, incluindo as religiosas, científicas, médicas e sociais. O modelo médico é fundamental na prevenção e reabilitação adequada, no entanto, é também um grande gerador de deficiências. O objetivo deste trabalho é apresentar a relação do modelo médico de deficiência e do enfoque biomédico como geradores de deficiência e propor uma aproximação teórica para novos modelos e enfoques que permitam uma abordagem ético-ontológica. Trata-se de um artigo de exposição em duas etapas: na primeira, foi feita uma revisão da literatura sobre deficiência. Na segunda, são apresentados os resultados da discussão entre os autores para comparar e identificar argumentos e contra-argumentos dos modelos tradicionais, no que diz respeito às novas formas de análise a partir da bioética. Uma das principais conclusões dessa análise é que o modelo médico fez contribuições fundamentais na conceituação e classificação da deficiência. No entanto, o enfoque monocausal positivista acaba favorecendo a medicalização e a deficiência, além de demandar mais recursos. A deficiência é uma questão em evolução, na qual as carências individuais e as barreiras pessoais e ambientais interagem, sendo necessário superar o paradigma médico e fortalecer o biopsicossocial.

[Challenges of the right to health in the Colombian model]. / La nueva reforma a la salud en Colombia: el derecho, el aseguramiento y el sistema de salud.

Health in Colombia is now a fundamental right that has to be provided and protected by the government. We evaluated the strengths and difficulties of the health system with respect to the statutory law enacted in February 2015, using methodologies for analysis of health systems proposed by the WHO and the World Bank. The challenges include the fragmentation and specialization of services, access barriers and incentives that are not aligned with the quality, weak governance, multiple actors with little coordination and information system that does not measure results. The government needs to find a necessary social agreement, a balance between the particular and the collective benefit.

La nueva reforma a la salud en Colombia: el derecho, el aseguramiento y el sistema de salud / Challenges of the right to health in the Colombian model

La salud en Colombia es ahora un derecho fundamental que tiene que ser provisto y protegido por el Estado. A partir de metodologías de análisis de sistemas de salud propuestos por la OMS y el Banco Mundial, se evidencian las falencias, fortalezas y dificultades del sistema de salud con respecto a la ley estatutaria aprobada en febrero de 2015. Éstas incluyen la fragmentación y especialización de los servicios, barreras de acceso, incentivos no alineados con la calidad, débil gobernanza, múltiples actores con poca coordinación y sistema de información que no mide resultados. Es necesario un acuerdo social, un equilibrio y control de la tensión por parte del Estado entre el beneficio particular y el beneficio colectivo.

Health in Colombia is now a fundamental right that has to be provided and protected by the government. We evaluated the strengths and difficulties of the health system with respect to the statutory law enacted in February 2015, using methodologies for analysis of health systems proposed by the WHO and the World Bank. The challenges include the fragmentation and specialization of services, access barriers and incentives that are not aligned with the quality, weak governance, multiple actors with little coordination and information system that does not measure results. The government needs to find a necessary social agreement, a balance between the particular and the collective benefit.

Seminário Nacional Direito e Saúde, 8º, 2009 e Seminário Internacional Direito e Saúde, 4º, 2009 - Samuel R. Barbosa

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