The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen.

Collagen, a versatile family of proteins with 28 members and 44 genes, is pivotal in maintaining tissue integrity and function. It plays a crucial role in physiological processes like wound healing, hemostasis, and pathological conditions such as fibrosis and cancer. Collagen is a target in these processes. Direct methods for collagen modulation include enzymatic breakdown and molecular binding approaches. For instance, Clostridium histolyticum collagenase is effective in treating localized fibrosis. Polypeptides like collagen-binding domains offer promising avenues for tumor-specific immunotherapy and drug delivery. Indirect targeting of collagen involves regulating cellular processes essential for its synthesis and maturation, such as translation regulation and microRNA activity. Enzymes involved in collagen modification, such as prolyl-hydroxylases or lysyl-oxidases, are also indirect therapeutic targets. From another perspective, collagen is also a natural source of drugs. Enzymatic degradation of collagen generates bioactive fragments known as matrikines and matricryptins, which exhibit diverse pharmacological activities. Overall, collagen-derived peptides present significant therapeutic potential beyond tissue repair, offering various strategies for treating fibrosis, cancer, and genetic disorders. Continued research into specific collagen targeting and the application of collagen and its derivatives may lead to the development of novel treatments for a range of pathological conditions.

Is There a Link between the Molecular Basis of Juvenile Idiopathic Arthritis and Autoimmune Diseases? Systematic Review.

Juvenile Idiopathic Arthritis (JIA) is currently the most common chronic rheumatic disease in children. It is known to have no single identity, but a variety of diagnoses. Under-diagnosis is a barrier to early treatment and reduced complications of the disease. Other immune-mediated diseases may coexist in the same patient, making research in this area relevant. The main objective was to analyse whether links could be established between the molecular basis of JIA and other immune-mediated diseases. Early diagnosis may benefit patients with JIA, which in most cases goes undetected, leading to under-diagnosis, which can have a negative impact on children affected by the disease as they grow up. METHODS: We performed a PRISMA systematic review focusing on immune molecules present in different autoimmune diseases. RESULTS: A total of 13 papers from different countries dealing with the molecular basis of JIA and other immune diseases were evaluated and reviewed. CONCLUSIONS: Most of the autoimmune diseases analysed responded to the same group of drugs. Unfortunately, the reason for the under-diagnosis of these diseases remains unknown, as no evidence has been found to correlate the immunomolecular basis with the under-diagnosis of these immune-mediated diseases. The lack of information in this area means that further research is needed in order to provide a sound basis for preventing the development of immune-mediated diseases, especially in children, and to improve their quality of life through early diagnosis and treatment.

Analysis of the Psychosocial Sphere of Older Adults in Extreme Poverty in the Peruvian Amazon.

The situation of social exclusion in which older adults live in extreme poverty is a problem that leads to psychological alterations such as depression or cognitive deterioration. Our objective was to analyze the living conditions and the psychosocial sphere of older adult people living in extreme poverty in Requena del Tapiche in Peru. This was an observational, descriptive, cross-sectional study. Sixty participants between 60 and 100 years of age of both sexes were included who gave their informed consent. Sociodemographic variables were analyzed, and the Gijón, family Apgar, Yesavage, and Pfeiffer scales were used. The sample was composed of 55% women and 45% men, with a mean age of 79.2 years (SD 6.67). More than half live alone or with their spouse. Fifty-seven percent sleep on the floor or on wood, and about 82% do not have safe water. Family dysfunction is found in 40%, and 98% are at social risk or with an established social problem and a precarious economic situation. More than 60% suffer from depressive symptoms, which are more frequent in women. We conclude that older adults perceive deficient family support, observing a deteriorated social situation. Most of them are at risk of social exclusion and loneliness, making them more vulnerable. They show sadness, with a high rate of depression. People with more cognitive impairment live alone, and those in social exclusion suffer a higher degree of depression. More cooperative projects and health promotion interventions developed in the peripheral neighborhoods of Requena del Tapiche are needed to improve the impact on the health of older adult people in extreme poverty.

More Than Three Years for Normalisation of Routine Laboratory Values after Gluten Withdrawal in Paediatric Coeliac Patients.

The assessment of the nutritional and inflammatory status of paediatric patients with coeliac disease is an interesting approach to early diagnosis and functional follow-up. Most authors agree that the normalisation of symptoms takes about one year. The aim of the study was to evaluate the clinical manifestation and normalisation of routine analytics in Spanish children diagnosed with celiac disease. METHODS: We performed a retrospective case-control study in Spanish paediatric patients, including 21 celiac patients and 20 healthy controls. The 21 patients selected in the case-control study were followed for 5 years after starting a gluten-free diet (GFD). All patients had type 3 villous atrophy according to the Marsh-Oberhuber classification. A total of 39 blood samples were taken before the start of the GFD, and 109 were taken after. Twenty control sera from healthy donors were used for comparison. RESULTS: We found that patients had a subclinical but statistically significant increase in blood calcium, transaminases, and white blood cells, and a decrease in serum iron, at the time of diagnosis. Our study also shows that analytical values normalise within five years on a gluten-free diet. CONCLUSIONS: The use of a combination of subclinical changes, including low iron, high calcium, elevated leukocytes, lymphocytes, and ALT levels in blood samples, together with a low growth percentile, is pertinent in detecting coeliac disease. This set of parameters could help in the diagnosis of patients without clinical symptoms. We can also show that the levels of Fe, Ca, transaminases, and leucocytes remain subclinically altered after 3 years, despite the gluten-free diet.

Atezolizumab and Bevacizumab Combination Therapy in the Treatment of Advanced Hepatocellular Cancer.

Liver cancer, particularly hepatocellular carcinoma, is a global concern. This study focuses on the evaluation of Atezolizumab and Bevacizumab combination therapy as a promising alternative in the treatment of advanced hepatocellular carcinoma. The objectives of this systematic review include evaluating the efficacy of Atezolizumab and Bevacizumab combination therapy compared to conventional therapies with Sorafenib and other conventional therapies, analyzing the associated adverse effects, and exploring prognostic factors in the setting of advanced hepatocellular carcinoma. A systematic literature review was carried out using the PubMed and Web of Science databases. Fifteen related articles were included and evaluated according to their level of evidence and recommendation. Results: The combination therapy of Atezolizumab and Bevacizumab, along with Sorafenib, showed positive results in the treatment of patients with advanced hepatocellular carcinoma. Significant adverse effects were identified, such as gastrointestinal bleeding, arterial hypertension, and proteinuria, which require careful attention. In addition, prognostic factors, such as transforming growth factor beta (TGF-ß), alpha-fetoprotein (AFP), and vascular invasion, were highlighted as key indicators of hepatocellular carcinoma progression. Conclusions: The combination of Atezolizumab and Bevacizumab is shown to be effective in the treatment of advanced hepatocellular carcinoma, although it is essential to take into consideration the associated adverse effects. The prognostic factors identified may provide valuable information for the clinical management of this disease. This study provides a comprehensive overview of a promising emerging therapy for liver cancer.

SP1 and NFY Regulate the Expression of PNPT1, a Gene Encoding a Mitochondrial Protein Involved in Cancer.

The Polyribonucleotide nucleotidyltransferase 1 gene (PNPT1) encodes polynucleotide phosphorylase (PNPase), a 3'-5' exoribonuclease involved in mitochondrial RNA degradation and surveillance and RNA import into the mitochondrion. Here, we have characterized the PNPT1 promoter by in silico analysis, luciferase reporter assays, electrophoretic mobility shift assays (EMSA), chromatin immunoprecipitation (ChIP), siRNA-based mRNA silencing and RT-qPCR. We show that the Specificity protein 1 (SP1) transcription factor and Nuclear transcription factor Y (NFY) bind the PNPT1 promoter, and have a relevant role regulating the promoter activity, PNPT1 expression, and mitochondrial activity. We also found in Kaplan-Meier survival curves that a high expression of either PNPase, SP1 or NFY subunit A (NFYA) is associated with a poor prognosis in liver cancer. In summary, our results show the relevance of SP1 and NFY in PNPT1 expression, and point to SP1/NFY and PNPase as possible targets in anti-cancer therapy.

Selective targeting of collagen IV in the cancer cell microenvironment reduces tumor burden.

Goodpasture antigen-binding protein (GPBP) is an exportable1 Ser/Thr kinase that induces collagen IV expansion and has been associated with chemoresistance following epithelial-to-mesenchymal transition (EMT). Here we demonstrate that cancer EMT phenotypes secrete GPBP (mesenchymal GPBP) which displays a predominant multimeric oligomerization and directs the formation of previously unrecognized mesh collagen IV networks (mesenchymal collagen IV). Yeast two-hybrid (YTH) system was used to identify a 260SHCIE264 motif critical for multimeric GPBP assembly which then facilitated design of a series of potential peptidomimetics. The compound 3-[4''-methoxy-3,2'-dimethyl-(1,1';4',1'')terphenyl-2''-yl]propionic acid, or T12, specifically targets mesenchymal GPBP and disturbs its multimerization without affecting kinase catalytic site. Importantly, T12 reduces growth and metastases of tumors populated by EMT phenotypes. Moreover, low-dose doxorubicin sensitizes epithelial cancer precursor cells to T12, thereby further reducing tumor load. Given that T12 targets the pathogenic mesenchymal GPBP, it does not bind significantly to normal tissues and therapeutic dosing was not associated with toxicity. T12 is a first-in-class drug candidate to treat cancer by selectively targeting the collagen IV of the tumor cell microenvironment.

Expression of the human TIMM23 and TIMM23B genes is regulated by the GABP transcription factor.

The TIM23 protein is a key component of the mitochondrial import machinery in yeast and mammals. TIM23 is the channel-forming subunit of the translocase of the inner mitochondrial membrane (TIM23) complex, which mediates preprotein translocation across the mitochondrial inner membrane. In this paper, we aimed to characterize the promoter region of the highly similar human TIM23 orthologs: TIMM23 and TIMM23B. Bioinformatic analysis revealed putative sites for the GA-binding protein (GABP) and the recombination signal binding protein for immunoglobulin kappa J (RBPJ) transcription factors in both promoters. Luciferase reporter assays, electrophoretic mobility shift assays, and chromatin immunoprecipitation experiments showed three functional sites for GABP and one functional site for RBPJ in both promoters. Moreover, silencing of GABPA, the gene encoding the DNA-binding subunit of the GABP transcription factor, resulted in reduced expression of TIMM23 and TIMM23B. Our results show an essential role of GABP in activating TIMM23 expression. More broadly, they suggest that physiological signals involved in activating mitochondrial biogenesis and oxidative function also enhance the transcription but not the protein level of TIMM23, which is essential for maintaining mitochondrial function and homeostasis.

Analysis of the characteristics of interconsultations performed by emergency physicians to other hospital specialists and their evolution over time.

OBJECTIVE: The objective of this study was to describe the type of interconsultations carried out in the Emergency Department (ED) to hospital specialists and analyze their pattern over time. METHODS: The study was carried out during the period from 2006 to 2012. It was carried out at EDs attending to all types of interconsultations except pediatrics and obstetrics-gynecology. There were no changes in physical structure, number of personnel, or organization during the study period. The main measurements taken were as follows: monthly ED census, number of interconsultations and specialties consulted, main reason for presentation at the ED during the first (2006) and last year (2012), and, for specialties demonstrating substantial quantitative changes, main reasons for the interconsultation from the ED at the beginning (2006) and the end (2012) of the study. Linear regression analysis was carried out for the relationship between time and number of interconsultations. RESULTS: A total of 628 256 care interventions were carried out, with 128 008 interconsultations (20.4%). Orthopedic surgery and traumatology, psychiatry, and general and digestive surgery were the departments most frequently consulted (54.5% of the interconsultations). Consultations significantly reduced over time (R=0.29; P<0.001) but the percentage of interconsultations (related to ED census) remained unchanged (R=0.01; P=0.49). The behavior related to specialties was heterogeneous: consultations to general and digestive surgery, hematology and hemostasis, and urology specialists decreased, whereas to thoracic surgery, angiology and vascular surgery, neurology, nephrology, neurosurgery, psychiatry, orthopedic surgery and traumatology, and critical care medicine specialists increased. Some of the reasons for specialist consultation also significantly changed over time. CONCLUSION: The study of interconsultations allows us to identify areas of lesser autonomy of emergency physicians. Changes in the pattern of these interconsultations over time may reflect both learning processes and changes in the healthcare circuits in the ED.

Presión aórtica central y parámetros de reflexión de onda. Importancia clínica y análisis de consistencias y discrepancias con niveles de presión periférica / Central aortic pressure wave reflection parameters. Clinical significance and analysis of consistencies and discrepancies with peripheral pressure levels

Introducción: se presenta un trabajo de revisión sobre las diferencias entre la presión aórtica central (PAC) y la presión arterial periférica (PAP), y sobre la importancia biomédica de la PAC. Adicionalmente, se presenta un trabajo de investigación original que permitió determinar curvas por edad para la PAC de una población uruguaya y determinar los porcentajes de individuos (discriminando por edad, sexo y nivel de PAP) que presentan niveles de PAC hipertensivos. Material y método: en 785 uruguayos (edad: 6-79 años), sin enfermedad cardiovascular, hipertensión arterial, diabetes e insuficiencia renal, y sin empleo de fármacos vasoactivos, se midió la PAC y parámetros de reflexión de onda (índice de aumento, presión de aumento aórtica) mediante tonometría de aplanamiento radial y aplicación de una función transferencia generalizada. Resultados: se obtuvieron las tendencias por edad esperables de encontrar para los parámetros de PAC y reflexiones de onda. El 3% y 24% de personas con PAP normal/normal alta, respectivamente, presentaron PAC sistólica mayor del valor deseado. El 32% de personas con PAP clasificable como HTA 1 no presentarían PAC hipertensiva. El 11%-17% de las personas con niveles de PAP óptimos presentaron presión de pulso (PP) aórticas hipertensivas. El 22% y 35% de las personas con PAP normal/normal alta, respectivamente, presentaron PP aórtica hipertensivas. El 43% de personas con niveles de PAP clasificable como HTA 1 no presentaron PP aórtica hipertensiva. Conclusión: medir la PAC contribuiría en la evaluación y clasificación de estados hipertensivos, la valoración de la respuesta al tratamiento y en la determinación del riesgo vascular del paciente.

Health informatics design for assisted diagnosis of subclinical atherosclerosis, structural, and functional arterial age calculus and patient-specific cardiovascular risk evaluation.

Traditional methods used to assess cardiovascular risk (i.e., the Framingham Risk Score) exhibit clear limitations. To aid in patient-specific risk stratification and diagnosis it has been proposed to evaluate noninvasively structural and functional arterial parameters. A National Public University Center (CUiiDARTE) was created in Uruguay with the aim of developing and applying strategies to improve cardiovascular risk stratification and subclinical vascular disease detection. To this end a health informatics approach and tool was designed, developed, and implemented in CUiiDARTE. Its goals were to: 1) promote screening for subclinical atherosclerosis, 2) develop a centralized database to store information obtained noninvasively from anywhere in our country, 3) develop a biomathematical model integrating values for arterial structure and function into traditional cardiovascular risk assessment, 4) generate a detailed and comprehensive report for the specialist comparing patient data with reference data from the healthy population, 5) generate a similar report (using a structural and functional arterial age calculator) for the patients assessing the state of their arteries. In this paper, we present the main characteristics of the CUiiDARTE health informatics development.

Goodpasture antigen-binding protein is a soluble exportable protein that interacts with type IV collagen. Identification of novel membrane-bound isoforms.

Goodpasture-antigen binding protein (GPBP) is a nonconventional Ser/Thr kinase for basement membrane type IV collagen. Various studies have questioned these findings and proposed that GPBP serves as transporter of ceramide between the endoplasmic reticulum and the Golgi apparatus. Here we show that cells expressed at least two GPBP isoforms resulting from canonical (77-kDa) and noncanonical (91-kDa) mRNA translation initiation. The 77-kDa polypeptide interacted with type IV collagen and localized as a soluble form in the extracellular compartment. The 91-kDa polypeptide and its derived 120-kDa polypeptide associated with cellular membranes and regulated the extracellular levels of the 77-kDa polypeptide. A short motif containing two phenylalanines in an acidic tract and the 26-residue Ser-rich region were required for efficient 77-kDa polypeptide secretion. Removal of the 26-residue Ser-rich region by alternative exon splicing rendered the protein cytosolic and sensitive to the reduction of sphingomyelin cellular levels. These and previous data implicate GPBPs in a multicompartmental program for protein secretion (i.e. type IV collagen) that includes: 1) phosphorylation and regulation of protein molecular/supramolecular organization and 2) interorganelle ceramide trafficking and regulation of protein cargo transport to the plasma membrane.