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In the age of information technology and the additional computational search tools and software available, this systematic review aimed to identify potential therapeutic targets for obesity, evaluated in silico and subsequently validated in vivo. The systematic review was initially guided by the research question "What therapeutic targets have been used in in silico analysis for the treatment of obesity?" and structured based on the acronym PECo (P, problem; E, exposure; Co, context). The systematic review protocol was formulated and registered in PROSPERO (CRD42022353808) in accordance with the Preferred Reporting Items Checklist for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and the PRISMA was followed for the systematic review. The studies were selected according to the eligibility criteria, aligned with PECo, in the following databases: PubMed, ScienceDirect, Scopus, Web of Science, BVS, and EMBASE. The search strategy yielded 1142 articles, from which, based on the evaluation criteria, 12 were included in the systematic review. Only seven these articles allowed the identification of both in silico and in vivo reassessed therapeutic targets. Among these targets, five were exclusively experimental, one was exclusively theoretical, and one of the targets presented an experimental portion and a portion obtained by modeling. The predominant methodology used was molecular docking and the most studied target was Human Pancreatic Lipase (HPL) (n = 4). The lack of methodological details resulted in more than 50% of the papers being categorized with an "unclear risk of bias" across eight out of the eleven evaluated criteria. From the current systematic review, it seems evident that integrating in silico methodologies into studies of potential drug targets for the exploration of new therapeutic agents provides an important tool, given the ongoing challenges in controlling obesity.
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Simulação por Computador , Obesidade , Humanos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Animais , Simulação de Acoplamento Molecular , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Lipase/metabolismo , Lipase/antagonistas & inibidores , Terapia de Alvo Molecular/métodosRESUMO
OBJECTIVE: To evaluate the surgical anatomy of the kidney collecting system through a narrative review of the literature, highlighting its importance during diagnosis and its approach during surgical procedures for the treatment of renal stones. MATERIAL AND METHODS: We carried out a review about the anatomy of the kidney collecting system. We analyzed papers published in the past 40 years in the databases Pubmed, Embase and Scielo, and we included only papers in English and excluded case reports, editorials and opinions of specialists. RESULTS: Renal collecting system could be divided in four groups: A1 - kidney midzone (KM), drained by minor calyx that are dependent on the superior or the inferior caliceal groups; A2 - KM drained by crossed calyx, one draining into the superior caliceal group and another draining into the inferior caliceal group; B1 - KM drained by a major caliceal group independent of both the superior and inferior groups; and B2 - KM drained by minor calyx entering directly into the renal pelvis. Some details and anatomic variations of the collecting system are related to clinical and radiological aspects, particularly perpendicular calyces, interpyelocalyx space, position of calyces in relation to renal border, classification of the renal collecting system, infundibular diameter and the angle between the lower infundibulum and renal pelvis. CONCLUSION: The knowledge of intra-renal collecting system divisions and variations as the angle between the renal pelvis and lower infundibula, position of the calices in relationship with renal edge and the diameter and position of the calyces are important for the planning of minimally invasive renal surgeries.
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Cálculos Renais , Rim , Humanos , Rim/diagnóstico por imagem , Rim/cirurgia , Cálices Renais/diagnóstico por imagem , Cálices Renais/cirurgia , Pelve Renal/diagnóstico por imagem , Pelve Renal/cirurgia , Cálculos Renais/diagnóstico por imagem , Cálculos Renais/cirurgia , Bases de Dados FactuaisRESUMO
PURPOSE: The gubernaculum seems to be the most important anatomical structure in the testicular migration process. The objective of this paper is to review current literature regarding the role of gubernaculum testis nerves in testicular migration. We conducted a comprehensive literature review about the gubernaculum testis innervation. A PubMed database search was performed in April 2024, focusing on gubernaculum testis and cryptorchidism and genitofemoral nerve (GFN) and calcitonin gene-related peptide (CGRP) gene. The gubernaculum has its own nerve supply, the GFN, descending on the anteromedial surface of the psoas muscle from L1-L2 segments. The second phase of testicular descent is regulated by androgens and CGRP, released from the sensory nucleus of the GFN. The GFN doesn't directly play a role in testicular migration but there is a theory that shows a regulatory function of this nerve in hormonal action during this process. The gubernaculum testis has important structural alterations during the testicular migration and the genitofemoral nerve and CGRP gene are of great importance in this process. The genitofemoral nerve provides motor innervation to the cremaster muscle and gubernaculum, which helps regulate the position of the testes within the scrotum.
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Criptorquidismo , Gubernáculo , Testículo , Humanos , Masculino , Testículo/fisiologia , Testículo/embriologia , Gubernáculo/fisiologia , Gubernáculo/embriologia , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Feto/fisiologiaRESUMO
BACKGROUND AND AIM: PTSD after childbirth is a significant but often under-recognised mental health problem. This systematic review aims to examine the measures used to assess childbirth-related PTSD (CB-PTSD) and posttraumatic stress symptoms (CB-PTSS) in mothers in the first year postpartum and to evaluate their psychometric properties. METHODS: Following PRISMA guidelines, a comprehensive search of multiple databases and grey literature sources was conducted. Studies that involved mothers in the first year postpartum and reported measures of CB-PTSD and/or CB-PTSS were included. Quality assessment was based on the CASP Checklist. RESULTS: 149 studies met the inclusion criteria. Self-report questionnaires, particularly the IES and its revisions, were the most commonly used measurement instruments. In recent years, however, specialised instruments such as the City Birth Trauma Scale have emerged that were developed specifically for assessing CB-PTSD. Psychometric properties varied from study to study, with some lacking detailed information on validity and reliability. CONCLUSION: The results emphasises the importance of using validated and tailored tools for the assessment of CB-PTSD. Whilst self-report questionnaires remain widely used, the development and use of specialised instruments such as the City BiTS provide greater precision in the assessment of CB-PTSD symptoms. Future research should focus on refining measurement tools, conducting longitudinal studies to explore symptom trajectories, and investigating the effectiveness of early intervention strategies. By refining measurement methods and intervention approaches, clinicians can better support mothers with CB-PTSD and ultimately fostering improve the mental health outcomes for both mothers and their families.
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This study assessed the histones methylation profile (H3K4me3 and H3K9me3) in late preantral (PA) and early antral (EA) caprine follicles grown in vivo and in vitro, and the anethole effect during in vitro culture of PA follicles. Uncultured in vivo-grown follicles (PA, n = 64; EA, n = 73) were used as controls to assess the methylation profile and genes' expression related to apoptosis cascade (BAX, proapoptotic; BCL2, antiapoptotic), steroidogenesis (CYP17, CYP19A1), and demethylation (KDM1AX1, KDM1AX2, KDM3A). The isolated PA follicles (n = 174) were cultured in vitro for 6 days in α-MEM+ in either absence (control) or presence of anethole. After culture, EA follicles were evaluated for methylation, mRNA abundance, and morphometry. Follicle diameter increased after culture, regardless of treatment. The methylation profile and the mRNA abundance were similar between in vivo-grown PA and EA follicles. Anethole treatment led to higher H3K4me3 fluorescence intensity in EA follicles. The mRNA abundances of BAX, CYP17, and CYP19A1 were higher, and BCL2 and KDM3A were lower in in vitro-grown EA follicles than in vivo-grown follicles. In conclusion, in vitro follicle culture affected H3K4me3 fluorescence intensity, mRNA abundance of apoptotic genes, and steroidogenic and demethylase enzymes compared with in vivo-grown follicles.
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Cabras , Lisina , Animais , Proteína X Associada a bcl-2/metabolismo , Cabras/metabolismo , Histonas , Esteroide 17-alfa-Hidroxilase/metabolismo , RNA Mensageiro/genética , Oócitos/metabolismoRESUMO
Bacterial infections have become a global concern, stimulating the growing demand for natural and biologically safe therapeutic agents with antibacterial action. This study was evaluated the genotoxicity of the trypsin inhibitor isolated from tamarind seeds (TTI) and the antibacterial effect of TTI theoric model, number 56, and conformation number 287 (TTIp 56/287) and derived peptides in silico. TTI (0.3 and 0.6 mg.mL-1) did not cause genotoxicity in cells (p > 0.05). In silico, a greater interaction of TTIp 56/287 with the Gram-positive membrane (GP) was observed, with an interaction potential energy (IPE) of -1094.97 kcal.mol-1. In the TTIp 56/287-GP interaction, the Arginine, Threonine (Thr), and Lysine residues presented lower IPE. In molecular dynamics (MD), Peptidotrychyme59 (TVSQTPIDIPIGLPVR) showed an IPE of -518.08 kcal.mol-1 with the membrane of GP bacteria, and the Thr and Arginine residues showed the greater IPE. The results highlight new perspectives on TTI and its derived peptides antibacterial activity.
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Tamarindus , Inibidores da Tripsina , Inibidores da Tripsina/farmacologia , Tamarindus/química , Peptídeos/química , Sementes/química , Antibacterianos/farmacologia , Antibacterianos/análise , Arginina/análise , Arginina/químicaRESUMO
Community Health Workers (CHWs) are the link between the Brazilian primary health care system and the community. Since CHWs live in the same neighborhoods they work, they are involved in what happens in the community, including observants and or potential targets of violence. However, it is not known if female and male CHWs perceive and suffer violence similarly. This study aimed to investigate the violence to which CHWs are exposed and if female CHWs experience and or perceive violence the same way as male CHWs. A structured questionnaire was used to collect information from CHWs. Two periods (2019 [n=1402] and 2021 [n=364]) were compared. The data show that more than 80% of CHWs were exposed to violence, either as victims or witnesses within the community they served. In general, while the occurrence of violence towards CHWs decreased, their perception of community violence increased. Over time, the perception of urban/community violence remained constant among male CHWs, but increased among female CHWs, as shown by the significant rise between 2019 and 2021 in the percentage of female CHWs reporting witnessing or hearing about manifestations of violence (e.g., physical aggression; assault; stabbing; lethal gunshot; non-lethal gunshot; and gang violence). Among male CHWs, perception only increased with regard to the item assault. Given the complexity of violence and its repercussions on the daily routines of CHWs, intersectoral and interdisciplinary partnerships between health workers and other stakeholders are needed to create strategies capable of dealing with expressions of violence in the territories served.
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Agentes Comunitários de Saúde , Vítimas de Crime , Humanos , Masculino , Feminino , Brasil/epidemiologia , Violência , Pesquisa QualitativaRESUMO
Rumination is an emotional regulation mechanism strongly associated with the development and maintenance of internalising psychopathology in adolescence and adulthood. Parenting behaviours (PBs) play a pivotal role in the development of rumination in children and adolescents. Nonetheless, the specific PBs that can either protect against or increase the risk of rumination development remain poorly understood. This systematic review aimed to explore the (1) temporal associations between PBs and adolescents' rumination and (2) potential moderators influencing these associations. We conducted a comprehensive search across Web of Science, Scopus, PubMed, Academic Search Complete and Eric databases, adhering to PRISMA reporting guidelines. Out of 1,868 abstracts screened, 182 articles underwent full-text examination, with nine meeting the inclusion criteria for the systematic review. Overall, the studies indicated that PBs characterised by criticism, rejection and control were positively associated with the development of rumination in adolescents, whilst PBs marked by authoritative practises exhibited a negative association with rumination. Gender, temperament, environmental sensitivity and pubertal timing emerged as significant moderators in the effects of PBs on rumination. However, conclusions were limited due to the studies' methodological heterogeneity. Future studies on PBs and rumination should address various dimensions of PBs and different moderators to identify factors that can modify the development of rumination across adolescence. Findings may inform family-based prevention programmes to promote emotion regulation in adolescents as a protective factor against internalising psychopathology across adulthood.
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The present study investigated the effect of gelatin-based nanoparticles (EPG) loaded with a carotenoid-rich crude extract (CE) on systemic and adipose tissue inflammatory response in a model with inflammation induced by a high glycemic index and high glycemic load diet (HGLI). Nanoparticles synthesized were characterized by different physical and chemical methods. The in vivo investigation evaluated Wistar rats (n = 20, 11 days, adult male with 21 weeks) subdivided into untreated (HGLI diet), conventional treatment (nutritionally adequate diet), treatment 1 (HGLI + crude extract (12.5 mg/kg)), and treatment 2 (HGLI + EPG (50 mg/kg)) groups. Dietary intake, caloric intake and efficiency, weight, inflammatory cytokines tissue concentration, visceral adipose tissue (VAT) weight, histopathological analysis, and antioxidant activity in plasma and VAT were investigated. EPG showed the same physical and chemical characteristics as previous batches (95.2 nm, smooth surface, and chemical interactions between materials). The EPG-treated group was the only group promoting negative ∆dietary intake, ∆caloric efficiency, and ∆weight. In addition, it presented a significant reduction (p < 0.05) in IL-6 and leptin levels and a greater presence of multilocular adipocytes. The results suggest that EPG can act as a nutraceutical in adjuvant therapy for treating inflammatory diseases associated with adipose tissue accumulation.
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Citocinas , Obesidade , Ratos , Animais , Masculino , Ratos Wistar , Obesidade/patologia , Citocinas/farmacologia , Gelatina/farmacologia , Tecido Adiposo/patologia , Adipócitos , Hipertrofia/patologia , Carotenoides/farmacologiaRESUMO
PURPOSE OF REVIEW: Even though checkpoint inhibitors have become a recent milestone for the treatment of many different tumor types, eventually, most part of patients will develop resistance mechanisms and their disease will progress. New generations of checkpoint inhibitors, as the ones directed to TIM-3, are on research. RECENT FINDINGS: TIM-3 expression has been associated with more advanced stages and shorter survival in several tumor types, due to its association with T-cell dysfunction, and has become an interesting target to explore. Early phase clinical trials with different anti-TIM-3 monoclonal antibodies have shown a safe toxicity profile, as cobolimab, LY3321367, or sabatolimab; however, the general antitumor activity remains to be determined and further investigations are needed. TIM-3 is implicated in resistance to immunotherapy due to its role in T cell exhaustion. However, the TIM-3 pathway is highly complex in terms of non-canonical signaling, broad expression by different immune cells and multiple ligands. Different anti-TIM-3 inhibitors are currently on research, either as monotherapy or in combination with other immunotherapies or chemotherapy, aiming to overcome resistance.
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Antineoplásicos , Inibidores de Checkpoint Imunológico , Neoplasias , Antineoplásicos/uso terapêutico , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Neoplasias/tratamento farmacológico , Linfócitos TRESUMO
This systematic review (SR) aimed to gather studies describing the antibacterial action mechanisms and mode of trypsin inhibitors. The review protocol was registered (PROSPERO: CRD42020189069). Original articles resulting from studies in animal models, in bacterial culture, and using cells that describe antibacterial action of trypsin inhibitor-type peptides or proteins were selected in PubMed, Science Direct, Scopus, Web of Science, BVS, and EMBASE. The methodological quality assessment was performed using the PRISMA and OHAT tool. 2382 articles were retrieved, 17 of which were eligible. Four studies demonstrated the action mechanism directly on the bacterial membrane, and the fifth study on endogenous proteases extracted from the bacteria themselves. The antibacterial action mode was presented in the other studies, which can generate bacteriostatic or bactericidal effects without describing the mechanisms. This study generated information to enable new preclinical or clinical studies with molecules contributing to public health.
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Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Inibidores da Tripsina/farmacologia , Tripsina/metabolismo , Antibacterianos/química , Bactérias/metabolismo , Testes de Sensibilidade Microbiana , Inibidores da Tripsina/químicaRESUMO
Male butterflies in the hyperdiverse tribe Eumaeini possess an unusually complex and diverse repertoire of secondary sexual characteristics involved in pheromone production and dissemination. Maintaining multiple sexually selected traits is likely to be metabolically costly, potentially resulting in trade-offs in the evolution of male signals. However, a phylogenetic framework to test hypotheses regarding the evolution and maintenance of male sexual traits in Eumaeini has been lacking. Here, we infer a comprehensive, time-calibrated phylogeny from 379 loci for 187 species representing 91% of the 87 described genera. Eumaeini is a monophyletic group that originated in the late Oligocene and underwent rapid radiation in the Neotropics. We examined specimens of 818 of the 1096 described species (75%) and found that secondary sexual traits are present in males of 91% of the surveyed species. Scent pads and scent patches on the wings and brush organs associated with the genitalia were probably present in the common ancestor of Eumaeini and are widespread throughout the tribe. Brush organs and scent pads are negatively correlated across the phylogeny, exhibiting a trade-off in which lineages with brush organs are unlikely to regain scent pads and vice versa. In contrast, scent patches seem to facilitate the evolution of scent pads, although they are readily lost once scent pads have evolved. Our results illustrate the complex interplay between natural and sexual selection in the origin and maintenance of multiple male secondary sexual characteristics and highlight the potential role of sexual selection spurring diversification in this lineage.
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Borboletas , Animais , Evolução Biológica , Masculino , Fenótipo , Feromônios , FilogeniaRESUMO
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was recognised by the WHO as a pandemic in 2020. Host preparation to combat the virus is an important strategy to avoid COVID-19 severity. Thus, the relationship between eating habits, nutritional status and their effects on the immune response and further implications in viral respiratory infections is an important topic discussed in this review. Malnutrition causes the most diverse alterations in the immune system, suppressing of the immune response and increasing the susceptibility to infections such as SARS-CoV-2. On the other hand, obesity induces low-grade chronic inflammation caused by excess adiposity, which increases angiotensin-converting enzyme 2. It decreases the immune response favouring SARS-CoV-2 virulence and promoting respiratory distress syndrome. The present review highlights the importance of food choices considering their inflammatory effects, consequently increasing the viral susceptibility observed in malnutrition and obesity. Healthy eating habits, micronutrients, bioactive compounds and probiotics are strategies for COVID-19 prevention. Therefore, a diversified and balanced diet can contribute to the improvement of the immune response to viral infections such as COVID-19.
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COVID-19/etiologia , Dieta/efeitos adversos , Suscetibilidade a Doenças/virologia , Estado Nutricional , SARS-CoV-2 , COVID-19/prevenção & controle , COVID-19/virologia , Dieta Saudável/métodos , Suscetibilidade a Doenças/fisiopatologia , Fast Foods/efeitos adversos , Humanos , Desnutrição/etiologia , Desnutrição/virologia , Obesidade/etiologia , Obesidade/virologiaRESUMO
OBJECTIVE: To investigate the efficacy and safety of hu3S193, a humanized anti-Lewis-Y monoclonal antibody, as a consolidation strategy in patients with platinum-sensitive recurrent epithelial ovarian cancer who achieved a second complete response after salvage platinum-doublet chemotherapy. METHODS: This single-arm phase II study accrued patients with recurrent epithelial ovarian cancer with Lewis-Y expression by immunohistochemistry who had achieved a second complete response after five to eight cycles of platinum-based chemotherapy. Patients received intravenous infusions of hu3S193, 30 mg/m2 every 2 weeks starting no more than 8 weeks after the last dose of chemotherapy and continuing for 12 doses, until disease progression, or unacceptable toxicity. The primary endpoint was progression-free survival of the second remission. Secondary objectives were safety and pharmacokinetics. RESULTS: Twenty-nine patients were enrolled. Most had a papillary/serous histology tumor (94%), stage III disease at diagnosis (75%), and five (17%) underwent secondary cytoreduction before salvage chemotherapy. Two patients were not eligible for efficacy but were considered for toxicity analysis. Eighteen patients (62%) completed the full consolidation treatment while nine patients progressed on treatment. At the time of analysis, 23 patients (85%) of the eligible population had progressed and seven of these patients (26%) had died. Median progression-free survival of the second remission was 12.1 months (95% CI: 10.6-13.9), with a 1-year progression-free survival of the second remission rate of 50.1%. The trial was terminated early since it was unlikely that the primary objective would be achieved. The most commonly reported treatment-related adverse events were nausea (55%) and vomiting (51%). CONCLUSIONS: Hu3S193 did not show sufficient clinical activity as consolidation therapy in patients with recurrent epithelial ovarian cancer who achieved a second complete response after platinum-based chemotherapy. TRIAL REGISTRATION: NCT01137071.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Quimioterapia de Consolidação/métodos , Indução de Remissão/métodos , Adulto , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
The global COVID-19 (coronavirus disease 2019) pandemic has become a complex problem that overlaps with a growing public health problem, obesity. Obesity alters different components of the innate and adaptive immune responses, creating a chronic and low-grade state of inflammation. Nutritional status is closely related to a better or worse prognosis of viral infections. Excess weight has been recognised as a risk factor for COVID-19 complications. In addition to the direct risk, obesity triggers other diseases such as diabetes and hypertension, increasing the risk of severe COVID-19. The present review explains the diets that induce obesity and the importance of different foods in this process. We also review tissue disruption in obesity, leading to impaired immune responses and the possible mechanisms by which obesity and its co-morbidities increase COVID-19 morbidity and mortality. Nutritional strategies that support the immune system in patients with obesity and with COVID-19 are also discussed in light of the available data, considering the severity of the infection. The discussions held may contribute to combating this global emergency and planning specific public health policy.
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COVID-19 , Dieta , Humanos , Obesidade/epidemiologia , Pandemias , SARS-CoV-2RESUMO
Trypsin inhibitors from tamarind seed have been studied in vitro and in preclinical studies for the treatment of obesity, its complications and associated comorbidities. It is still necessary to fully understand the structure and behaviour of these molecules. We purifed this inhibitor, sequenced de novo by MALDI-TOF/TOF, performed its homology modelling, and assessed the interaction with the trypsin enzyme through molecular dynamics (MD) simulation under physiological conditions. We identified additional 75 amino acid residues, reaching approximately 72% of total coverage. The four best conformations of the best homology modelling were submitted to the MD. The conformation n°287 was selected considering the RMSD analysis and interaction energy (-301.0128 kcal.mol-1). Residues Ile (54), Pro (57), Arg (59), Arg (63), and Glu (78) of pTTI presented the highest interactions with trypsin, and arginine residues were mainly involved in its binding mechanism. The results favour bioprospecting of this protein for pharmaceutical health applications.
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Simulação de Dinâmica Molecular , Extratos Vegetais/farmacologia , Tamarindus/química , Inibidores da Tripsina/farmacologia , Tripsina/metabolismo , Relação Dose-Resposta a Droga , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Sementes/química , Relação Estrutura-Atividade , Inibidores da Tripsina/química , Inibidores da Tripsina/isolamento & purificaçãoRESUMO
Coronaviruses (CoVs) stand out among RNA viruses because of their unusually large genomes (â¼30 kb) associated with low mutation rates. CoVs code for nsp14, a bifunctional enzyme carrying RNA cap guanine N7-methyltransferase (MTase) and 3'-5' exoribonuclease (ExoN) activities. ExoN excises nucleotide mismatches at the RNA 3'-end in vitro, and its inactivation in vivo jeopardizes viral genetic stability. Here, we demonstrate for severe acute respiratory syndrome (SARS)-CoV an RNA synthesis and proofreading pathway through association of nsp14 with the low-fidelity nsp12 viral RNA polymerase. Through this pathway, the antiviral compound ribavirin 5'-monophosphate is significantly incorporated but also readily excised from RNA, which may explain its limited efficacy in vivo. The crystal structure at 3.38 Å resolution of SARS-CoV nsp14 in complex with its cofactor nsp10 adds to the uniqueness of CoVs among RNA viruses: The MTase domain presents a new fold that differs sharply from the canonical Rossmann fold.
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Coronavirus/metabolismo , RNA Viral/metabolismo , Ribavirina/metabolismo , Replicação Viral , Antivirais/metabolismo , Antivirais/farmacologia , Coronavirus/efeitos dos fármacos , Coronavirus/genética , Cristalografia por Raios X , Exorribonucleases/química , Exorribonucleases/genética , Exorribonucleases/metabolismo , Humanos , Metiltransferases/química , Metiltransferases/genética , Metiltransferases/metabolismo , Modelos Moleculares , Ligação Proteica , Domínios Proteicos , RNA Viral/genética , Ribavirina/farmacologia , Síndrome Respiratória Aguda Grave/virologia , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismoRESUMO
Several studies have sought new therapies for obesity and liver diseases. This study investigated the effect of the trypsin inhibitor isolated from tamarind seeds (TTI), nanoencapsulated in chitosan and whey protein isolate (ECW), on the liver health status of the Wistar rats fed with a high glycemic index (HGLI) diet. The nanoformulations without TTI (CW) and ECW were obtained by nanoprecipitation technique, physically and chemically characterized, and then administered to the animals. The adult male Wistar rats (n = 20) were allocated to four groups: HGLI diet + water; standard diet + water; HGLI diet + ECW (12.5 mg/kg); and HGLI diet + CW (10.0 mg/kg), 1 mL per gagave, for ten days. They were evaluated using biochemical and hematological parameters, Fibrosis-4 Index for Liver Fibrosis (FIB-4), AST to Platelet Ratio Index (APRI) scores, and liver morphology. Both nanoparticles presented spherical shape, smooth surface, and nanometric size [120.7 nm (ECW) and 136.4 nm (CW)]. In animals, ECW reduced (p < 0.05) blood glucose (17%), glutamic oxalacetic transaminase (39%), and alkaline phosphatase (24%). Besides, ECW reduced (p < 0.05) APRI and FIB-4 scores and presented a better aspect of hepatic morphology. ECW promoted benefits over a liver injury caused by the HGLI diet.
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Quitosana/química , Dieta , Índice Glicêmico , Fígado/lesões , Nanopartículas/química , Tamarindus/química , Inibidores da Tripsina/farmacologia , Proteínas do Soro do Leite/química , Animais , Glicemia/metabolismo , Jejum/sangue , Homeostase , Insulina/sangue , Resistência à Insulina , Rim/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/fisiopatologia , Masculino , Nanopartículas/ultraestrutura , Ratos Wistar , Valores de ReferênciaRESUMO
Two heterometallic photocatalysts were designed and probed for water reduction. Both [(bpy)2 RuII NiII (L1 )](ClO4 )2 (1) and [(bpy)2 RuII NiII (L2 )2 RuII (bpy)2 ](ClO4 )2 (2) can generate the low-valent precursor involved in hydride formation prior to dihydrogen generation. However, while the bimetallic [RuII NiII ] (1) requires the presence of an external photosensitizer to trigger catalytic activity, the trimetallic [RuII NiII RuII ] (2) displays significant coupling between the catalytic and light-harvesting units to promote intramolecular multielectron transfer and perform photocatalysis at the Ni center. A concerted experimental and theoretical effort proposes mechanisms to explain why 1 is unable to achieve self-supported catalysis, while 2 is fully photocatalytic.
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Biallelic variants of the gene DNAJC12, which encodes a cochaperone, were recently described in patients with hyperphenylalaninemia (HPA). This paper reports the retrospective genetic analysis of a cohort of unsolved cases of HPA. Biallelic variants of DNAJC12 were identified in 20 patients (generally neurologically asymptomatic) previously diagnosed with phenylalanine hydroxylase (PAH) deficiency (phenylketonuria [PKU]). Further, mutations of DNAJC12 were identified in four carriers of a pathogenic variant of PAH. The genetic spectrum of DNAJC12 in the present patients included four new variants, two intronic changes c.298-2A>C and c.502+1G>C, presumably affecting the splicing process, and two exonic changes c.309G>T (p.Trp103Cys) and c.524G>A (p.Trp175Ter), classified as variants of unknown clinical significance (VUS). The variant p.Trp175Ter was detected in 83% of the mutant alleles, with 14 cases homozygous, and was present in 0.3% of a Spanish control population. Functional analysis indicated a significant reduction in PAH and its activity, reduced tyrosine hydroxylase stability, but no effect on tryptophan hydroxylase 2 stability, classifying the two VUS as pathogenic variants. Additionally, the effect of the overexpression of DNAJC12 on some destabilizing PAH mutations was examined and a mutation-specific effect on stabilization was detected suggesting that the proteostasis network could be a genetic modifier of PAH deficiency and a potential target for developing mutation-specific treatments for PKU.