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Cell Death & Disease Oct 2022Acute pancreatitis is a common acute inflammatory abdominal disease. When acute pancreatitis progresses to severe acute pancreatitis (SAP), it can lead to systemic...
Acute pancreatitis is a common acute inflammatory abdominal disease. When acute pancreatitis progresses to severe acute pancreatitis (SAP), it can lead to systemic inflammation and even multiple organ failure. Thioredoxin-interacting protein (TXNIP) is an important protein involved in redox reactions of the inflammatory response. However, the specific role of TXNIP in SAP remains unclear. In this study, we investigated the role of thioredoxin interacting protein (TXNIP) in acute pancreatitis when induced by high doses of arginine. We found that pancreatic damage and the inflammatory response associated with acute pancreatitis were largely restrained in TXNIP knock-out mice but were enhanced in mice overexpressing TXNIP. Interestingly, the phosphorylation of p38, JNK, and ASK1 diminished in TXNIP-KO mice with pancreatitis in comparison with wild-type mice. The role of oxidative stress in SAP was explored in two models: TXNIP and AVV-TXNIP. TXNIP knockdown or the inhibition of ASK1 by gs-4997 abrogated the increase in p-p38, p-JNK, and p-ASK1 in AR42J cells incubated with L-Arg. The administration of gs-4997 to mice with pancreatitis largely reduced the upregulation of IL-6, IL-1β, TNF-α, and MCP-1. Systemic inflammatory reactions and injury in the lungs and kidneys were assessed in TXNIP-KO and AVV-TXNIP mice with expected outcomes. In conclusion, TXNIP is a novel mediator of SAP and exerts action by regulating inflammatory responses and oxidative stress via the ASK1-dependent activation of the JNK/p38 pathways. Thus, targeting TXNIP may represent a promising approach to protect against SAP.
Topics: Animals; Mice; Acute Disease; Apoptosis; MAP Kinase Kinase Kinase 5; Pancreatitis; Protein Deficiency; Thioredoxins
PubMed: 36316322
DOI: 10.1038/s41419-022-05355-x -
Journal of Community Hospital Internal... Jun 2021Kwashiorkor syndrome is a form of severe protein-energy malnutrition characterized by protein deficiency and bilateral extremity swelling. Worldwide, most affected...
Kwashiorkor syndrome is a form of severe protein-energy malnutrition characterized by protein deficiency and bilateral extremity swelling. Worldwide, most affected regions include Southeast Asia, South Africa and Central America; it is rare in developed countries such as the USA. We report a case of profound kwashiorkor in a 38-year-old male with an underlying psychiatric disorder and restricted diet who presented with extensive abdominal distention and systemic findings indicative of protein malnutrition.
PubMed: 34211663
DOI: 10.1080/20009666.2021.1933718 -
Nutrients Apr 2019Skeletal muscle (SM) mass, the chief component of the structural compartment belonging to lean body mass (LBM), undergoes sarcopenia with increasing age. Decreased SM in... (Review)
Review
Skeletal muscle (SM) mass, the chief component of the structural compartment belonging to lean body mass (LBM), undergoes sarcopenia with increasing age. Decreased SM in elderly persons is a naturally occurring process that may be accelerated by acute or chronic nutritional deficiencies and/or inflammatory disorders, declining processes associated with harmful complications. A recently published position paper by European experts has provided an overall survey on the definition and diagnosis of sarcopenia in elderly persons. The present review describes the additional contributory role played by the noninvasive transthyretin (TTR) micromethod. The body mass index (BMI) formula is currently used in clinical studies as a criterion of good health to detect, prevent, and follow up on the downward trend of muscle mass. The recent upsurge of sarcopenic obesity with its multiple subclasses has led to a confused stratification of SM and fat stores, prompting workers to eliminate BMI from screening programs. As a result, investigators are now focusing on indices of protein status that participate in SM growth, maturation, and catabolism that might serve to identify sarcopenia trajectories. Plasma TTR is clearly superior to all other hepatic biomarkers, showing the same evolutionary patterns as those displayed in health and disease by both visceral and structural LBM compartments. As a result, this TTR parameter maintains positive correlations with muscle mass downsizing in elderly persons. The liver synthesis of TTR is downregulated in protein-depleted states and suppressed in cytokine-induced inflammatory disorders. TTR integrates the centrally-mediated regulatory mechanisms governing the balance between protein accretion and protein breakdown, emerging as the ultimate indicator of LBM resources. This review proposes the adoption of a gray zone defined by cut-off values ranging from 200 mg/L to 100 mg/L between which TTR plasma values may fluctuate and predict either the best or the worst outcome. The best outcome occurs when appropriate dietary, medicinal and surgical decisions are undertaken, resuming TTR synthesis which manifests rising trends towards pre-stress levels. The worst occurs when all therapeutic means fail to succeed, leading inevitably to complete exhaustion of LBM and SM metabolic resources with an ensuing fatal outcome. Some patients may remain unresponsive in the middle of the gray area, combining steady clinical states with persistent stagnant TTR values. Using the serial measurement of plasma TTR values, these last patients should be treated with the most aggressive and appropriate therapeutic strategies to ensure the best outcome.
Topics: Adipose Tissue; Aged; Biomarkers; Body Composition; Body Fluid Compartments; Body Mass Index; Humans; Inflammation; Liver; Muscle, Skeletal; Nutritional Status; Obesity; Prealbumin; Protein Deficiency; Sarcopenia
PubMed: 31010086
DOI: 10.3390/nu11040895 -
Journal of Inherited Metabolic Disease Jul 2022Mitochondrial trifunctional protein (MTP) is involved in long-chain fatty acid β-oxidation (lcFAO). Deficiency of one or more of the enzyme activities as catalyzed by...
Mitochondrial trifunctional protein (MTP) is involved in long-chain fatty acid β-oxidation (lcFAO). Deficiency of one or more of the enzyme activities as catalyzed by MTP causes generalized MTP deficiency (MTPD), long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), or long-chain ketoacyl-CoA thiolase deficiency (LCKATD). When genetic variants result in thermo-sensitive enzymes, increased body temperature (e.g. fever) can reduce enzyme activity and be a risk factor for clinical decompensation. This is the first description of five patients with a thermo-sensitive MTP deficiency. Clinical and genetic information was obtained from clinical files. Measurement of LCHAD and LCKAT activities, lcFAO-flux studies and palmitate loading tests were performed in skin fibroblasts cultured at 37°C and 40°C. In all patients (four MTPD, one LCKATD), disease manifested during childhood (manifestation age: 2-10 years) with myopathic symptoms triggered by fever or exercise. In four patients, signs of retinopathy or neuropathy were present. Plasma long-chain acylcarnitines were normal or slightly increased. HADHB variants were identified (at age: 6-18 years) by whole exome sequencing or gene panel analyses. At 37°C, LCHAD and LCKAT activities were mildly impaired and lcFAO-fluxes were normal. Remarkably, enzyme activities and lcFAO-fluxes were markedly diminished at 40°C. Preventive (dietary) measures improved symptoms for most. In conclusion, all patients with thermo-sensitive MTP deficiency had a long diagnostic trajectory and both genetic and enzymatic testing were required for diagnosis. The frequent absence of characteristic acylcarnitine abnormalities poses a risk for a diagnostic delay. Given the positive treatment effects, upfront genetic screening may be beneficial to enhance early recognition.
Topics: 3-Hydroxyacyl CoA Dehydrogenases; Adolescent; Cardiomyopathies; Child; Child, Preschool; Coenzyme A; Delayed Diagnosis; Fatty Acids; Humans; Lipid Metabolism, Inborn Errors; Mitochondrial Myopathies; Mitochondrial Trifunctional Protein; Muscular Diseases; Nervous System Diseases; Rhabdomyolysis
PubMed: 35403730
DOI: 10.1002/jimd.12503 -
Nutricion Hospitalaria Sep 2014Malnutrition in surgical patients is associated with delayed recovery, higher rates of morbidity and mortality, prolonged hospital stay, increased healthcare costs and a... (Review)
Review
BACKGROUND
Malnutrition in surgical patients is associated with delayed recovery, higher rates of morbidity and mortality, prolonged hospital stay, increased healthcare costs and a higher early re-admission rate.
METHODS
Data synthesis after review of pertinent literature.
RESULTS
The aetiology of malnutrition is multifactorial. In cancer patients, there is an abnormal peripheral glucose disposal, gluconeogenesis, and whole-body glucose turnover. Malnourished cancer patients undergoing major operations are at significant risk from perioperative complications such as infectious complications. Surgical aggression generates an inflammatory response which worsens intermediary metabolism.
CONCLUSIONS
Nutritional evaluation and nutritional support must be performed in all surgical patients, in order to minimize infectious complications. Enteral nutrition early in the postoperative period is effective and well tolerated reducing infectious complications, improving wound healing and reducing length of hospital stay. Pharmaconutrition is indicated in those patients, who benefit from enteral administration of arginine, omega 3 and RNA, as well as parenteral glutamine supplementation. When proximal sutures are used, tubes allowing early jejunal feeding should be used.
Topics: Bacterial Infections; Humans; Malnutrition; Nutritional Support; Postoperative Complications; Protein-Energy Malnutrition
PubMed: 25238824
DOI: 10.3305/nh.2014.30.3.7702 -
The Journal of Pediatric Pharmacology... 2021Spinal muscular atrophy (SMA) is a debilitating disorder characterized by degeneration of large motor neurons. It is a heterogeneous group of disorders caused by a... (Review)
Review
Spinal muscular atrophy (SMA) is a debilitating disorder characterized by degeneration of large motor neurons. It is a heterogeneous group of disorders caused by a homozygous deletion in the survival motor neuron () gene on chromosome 5, resulting in a SMN protein deficiency. Small amounts of SMN protein are also produced by the gene, which that differs from by a single nucleotide. Spinal muscular atrophy types and phenotypic severity depend on the number of variations of the gene and the amount of SMN2 protein produced. Because the SMN protein deficiency is the root cause of the disease, treatment strategies for SMA revolve around increasing SMN protein production. Nusinersen (Spinraza, Biogen, Cambridge, MA) was the only treatment option available for SMA until the FDA approved onasemnogene abeparvovec-xioi (Zolgensma, AveXis Inc, Bannockburn, IL), a one-time-administered adeno-associated viral vector-based gene therapy that delivers the gene to the motor neuron cells. Data from clinical studies show significant improvement in motor milestone achievements and ventilator-free survival but are limited by approximately 5 years' worth of results. This one-time intravenous injection of this new gene therapy also bears a hefty price tag; however, it may be more cost effective in the long run versus the multiple intrathecal administrations needed with nusinersen. Drug access and use are hindered by drug cost, payer reimbursement issues, and lack of long-term data from clinical studies. Questions also remain regarding the safety and efficacy of repeated drug administration for patients with advanced disease.
PubMed: 34239394
DOI: 10.5863/1551-6776-26.5.437 -
The Journal of Thoracic and... Mar 2018
Topics: Cardiac Surgical Procedures; Humans; Infant; Mannose-Binding Lectin; Metabolism, Inborn Errors; Risk Factors
PubMed: 28986043
DOI: 10.1016/j.jtcvs.2017.08.105 -
Current Research in Physiology 2022Efficient reproductive function is an important characteristic that has evolved through natural selection. Nutrition can modulate reproductive activities at different...
BACKGROUND
Efficient reproductive function is an important characteristic that has evolved through natural selection. Nutrition can modulate reproductive activities at different levels, and its effect on reproduction is deemed complex and less predictable.
OBJECTIVE
This study aims at investigating the underlying effect of persistent dietary protein deficiency during early life on reproductive parameters of subsequent (F and F) generations.
METHOD
Rats in group of four (4) were fed daily, different ration of protein diet (PD) formulated as: 21% protein diet, 10%protein diet, 5%protein diet and control diet (rat chow, containing 16-18% protein). They were fed before mating, throughout gestation and lactation, and next generations were weaned to the maternal diet. Reproductive function analysis (which include; gestation and pubertal hormonal profiling, onset of puberty, oestrus cyclicity, sexual response) and morphometric analysis of the ovarian structure were carried out to assess associated consequences.
RESULTS
There was significant reduction in the fertility index (Control; 85.8%., 21%PD; 88.43%., as compared to 10%PD; 65.9%., 5%PD; 35.78%.,) at F also recurring in F respectively as a consequence of altered reproductive function in the protein deficient models at P ≤ 0.05. Low protein diet posed suboptimal intrauterine condition, which was linked to increased prenatal morbidity and mortality (control; 11.3%., 21%PD; 3.3%., 10%PD; 27.4%., 5%PD; 32.9%), low birthweight (control; 5.29, 4.9 g., 21%PD; 5.5, 5.06 g., 10%PD; 4.05, 3.86 g., 5%PD; 2.7, 2.5 g) at F and F respectively, delayed onset of puberty (with average pubertal age set at: control; PND 36, 21%PD; PND 38 while 10%PD; PND 62., and 5%PD; PND 67), followed by induced cycle irregularity, altered follicular maturation and endocrine dysfunction, more severe in 5%PD.
CONCLUSION
Reproductive status of a female organism depends on the maintenance of ovarian structure and function that has been associated with the hypothalamic pituitary-gonadal axis, hormonal events and sexual maturity. There is therefore an association between persistent early life protein deficiency and reproductive response which mechanistically involves life-long changes in key ovarian cytoarchitecture and function.
PubMed: 35024624
DOI: 10.1016/j.crphys.2021.12.003 -
Cellular and Molecular Gastroenterology... 2021Chronic amino acid (AA) deficiency, as in kwashiorkor, reduces the size of the pancreas through an effect on mammalian target of rapamycin complex 1 (mTORC1). Because of...
BACKGROUND & AIMS
Chronic amino acid (AA) deficiency, as in kwashiorkor, reduces the size of the pancreas through an effect on mammalian target of rapamycin complex 1 (mTORC1). Because of the physiological importance of AAs and their role as a substrate, a stimulant of mTORC1, and protein synthesis, we studied the effect of acute protein and AA deficiency on the response to feeding.
METHODS
ICR/CD-1 mice were fasted overnight and refed for 2 hours with 4 different isocaloric diets: control (20% Prot); Protein-free (0% Prot); control (AA-based diet), and a leucine-free (No Leu). Protein synthesis, polysomal profiling, and the activation of several protein translation factors were analyzed in pancreas samples.
RESULTS
All diets stimulated the Protein Kinase-B (Akt)/mTORC1 pathway, increasing the phosphorylation of the kinase Akt, the ribosomal protein S6 (S6) and the formation of the eukaryotic initiation factor 4F (eIF4F) complex. Total protein synthesis and polysome formation were inhibited in the 0% Prot and No Leu groups to a similar extent, compared with the 20% Prot group. The 0% Prot diet partially reduced the Akt/mTORC1 pathway and the activity of the guanine nucleotide exchange factor eIF2B, without affecting eIF2α phosphorylation. The No Leu diet increased the phosphorylation of eIF2α and general control nonderepressible 2, and also inhibited eIF2B activity, without affecting mTORC1. Essential and nonessential AA levels in plasma and pancreas indicated a complex regulation of their cellular transport mechanisms and their specific effect on the synthesis of digestive enzymes.
CONCLUSIONS
These studies show that dietary AAs are important regulators of postprandial digestive enzyme synthesis, and their deficiency could induce pancreatic insufficiency and malnutrition.
Topics: Animals; Diet, Protein-Restricted; Disease Models, Animal; Eukaryotic Initiation Factor-2; Exocrine Pancreatic Insufficiency; Humans; Leucine; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Pancreas; Phosphorylation; Postprandial Period; Protein Biosynthesis; Protein Deficiency
PubMed: 32735995
DOI: 10.1016/j.jcmgh.2020.07.008 -
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