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Orphanet Journal of Rare Diseases May 2020Limb-girdle muscular dystrophy recessive 1 calpain3-related (LGMDR1), previously known as LGMD2A, is a disease caused by mutations in the CAPN3 gene. It is characterized...
BACKGROUND
Limb-girdle muscular dystrophy recessive 1 calpain3-related (LGMDR1), previously known as LGMD2A, is a disease caused by mutations in the CAPN3 gene. It is characterized by progressive weakness and muscle degeneration. Frizzled related protein (FRZB), upregulated in LGMDR1, was identified as a key regulator of the crosstalk between Wnt and integrin signalling pathways. FRZB gene silencing showed a recovery in the expression of some of the costamere protein levels in myotubes.
RESULTS
Here, we performed a comprehensive characterization of Frzb mice muscles to study the absence of Frzb in skeletal muscle and eventual links with the molecular characteristics of LGMDR1 patient muscles. Frzb mice showed reduced muscle size and strength. Gait analysis showed that Frzb mice moved more slowly but no impaired regeneration capacity was observed after muscle injury. Additionally, Frzb mice muscle showed an increased number of mesoangioblasts. Lack of Frzb gene in Frzb mice and its increased expression in LGMDR1 patients, showed contrary regulation of Rora, Slc16a1, Tfrc and Capn3 genes. The reciprocal regulation of Frzb and Capn3 genes further supports this axis as a potential target for LGMDR1 patients.
CONCLUSIONS
Our data confirm a role for Frzb in the regulation of Rora, Slc16a1, Tfrc, and Capn3 genes in muscle cells. In vivo, reduced muscle strength and gait in the Frzb mice are intriguing features. The reciprocal relationship between FRZB and CAPN3 further supports a key role for this axis in patients with LGMDR1.
Topics: Animals; Calpain; Gait; Humans; Intracellular Signaling Peptides and Proteins; Mice; Muscle Proteins; Muscle Strength; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Protein Deficiency
PubMed: 32448375
DOI: 10.1186/s13023-020-01372-1 -
American Journal of Respiratory and... Feb 2019
Topics: Bronchioles; Epithelial Cells; Humans; Lung Neoplasms; Protein Deficiency; Respiratory Physiological Phenomena
PubMed: 30557514
DOI: 10.1164/rccm.201811-2117ED -
BioMed Research International 2022Gastric cancer (GC) is a major cause of cancer-related death in China. Immunotherapies based on PD-1/PD-L1 inhibitors have improved the survival of some patients with...
BACKGROUND
Gastric cancer (GC) is a major cause of cancer-related death in China. Immunotherapies based on PD-1/PD-L1 inhibitors have improved the survival of some patients with GC. Epstein-Barr virus (EBV) infection, mismatch repair (MMR) deficiency, and tumor immune microenvironment (TIME) markers (such as CD3, CD8, and PD-L1) may help to identify specific patients who will respond to PD-1/PD-L1 inhibitors. Considering racial heterogeneity, the pattern of TIME markers in Tibetan patients with GC is still unclear. We aimed to identify the prevalence of EBV infection and the MMR status and their association with immune markers in Tibetan GC to aid in patient selection for immunotherapy.
MATERIALS AND METHODS
From 2001 to 2015, we retrospectively collected 120 tissue samples from consecutive Tibetan GC patients and constructed tissue microarrays. EBV infection was assessed by Epstein-Barr-encoded RNA (EBER) in situ hybridization, and MMR protein levels were measured. Immune markers (including CD3 and CD8) in intraepithelial, stromal, and total areas were detected by immunohistochemistry (IHC). PD-L1 expression was assessed by the combined positive score (CPS). We also analyzed the relationships of EBV infection and MMR status with immune markers.
RESULTS
Of the 120 samples, 11 (9.17%) were EBV positive (+), and 6 (5%) were MMR deficient (dMMR). PD-L1 CPS ≥1% was found in 32.5% (39/120) of Tibetan GC patients. EBV infection was associated with higher numbers of CD3+ T cells ( < 0.05) and CD8+ T cells ( < 0.05) and higher PD-L1 expression ( < 0.05). For the limited number of dMMR patients, no significant relationship was observed between dMMR and TIME markers ( > 0.05).
CONCLUSIONS
In Tibetan GC patients, the rates of EBV infection, dMMR, and positive PD-L1 expression were 9.17%, 5%, and 32.5%, respectively. EBV infection was associated with the numbers of CD3+ T cells and CD8+ T cells and PD-L1 expression within the tumor. These markers may guide the selection of Tibetan GC patients for immunotherapy.
Topics: B7-H1 Antigen; Biomarkers, Tumor; Brain Neoplasms; Colorectal Neoplasms; DNA Mismatch Repair; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Immune Checkpoint Inhibitors; Neoplastic Syndromes, Hereditary; Prevalence; Programmed Cell Death 1 Receptor; Protein Deficiency; Retrospective Studies; Stomach Neoplasms; Tibet; Tumor Microenvironment
PubMed: 35734348
DOI: 10.1155/2022/2684065 -
Gut Feb 1995The pathogenesis of alcoholic pancreatitis is not fully understood. An increase in pancreatic digestive and lysosomal enzyme synthesis because of ethanol consumption...
The pathogenesis of alcoholic pancreatitis is not fully understood. An increase in pancreatic digestive and lysosomal enzyme synthesis because of ethanol consumption could contribute to the development of pancreatic injury in alcoholics. This study aimed, firstly, to determine the effect of ethanol on the content and messenger RNA levels of pancreatic digestive enzymes and on the messenger RNA level of the lysosomal enzyme cathepsin B, and secondly, to examine the influence of concomitant protein deficiency (a known association of alcoholism and pancreatic injury) on these effects. A rat model of chronic ethanol administration was used in which rats were fed in groups of four, and for four weeks, protein sufficient and protein deficient diets with or without ethanol. Ethanol increased the pancreatic content of lipase but did not influence chymotrypsinogen or trypsinogen values. mRNA levels for lipase, trypsinogen, and chymotrypsinogen were raised in rats fed ethanol. Protein deficiency resulted in reduced tissue levels of lipase, chymotrypsinogen, and amylase but did not influence trypsinogen values. mRNA levels for proteases were increased in protein deficient rats, while those for lipase remained unaltered. Both ethanol and protein deficiency increased mRNA levels for cathepsin B. It is concluded that chronic ethanol consumption, in both protein sufficient and protein deficient states, increases the capacity of the pancreatic acinar cell to synthesise digestive and lysosomal enzymes.
Topics: Amylases; Animals; Blotting, Northern; Cathepsin B; Chymotrypsinogen; Ethanol; Lipase; Male; Pancreas; Protein Deficiency; RNA, Messenger; Rats; Rats, Sprague-Dawley; Trypsinogen
PubMed: 7533742
DOI: 10.1136/gut.36.2.287 -
Glia Jul 2022Survival motor neuron (SMN) protein deficiency results in loss of alpha motor neurons and subsequent muscle atrophy in patients with spinal muscular atrophy (SMA)....
Survival motor neuron (SMN) protein deficiency results in loss of alpha motor neurons and subsequent muscle atrophy in patients with spinal muscular atrophy (SMA). Reactive microglia have been reported in SMA mice and depleting microglia rescues the number of proprioceptive synapses, suggesting a role in SMA pathology. Here, we explore the contribution of lymphocytes on microglia reactivity in SMA mice and investigate how SMN deficiency alters the reactive profile of human induced pluripotent stem cell (iPSC)-derived microglia. We show that microglia adopt a reactive morphology in spinal cords of SMA mice. Ablating lymphocytes did not alter the reactive morphology of SMA microglia and did not improve the survival or motor function of SMA mice, indicating limited impact of peripheral immune cells on the SMA phenotype. We found iPSC-derived SMA microglia adopted an amoeboid morphology and displayed a reactive transcriptome profile, increased cell migration, and enhanced phagocytic activity. Importantly, cell morphology and electrophysiological properties of motor neurons were altered when they were incubated with conditioned media from SMA microglia. Together, these data reveal that SMN-deficient microglia adopt a reactive profile and exhibit an exaggerated inflammatory response with potential impact on SMA neuropathology.
Topics: Animals; Disease Models, Animal; Humans; Induced Pluripotent Stem Cells; Mice; Microglia; Motor Neurons; Muscular Atrophy, Spinal; Protein Deficiency; Survival of Motor Neuron 1 Protein
PubMed: 35373853
DOI: 10.1002/glia.24177 -
Nutrients May 2021Dietary intakes must cover protein and essential amino acid (EAA) requirements. For this purpose, different methods have been developed such as the nitrogen balance...
OBJECTIVE
Dietary intakes must cover protein and essential amino acid (EAA) requirements. For this purpose, different methods have been developed such as the nitrogen balance method, factorial method, or AA tracer studies. However, these methods are either invasive or imprecise, and the Food and Agriculture Organization of the United Nations (FAO, 2013) recommends new methods and, in particular, metabolomics. The aim of this study is to determine total protein/EAA requirement in the plasma and urine of growing rats.
METHODS
36 weanling rats were fed with diets containing 3, 5, 8, 12, 15, and 20% protein for 3 weeks. During experimentation, urine was collected using metabolic cages, and blood from the portal vein and vena was taken at the end of the experiment. Metabolomics analyses were performed using LC-MS, and the data were analyzed with a multivariate analysis model, partial least Squares (PLS) regression, and independent component-discriminant analysis (ICDA). Each discriminant metabolite identified by PLS or ICDA was tested by one-way ANOVA to evaluate the effect of diet.
RESULTS
PLS and ICDA allowed us to identify discriminating metabolites between different diet groups. Protein deficiency led to an increase in the AA catabolism enzyme systems inducing the production of breakdown metabolites in the plasma and urine.
CONCLUSION
These results indicate that metabolites are specific for the state of EAA deficiency and sufficiency. Some types of biomarkers such as AA degradation metabolites appear to be specific candidates for protein/EAA requirement.
Topics: Amino Acids, Essential; Analysis of Variance; Animal Feed; Animals; Biomarkers; Deficiency Diseases; Dietary Proteins; Discriminant Analysis; Disease Models, Animal; Least-Squares Analysis; Metabolomics; Multivariate Analysis; Nutrition Assessment; Nutritional Requirements; Protein Deficiency; Rats
PubMed: 34066958
DOI: 10.3390/nu13051567 -
Clinical Nutrition (Edinburgh, Scotland) May 2021Nutrition therapy, by enteral, parenteral, or both routes combined, is a key component of the management of critically ill, surgical, burns, and oncology patients.... (Review)
Review
Nutrition therapy, by enteral, parenteral, or both routes combined, is a key component of the management of critically ill, surgical, burns, and oncology patients. Established evidence indicates overfeeding (provision of excessive calories) results in increased risk of infection, morbidity, and mortality. This has led to the practice of "permissive underfeeding" of calories; however, this can often lead to inadequate provision of guideline-recommended protein intakes. Acutely ill patients requiring nutritional therapy have high protein requirements, and studies demonstrate that provision of adequate protein can result in reduced mortality and improvement in quality of life. However, a significant challenge to adequate protein delivery is the current lack of concentrated protein solutions. Patients often have fluid administration restrictions and existing protein solutions are frequently not sufficiently concentrated to deliver a patient's protein requirements. This has led to the development of new enteral and parenteral nutrition solutions incorporating higher levels of protein in smaller volumes. This review article summarizes current evidence supporting the role of higher protein intakes, especially during the early phases of nutrition therapy in acute illness, methods for assessing protein requirements, as well as, the currently available high-protein enteral and parenteral nutrition solutions. There is sufficient evidence (albeit limited from true randomized, controlled studies) to indicate that earlier provision of guideline-recommended protein intakes may be key to improving patient outcomes and that nutritional therapy that tailors caloric and protein intake to the patients' needs should be considered a desired standard of care.
Topics: Acute Disease; Critical Care; Critical Illness; Dietary Proteins; Humans; Nutritional Requirements; Nutritional Support; Protein Deficiency
PubMed: 33451860
DOI: 10.1016/j.clnu.2020.12.032 -
Cancer Medicine Apr 2024While previous studies have indicated variability in distant metastatic potential among different mismatch repair (MMR) states in colorectal cancer (CRC), their findings... (Meta-Analysis)
Meta-Analysis
BACKGROUND
While previous studies have indicated variability in distant metastatic potential among different mismatch repair (MMR) states in colorectal cancer (CRC), their findings remain inconclusive, especially considering potential differences across various ethnic backgrounds. Furthermore, the gene regulatory networks and the underlying mechanisms responsible for these variances in metastatic potential across MMR states have yet to be elucidated.
METHODS
We collected 2058 consecutive primary CRC samples from the South West of China and assessed the expression of MMR proteins (MLH1, MSH2, MSH6, and PMS2) using immunohistochemistry. To explore the inconsistencies between different MMR statuses and recurrence, we performed a meta-analysis. To delve deeper, we employed Weighted Gene Co-expression Network Analysis (WGCNA), ClueGo, and iRegulon, pinpointing gene expression networks and key regulatory molecules linked to metastasis and recurrence in CRC. Lastly, both univariate and multivariate Cox regression analyses were applied to determine the impact of core regulatory molecules on metastasis.
RESULTS
Of the samples, 8.2% displayed deficient MMR (dMMR), with losses of MLH1 and PSM2 observed in 40.8% and 63.9%, respectively. A unique 24.3% isolated loss of PMS2 without concurrent metastasis was identified, a result that diverges from established literature. Additionally, our meta-analysis further solidifies the reduced recurrence likelihood in dMMR CRC samples compared to proficient MMR (pMMR). Two gene expression networks tied to distant metastasis and recurrence were identified, with a majority of metastasis-related genes located on chromosomes 8 and 18. An IRF1 positive feedback loop was discerned in the metastasis-related network, and IRF1 was identified as a predictive marker for both recurrence-free and distant metastasis-free survival across multiple datasets.
CONCLUSION
Geographical and ethnic factors might influence peculiarities in MMR protein loss. Our findings also highlight new gene expression networks and crucial regulatory molecules in CRC metastasis, enhancing our comprehension of the mechanisms driving distant metastasis.
Topics: Humans; DNA-Binding Proteins; DNA Mismatch Repair; Mismatch Repair Endonuclease PMS2; Colorectal Neoplasms; Protein Deficiency
PubMed: 38545852
DOI: 10.1002/cam4.6994 -
The Journal of Nutrition Jan 2015Protein deficiency (PD) and intestinal nematode infections commonly co-occur during pregnancy and impair fetal growth, but the complex network of signals has not been...
BACKGROUND
Protein deficiency (PD) and intestinal nematode infections commonly co-occur during pregnancy and impair fetal growth, but the complex network of signals has not been explored.
OBJECTIVE
Our objective was to assess those stress hormones, growth factors, and cytokines affected by maternal PD and nematode infection and associated with fetal growth.
METHODS
Using a 2 × 2 factorial design, CD-1 mice, fed protein-sufficient (PS; 24%) or protein-deficient (PD; 6%) isoenergetic diets, were either uninfected or infected every 5 d with Heligmosomoides bakeri, beginning on gestational day (GD) 5. Biomarker concentrations were measured on GD 18 in maternal serum (m), fetal serum (f), and amniotic fluid (af) by using Luminex.
RESULTS
Maternal PD lowered fetal body mass (PS/uninfected 1.25 ± 0.02 g, PS/infected 1.19 ± 0.02 g vs. PD/uninfected 1.11 ± 0.02 g, PD/infected 0.97 ± 0.02 g; P = 0.02), fetal lung (P = 0.005), and liver (P = 0.003) but not brain mass, whereas maternal infection lowered fetal length (PS/uninfected 2.28 ± 0.02 cm, PD/uninfected 2.27 ± 0.03 cm vs. PS/infected 2.21 ± 0.03 cm, PD/infected 2.11 ± 0.02 cm; P = 0.05) and kidney mass (P = 0.04). PD elevated stress hormones (m-adrenocortiotropic hormone, f-corticosterone, af-corticosterone) and reduced insulin-like growth factor 1 in all compartments (P ≤ 0.01), but these were unassociated with fetal mass or length. Fetal mass was positively associated with f-leptin (R(2) = 0.71, P = 0.0001) and negatively with fetal cytokines [tumor necrosis factor-α: R(2) = 0.62, P = 0.001; interleukin-4 (IL-4): R(2) = 0.63, P = 0.0004]. In contrast, maternal infection lowered f-prolactin (P = 0.02) that was positively associated with fetal length (R(2) = 0.43; P = 0.03); no other biomarker was affected by infection. Regression analyses showed associations between organ growth, cytokines, and growth factors: 1) thymus, spleen, heart, and brain with m-IL-10; 2) brain and kidney with f-vascular endothelial growth factor, af-monocyte chemotactic protein 1, af-interferon-γ, and af-eotaxin; and 3) liver and lung with f-leptin and af-corticosterone (all P ≤ 0.02).
CONCLUSIONS
PD and nematode infection impaired fetal mass and linear growth, respectively. Fetal mass, length, and individual organ masses were regulated by different hormones, growth factors, and cytokines.
Topics: Adrenocorticotropic Hormone; Amniotic Fluid; Animals; Biomarkers; Corticosterone; Cytokines; Female; Fetal Development; Fetal Organ Maturity; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Intestinal Diseases, Parasitic; Mice; Nematode Infections; Pregnancy; Pregnancy Complications; Protein Deficiency; Vascular Endothelial Growth Factor A
PubMed: 25355841
DOI: 10.3945/jn.114.202630 -
The American Journal of Pathology Sep 1976Several experiments conducted by our group over a period of 6 years have shown that nutritional stress, especially protein and/or calorie deprivation, leads to many,... (Review)
Review
Several experiments conducted by our group over a period of 6 years have shown that nutritional stress, especially protein and/or calorie deprivation, leads to many, often dramatic, changes in the immune responses of mice, rats, and guinea pigs. Chronic protein deprivation (CPD) has been shown to create an enhancing effect on the cell-mediated immune responses of these animals. Humoral responses under CPD conditions were most often found to be depressed, but sometimes were unaffected, depending on the nature of the antigen employed. Chronic protein deprivation, consistent with the pattern just mentioned, improved tumor immunity by depressing production of B-cell blocking factors, and, in at least one instance, resistance to development of mammary adenocarcinoma in C3H mice was associated with evidence of increased numbers of T suppressor cells. Profound nutritional deficits (less than 5% protein per total daily food intake) depressed both cellular and humoral immunity. Early, though temporary, protein deprivation caused a long-term depression of both cellular and humoral immunity also, with the humoral component being the first to recover. Manipulation of protein and calories was found to have a profound effect on certain autoimmune conditions. Diets high in fat and low in protein favored reproduction but shortened the life of NZB mice, whereas diets high in protein and low in fat inhibited development of autoimmunity and prolonged life. Chronic moderate protein restriction permitted NZB mice to maintain their normally waning immunologic functions much longer than mice fed a normal protein intake. Further, the low-protein diet was associated with a delay in development of manifestations of autoimmunity. Decreasing dietary calories by a reduction of fats, carbohydrates, and proteins more than doubled the average life span of (NZB X NZW)F1 mice, a strain prone to early death from autoimmune disease. Histopathologic studies using immunofluorescent microscopy revealed that the development of the renal lesions caused by the deposition of antigen-antibody complexes, which is so characteristic of these mice, was markedly delayed.
Topics: Anemia, Hemolytic; Animals; Antibody-Producing Cells; Autoimmune Diseases; Chronic Disease; Cytotoxicity Tests, Immunologic; Disease; Graft Rejection; Graft vs Host Reaction; Hemolytic Plaque Technique; Immunity; Immunity, Cellular; Longevity; Male; Mammary Glands, Animal; Neoplasms; Nutrition Disorders; Protein Deficiency; Spleen; T-Lymphocytes
PubMed: 8988
DOI: No ID Found