Increase In Insulin-like Growth Factor Research Articles

The Essential Role of Right Amount and Quality of Protein for Ensuring Child Growth and Maintenance of Bone and Muscle Mass

Protein is a vital macronutrient, essential for growth, tissue repair, and immune function. However, the impact of elevated protein intake during childhood and adolescence remains controversial. While high protein intake in older adults is often recommended for maintaining muscle mass and preventing frailty, excessive intake in younger populations has raised concerns about potential health risks, particularly related to obesity. This review aims to update current literature on the long-term effects of protein consumption in children and adolescents (ages 4-18) and to explore emerging methods for evaluating protein metabolism in this age group. The RDA for protein varies based on age, sex, and activity level. Generally, it is suggested that children consume about 0.95-1.3 grams of protein per kilogram of body weight per day, depending on age and specific requirements. In many developed countries, children and adolescents often consume protein at levels 2-3 times higher than the RDA, potentially leading to both positive and negative health outcomes. Protein is critical for normal growth and development during childhood and adolescence. Adequate intake supports muscle development, immune function, and the production of hormones. Studies suggest that elevated protein intake may be linked to increased Fat-Free Mass Index (FFMI), which is beneficial for muscle development and overall body composition. High protein diets have been associated with increased satiety, which can help in managing appetite and potentially reducing overall caloric intake, thus contributing to healthier weight maintenance. Some evidence suggests a correlation between high protein intake in infancy and childhood and increased risk of obesity later in life. This association may be due to the overactivation of growth pathways and increased insulin-like growth factor-1 (IGF-1) levels. Excessive protein intake has been hypothesized to strain kidney function, especially in individuals with pre-existing kidney conditions. However, current evidence in healthy children and adolescents is inconclusive. This narrative review emphasizes the need for a nuanced understanding of protein intake in children and adolescents, considering both the benefits and potential risks associated with high protein consumption. As research evolves, dietary guidelines may need to be adjusted to reflect the latest findings.

Insulin-like growth factor 2 drives fibroblast-mediated tumor immunoevasion and confers resistance to immunotherapy.

T cell exclusion is crucial in enabling tumor immune evasion and immunotherapy resistance. However, the key genes driving this process remain unclear. We uncovered a notable increase of insulin-like growth factor 2 (IGF2) in immune-excluded tumors, predominantly secreted by cancer-associated fibroblasts (CAFs). Using mice with systemic or fibroblast-specific deletion of IGF2, we demonstrated that IGF2 deficiency enhanced the infiltration and cytotoxic activity of CD8+ T cells, leading to a reduction in tumor burden. Integration of spatial and single-cell transcriptomics revealed that IGF2 promoted interaction between CAFs and T cells via CXCL12 and programmed death ligand 1 (PD-L1). Mechanistically, autocrine IGF2 activated PI3K/AKT signaling by binding to the IGF1 receptor (IGF1R) on CAFs, which was required for the immunosuppressive functions of CAFs. Furthermore, genetic ablation of IGF2 or targeted inhibition of the IGF2/IGF1R axis with the inhibitor linsitinib markedly boosted the response to immune checkpoint blockade. Clinically, elevated levels of IGF2 in tumors or plasma correlated with an adverse prognosis and reduced efficacy of anti-programmed death 1 treatment. Together, these results highlight the pivotal role of IGF2 in promoting CAF-mediated immunoevasion, indicating its potential as a biomarker and therapeutic target in immunotherapy.

The Role of Physical Activity in the Molecular Impact of Increased Insulin-Like Growth Factor-1 (IGF-1) Levels: A Literature Review

Insulin-like growth factor-1 (IGF-1) is a key mediator of human growth hormone (HGH), which plays an important role in promoting cell growth and differentiation in childhood and continues to exert anabolic effects in adults. IGF-1 is a small peptide that circulates in serum bound to a high affinity binding protein. IGF-1 is part of a vast network of growth factors, receptors, and binding proteins involved in mediating cell proliferation, differentiation, and apoptosis IGF-I-like growth factor has broad anabolic and insulin-sensitising effects, which are generated through endocrine (in circulation) as well as paracrine/autocrine mechanisms. Serum concentrations of IGF-1 steadily increase during childhood and peak at puberty, and continue to decline since then, as does the secretion of human growth hormone. This study aims to determine the role of physical activity in molecular impact on increasing IGF-1 levels. This article is the result of a review of various research references related to the role of physical activity in molecular impact on increasing IGF-1 levels. Physical Activity in Molecular has an impact on increasing IGF-1 levels.

Sex-dependent regulation of vertebrate somatic growth and aging by germ cells.

The function of germ cells in somatic growth and aging has been demonstrated in invertebrate models but remains unclear in vertebrates. We demonstrated sex-dependent somatic regulation by germ cells in the short-lived vertebrate model Nothobranchius furzeri. In females, germ cell removal shortened life span, decreased estrogen, and increased insulin-like growth factor 1 (IGF-1) signaling. In contrast, germ cell removal in males improved their health with increased vitamin D signaling. Body size increased in both sexes but was caused by different signaling pathways, i.e., IGF-1 and vitamin D in females and males, respectively. Thus, vertebrate germ cells regulate somatic growth and aging through different pathways of the endocrine system, depending on the sex, which may underlie the sexual difference in reproductive strategies.

Potential of Lycii Radicis Cortex as an Ameliorative Agent for Skeletal Muscle Atrophy.

Lycii Radicis Cortex (LRC) is a traditional medicine in East Asia with various beneficial effects, including antioxidant, anti-inflammatory, anti-tumor, anti-diabetic, and anti-depressant properties. However, its potential effects on skeletal muscle atrophy have not been studied. In this study, the protective effects of LRC extract (LRCE) on dexamethasone (DEX)-induced muscle atrophy were investigated in C2C12 myotubes and mice. We evaluated the effect of LRCE on improving muscle atrophy using a variety of methods, including immunofluorescence staining, quantitative polymerase chain reaction (qPCR), Western blot, measurements of oxidative stress, apoptosis, ATP levels, and muscle tissue analysis. The results showed that LRCE improved myotube diameter, fusion index, superoxide dismutase (SOD) activity, mitochondrial content, ATP levels, expression of myogenin and myosin heavy chain (MHC), and reduced reactive oxygen species (ROS) production in dexamethasone-induced C2C12 myotubes. LRCE also enhanced protein synthesis and reduced protein degradation in the myotubes. In mice treated with DEX, LRCE restored calf thickness, decreased mRNA levels of muscle-specific RING finger protein 1 (MuRF1) and atrogin-1, and increased insulin-like growth factor 1 (IGF-1) mRNA level. Moreover, LRCE also repaired gastrocnemius muscle atrophy caused by DEX. Although human studies are not available, various preclinical studies have identified potential protective effects of LRCE against muscle atrophy, suggesting that it could be utilized in the prevention and treatment of muscle atrophy.

Effects of glycyrrhiza polysaccharides on growth performance, meat quality, serum parameters and growth/meat quality-related gene expression in broilers.

With growing restrictions on the use of antibiotics in animal feed, plant extracts are increasingly favored as natural feed additive sources. Glycyrrhiza polysaccharide (GP), known for its multifaceted biological benefits including growth promotion, immune enhancement, and antioxidative properties, has been the focus of recent studies. Yet, the effects and mechanisms of GP on broiler growth and meat quality remain to be fully elucidated. This study aimed to investigate the effects of GP on growth, serum biochemistry, meat quality, and gene expression in broilers. The broilers were divided into five groups, each consisting of five replicates with six birds. These groups were supplemented with 0, 500, 1,000, 1,500, and 2,000 mg/kg of GP in their basal diets, respectively, for a period of 42 days. The results indicated that from day 22 to day 42, and throughout the entire experimental period from day 1 to day 42, the groups receiving 1,000 and 1,500 mg/kg of GP showed a significant reduction in the feed-to-gain ratio (F:G) compared to the control group. On day 42, an increase in serum growth hormone (GH) levels was shown in groups supplemented with 1,000 mg/kg GP or higher, along with a significant linear increase in insulin-like growth factor-1 (IGF-1) concentration. Additionally, significant upregulation of GH and IGF-1 mRNA expression levels was noted in the 1,000 and 1,500 mg/kg GP groups. Furthermore, GP significantly elevated serum concentrations of alkaline phosphatase (AKP) and globulin (GLB) while reducing blood urea nitrogen (BUN) levels. In terms of meat quality, the 1,500 and 2,000 mg/kg GP groups significantly increased fiber density in pectoral muscles and reduced thiobarbituric acid (TBA) content. GP also significantly decreased cooking loss rate in both pectoral and leg muscles and the drip loss rate in leg muscles. It increased levels of linoleic acid and oleic acid, while decreasing concentrations of stearic acid, myristic acid, and docosahexaenoic acid. Finally, the study demonstrated that the 1,500 mg/kg GP group significantly enhanced the expression of myogenin (MyoG) and myogenic differentiation (MyoD) mRNA in leg muscles. Overall, the study determined that the optimal dosage of GP in broiler feed is 1,500 mg/kg.

Hydrolyzed Collagen Tripeptide Promotes Longitudinal Bone Growth in Childhood Rats via Increases in Insulin-Like Growth Factor-1 and Bone Morphogenetic Proteins.

Previous studies have reported that collagen tripeptide (CTP) derived from collagen hydrolysate has various beneficial effects on health by protecting against skin aging and improving bone formation and cartilage regeneration. Collagen-Tripep20TM (CTP20), which is a low-molecular-weight CTP derived from fish skin, contains a bioactive CTP, Gly-Pro-Hyp >3.2% with a tripeptide content >20%. Herein, we investigated the osteogenic effects and mechanisms of CTP20 (<500 Da) on MG-63 osteoblast-like cells and SW1353 chondrocytes. And we measured promoting ratio of the longitudinal bone growth in childhood rats. First, CTP20 at 100 μg/mL elevated the proliferation (15.0% and 28.2%), alkaline phosphatase activity (29.3% and 32.0%), collagen synthesis (1.25- and 1.14-fold), and calcium deposition (1.18- and 1.15-fold) in MG-63 cells and SW1353, respectively. In addition, we found that CTP20 could promote the longitudinal growth and height of the growth plate of the tibia in childhood rats. CTP20 enhanced the protein expression of insulin-like growth factor-1 (IGF-1) in MG-63 and SW1353 cells, and in the growth plate of childhood rats, along with Janus Kinase 2, and signal transducer and activator of transcription 5 activation in MG-63 and SW1353 cells. CTP20 also elevated the expression levels of bone morphogenetic proteins (BMPs) in MG-63 and SW1353 cells and in the growth plates of childhood rats. These results indicate that CTP20 may promote the endochondral ossification and longitudinal bone growth, through enhancing of IGF-1 and BMPs. (Clinical Trial Registration number: smecae 19-09-01).

Effects of Exercise on Circulating Muscle-related Cytokines in Adults with Type 2 Diabetes and/or Obesity.

Skeletal muscle is an endocrine organ that plays an important role in metabolic health by secreting a variety of myokines. Recent studies have shown that exercise significantly decreases interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in patients with type 2 diabetes (T2D). This paper explores the effect of chronic exercise on myokines in patients with T2D and/or obesity. The author searched for relevant English-language articles in PubMed. A total of 14 randomized controlled studies were found to be eligible for this short review. It has been observed that chronic exercise does not change brain-derived neurotrophic factor (BDNF), irisin, and secreted protein acidic and rich in cysteine levels, whereas it decreases TNF-α levels in patients with T2D. Combined aerobic exercise (AE) and resistance training (RT) or sprint interval training increase insulin-like growth factor 1 (IGF-1) levels and decrease IL-6 and IL-15 levels in patients with T2D. Combined AE and RT may also increase IL-15 levels in obese individuals. In addition, RT alone may increase BDNF, IGF-1, and IL-7 levels in overweight individuals. However, AE alone does not change circulating myokine levels in patients with T2D, while it may increase myonectin levels in obese individuals. This short review demonstrated that exercise appears to have favorable effects on some myokines in patients with T2D and/or obesity. However, it remains inconclusive due to the heterogeneity in subject characteristics and exercise modalities.

Skeletal complications in acromegaly.

Hypersecretion of growth hormone (GH) is rare and typically results from a pituitary functional tumor - somatotropinoma. It leads to excessive linear bone growth and manifests as gigantism if occurring in childhood and adolescence, before the closure of epiphyses or as a acromegaly in adulthood. The excess of GH impacts bone metabolism directly as well as indirectly through increased insulin-like growth factor 1 (IGF-1). In acromegaly as a consequence of overproduction of GH and IFG-1 and the influence of these hormones on bone osteoblasts, bone metabolism, growth and density increase. However, bone turnover is accelerated causing impaired bone microstructure and strength, which may lead to increased risk of vertebral fractures irrespective of normal bone mineral density. Apart from the changes in bone architecture, acromegaly also results in a degenerative joint disease of a different nature than primary osteoarthritis. Moreover, acromegaly leads to cardiovascular, metabolic and respiratory complications, and thus significantly impairs the quality of life. In this review, authors summarize the pathophysiology, diagnosis, and treatment of bone and joint disease in acromegaly.

Hesperidin Ameliorates Sarcopenia through the Regulation of Inflammaging and the AKT/mTOR/FoxO3a Signaling Pathway in 22-26-Month-Old Mice.

Faced with a globally aging society, the maintenance of health and quality of life in older people is very important. The age-related loss of muscle mass and strength, known as sarcopenia, severely reduces quality of life and increases the risks of various diseases. In this study, we investigated the inhibitory effect of hesperidin (HES) on inflammaging, with the intention of evaluating its potential use as a treatment for sarcopenia. We studied 22-26-month-old mice, corresponding to humans aged ≥70 years, with aging-related sarcopenia, and young mice aged 3-6 months. The daily administration of HES for 8 weeks resulted in greater muscle mass and strength and increased the fiber size of the old mice. HES also restored the immune homeostasis that had been disrupted by aging, such as the imbalance in M1/M2 macrophage ratio. In addition, we found that HES ameliorated the sarcopenia by regulating AKT/mammalian target of rapamycin/forkhead box 3a signaling through an increase in insulin-like growth factor (IGF)-1 expression in the old mice. Therefore, HES represents a promising candidate inhibitor of sarcopenia in older people, and its effects are achieved through the maintenance of immune homeostasis.

The skeletal safety of milk-derived proteins: A meta-analysis of randomized controlled trials.

There has been a persistent claim that dairy products contain calcium-leaching proteins, although the soundness of such a claim has been challenged. A meta-analysis of randomized controlled trials (RCTs) on the effects of milk-derived protein supplementation on bone health indices in adults was performed to reconcile the controversy surrounding the potential skeletal safety concerns of proteins of dairy origin. The PubMed and Web of Science databases were searched for relevant RCTs. A random-effects model was used to generate pooled effect sizes and 95% confidence intervals. Milk-derived protein supplementation did not significantly affect whole-body BMD (n = 7 RCTs) and BMD at the lumbar spine (n = 10), hip (n = 8), femoral neck (n = 9), trochanter (n = 5), intertrochanter (n = 2), and ultradistal radius (n = 2). The concentrations of bone formation markers (bone-specific alkaline phosphatase [n = 11], osteocalcin [n = 6], procollagen type 1 amino-terminal propeptide [n = 5]), bone resorption markers (N-terminal telopeptide of type 1 collagen [n = 7], C-terminal telopeptide of type 1 collagen [n = 7], deoxypyridinoline [n = 4]), and parathyroid hormone (n = 7) were not significantly affected. However, increased insulin-like growth factor-1 (IGF-1) concentrations (n = 13) were observed. Reduced IGF-1 concentrations were observed when soy protein was used as a comparator, and increased IGF-1 concentrations were observed when carbohydrate was used. Our findings do not support the claim that proteins of dairy origin are detrimental to bone health.

Preference of acromegaly patients for treatment attributes in Spain.

Acromegaly is a rare disease caused by increased growth hormone secretion and a subsequent increase in insulin-like growth factor I (IGF-I) levels. Patients display multiple comorbidities that affect their quality of life (QoL). Treatment aims to maintain good biochemical control, tumour control and reduce the risk of comorbidities; however, their impact on QoL has been overlooked until recently. We interviewed patients to explore their preferences with regard to treatment attributes. A cross-sectional study based on interviews and a discrete choice experiment (DCE) in a Spanish cohort. Adult patients diagnosed with acromegaly ≥1 year before the start of the study and under treatment were included. Treatment attributes were collected from patient testimony during face-to-face interviews. Then, a DCE was performed to elicit patient preferences for certain treatment attributes. Sixty-seven patients completed the study. QoL improvement was the most important treatment attribute (37%), followed by IGF-I control (20%), blood sugar control (17%) and tumour control (13%). Secondary attributes were pain associated with the route of administration (7%), diarrhoea (2%), administration method (2%) and storage conditions (2%). We then calculated the theoretical share of preference for existing treatments, based on the individual preference utility for each attribute and level. Pegvisomant obtained the highest share of preference overall, and the highest preference as a second-line treatment (53 and 95%, respectively). QoL greatly influences patient treatment preference. Since acromegaly patients are informed and aware of their disease, treatment choices should always be shared with patients.

Liver insulin-like growth factor-1 mediates effects of low-intensity vibration on wound healing in diabetic mice.

Chronic wounds in diabetic patients are associated with significant morbidity and mortality; however, few therapies are available to improve healing of diabetic wounds. Our group previously reported that low-intensity vibration (LIV) could improve angiogenesis and wound healing in diabetic mice. The purpose of this study was to begin to elucidate the mechanisms underlying LIV-enhanced healing. We first demonstrate that LIV-enhanced wound healing in db/db mice is associated with increased IGF1 protein levels in liver, blood, and wounds. The increase in insulin-like growth factor (IGF) 1 protein in wounds is associated with increased Igf1 mRNA expression both in liver and wounds, but the increase in protein levels preceded the increase in mRNA expression in wounds. Since our previous study demonstrated that liver was a primary source of IGF1 in skin wounds, we used inducible ablation of IGF1 in the liver of high-fat diet (HFD)-fed mice to determine whether liver IGF1 mediated the effects of LIV on wound healing. We demonstrate that knockdown of IGF1 in liver blunts LIV-induced improvements in wound healing in HFD-fed mice, particularly increased angiogenesis and granulation tissue formation, and inhibits the resolution of inflammation. This and our previous studies indicate that LIV may promote skin wound healing at least in part via crosstalk between the liver and wound. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Melatonin supplementation promotes muscle fiber hypertrophy and regulates lipid metabolism of skeletal muscle in weaned piglets.

Melatonin has been reported to play crucial roles in regulating meat quality, improving reproductive properties, and maintaining intestinal health in animal production, but whether it regulates skeletal muscle development in weaned piglet is rarely studied. This study was conducted to investigate the effects of melatonin on growth performance, skeletal muscle development, and lipid metabolism in animals by intragastric administration of melatonin solution. Twelve 28-d-old DLY (Duroc × Landrace × Yorkshire) weaned piglets with similar body weight were randomly divided into two groups: control group and melatonin group. The results showed that melatonin supplementation for 23 d had no effect on growth performance, but significantly reduced serum glucose content (P < 0.05). Remarkably, melatonin increased longissimus dorsi muscle (LDM) weight, eye muscle area and decreased the liver weight in weaned piglets (P < 0.05). In addition, the cross-sectional area of muscle fibers was increased (P < 0.05), while triglyceride levels were decreased in LDM and psoas major muscle by melatonin treatment (P < 0.05). Transcriptome sequencing showed melatonin induced the expression of genes related to skeletal muscle hypertrophy and fatty acid oxidation. Enrichment analysis indicated that melatonin regulated cholesterol metabolism, protein digestion and absorption, and mitophagy signaling pathways in muscle. Gene set enrichment analysis also confirmed the effects of melatonin on skeletal muscle development and mitochondrial structure and function. Moreover, quantitative real-time polymerase chain reaction analysis revealed that melatonin supplementation elevated the gene expression of cell differentiation and muscle fiber development, including paired box 7 (PAX7), myogenin (MYOG), myosin heavy chain (MYHC) IIA and MYHC IIB (P < 0.05), which was accompanied by increased insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 5 (IGFBP5) expression in LDM (P < 0.05). Additionally, melatonin regulated lipid metabolism and activated mitochondrial function in muscle by increasing the mRNA abundance of cytochrome c oxidase subunit 6A (COX6A), COX5B, and carnitine palmitoyltransferase 2 (CPT2) and decreasing the mRNA expression of peroxisome proliferator-activated receptor gamma (PPARG), acetyl-CoA carboxylase (ACC) and fatty acid-binding protein 4 (FABP4) (P < 0.05). Together, our results suggest that melatonin could promote skeletal muscle growth and muscle fiber hypertrophy, improve mitochondrial function and decrease fat deposition in muscle.

Stromal androgen signaling acts as tumor niches to drive prostatic basal epithelial progenitor-initiated oncogenesis

The androgen receptor (AR)-signaling pathways are essential for prostate tumorigenesis. Although significant effort has been devoted to directly targeting AR-expressing tumor cells, these therapies failed in most prostate cancer patients. Here, we demonstrate that loss of AR in stromal sonic-hedgehog Gli1-lineage cells diminishes prostate epithelial oncogenesis and tumor development using in vivo assays and mouse models. Single-cell RNA sequencing and other analyses identified a robust increase of insulin-like growth factor (IGF) binding protein 3 expression in AR-deficient stroma through attenuation of AR suppression on Sp1-regulated transcription, which further inhibits IGF1-induced Wnt/β-catenin activation in adjacent basal epithelial cells and represses their oncogenic growth and tumor development. Epithelial organoids from stromal AR-deficient mice can regain IGF1-induced oncogenic growth. Loss of human prostate tumor basal cell signatures reveals in basal cells of stromal AR-deficient mice. These data demonstrate a distinct mechanism for prostate tumorigenesis and implicate co-targeting stromal and epithelial AR-signaling for prostate cancer.

Significance of metabolomic disorders in infertility and miscarriage in patients with endometriosis

BACKGROUND: Despite numerous studies, the causal relationships of endometriosis, associated infertility and miscarriage have not yet been clarified.&#x0D; AIM: This article discusses the significance of insulin-like growth factor 1, matrix metalloproteinase 9 and activin A levels in the blood serum and peritoneal fluid of patients of reproductive age with endometriosis in the clinical aspects of infertility and miscarriage and as per stages of the disease.&#x0D; MATERIALS AND METHODS: The overall group consisted of patients with endometriosis (group I: stages III, n = 25; group II: stages IIIIV, n = 38). The control group comprised patients without the disease (group III: n = 25). The stage of endometriosis was classified during laparoscopy in accordance with revised American Society for Reproductive Medicine classification (1996).&#x0D; RESULTS: In endometriosis, primary infertility predominated (up to 40.8% of cases), while secondary infertility occured in 21.2% of cases. Primary infertility accounted for 68.0% of cases in stages III versus 39.5% of cases in stages IIIIV. Secondary infertility accounted for 28.0% versus 23.0% of cases, respectively. In minimal stages of the disease, non-developing pregnancies (12.0%) and spontaneous miscarriages (4.0%) occurred in 16.0% of cases. In severe stages, these nosologies occurred in an equal percentage of cases (5.2%).&#x0D; The group of patients with endometriosis showed multidirectional changes in activin A levels in the blood serum and peritoneal fluid, a decrease in matrix metalloproteinase 9 level by 27% in the peritoneal fluid and an increase in insulin-like growth factor 1 level by 36% in the blood serum. In minimal stages of endometriosis, the tendencies of changes in the parameters remained intact as compared to the overall group, the correspondence of matrix metalloproteinase 9 levels to the control values in the blood serum and peritoneal fluid being noteworthy. Stages IIIIV of the disease implied more significant changes as compared to the control or the overall group of patients. We found a decrease in insulin-like growth factor 1 level by 56% in the peritoneal fluid, a decrease in activin A level by 19% in the blood serum with an increase in the parameter by 27% in the peritoneal fluid, and a decrease in matrix metalloproteinase 9 level by 4% in the peritoneal fluid.&#x0D; CONCLUSIONS: Modifications of the studied compounds activin A, MPP-9 and IPFR-1 are associated with infertility and miscarriage in patients with endometriosis.

Safety and Feasibility Assessment of Repetitive Vascular Occlusion Stimulus (RVOS) Application to Multi-Organ Failure Critically Ill Patients: A Pilot Randomised Controlled Trial.

Muscle wasting is implicated in the pathogenesis of intensive care unit acquired weakness (ICU-AW), affecting 40% of patients and causing long-term physical disability. A repetitive vascular occlusion stimulus (RVOS) limits muscle atrophy in healthy and orthopaedic subjects, thus, we explored its application to ICU patients. Adult multi-organ failure patients received standard care +/− twice daily RVOS {4 cycles of 5 min tourniquet inflation to 50 mmHg supra-systolic blood pressure, and 5 min complete deflation} for 10 days. Serious adverse events (SAEs), tolerability, feasibility, acceptability, and exploratory outcomes of the rectus femoris cross-sectional area (RFCSA), echogenicity, clinical outcomes, and blood biomarkers were assessed. Only 12 of the intended 32 participants were recruited. RVOS sessions (76.1%) were delivered to five participants and two could not tolerate it. No SAEs occurred; 75% of participants and 82% of clinical staff strongly agreed or agreed that RVOS is an acceptable treatment. RFCSA fell significantly and echogenicity increased in controls (n = 5) and intervention subjects (n = 4). The intervention group was associated with less frequent acute kidney injury (AKI), a greater decrease in the total sequential organ failure assessment score (SOFA) score, and increased insulin-like growth factor-1 (IGF-1), and reduced syndecan-1, interleukin-4 (IL-4) and Tumor necrosis factor receptor type II (TNF-RII) levels. RVOS application appears safe and acceptable, but protocol modifications are required to improve tolerability and recruitment. There were signals of possible clinical benefit relating to RVOS application.

Tofacitinib enhances IGF1 via inhibiting STAT6 transcriptionally activated-miR-425-5p to ameliorate inflammation in RA-FLS.

Rheumatoid arthritis (RA) is a systemic autoimmune disease, which has been reported closely associated with the dysfunction of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. This study aims to explore the potential therapeutic effect of Tofacitinib, a putative JAK/STAT inhibitor, in RA. Tofacitinib suppressed proliferation and accelerated apoptosis of rheumatoid arthritis synovial fibroblasts (RA-FLS) as confirmed by CCK-8, EdU and Western blot assays. Tofacitinib significantly inhibited expression of pro-inflammatory factors including tumor necrosis factor-α (TNF-α), vascular endothelial growth factor A, matrix metalloproteinase 1, matrix metalloproteinase 3, interleukin-6 and interferon gamma in RA-FLS cells. mechanistically, tofacitinib decreased signal transducer and activator of transcription 6 (STAT6), which transcriptionally activates miR-425-5p, and thus increased insulin like growth factor 1 (IGF1) expression, a target of miR-425-5p in RA-FLS. Overexpression of STAT6 restored the expression of pro-inflammatory factors and proliferation inhibited by Tofacitinib in RA-FLS. Overall, Tofacitinib exerted inhibitory effect on proliferation and inflammation of RA-FLS through modulating STAT6/miR-425-5p/IGF1 signal axis. These findings shed light on the novel strategies for improving RA.

Effects of ivacaftor on systemic inflammation and the plasma proteome in people with CF and G551D

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator for people with CF and the G551D mutation. We aimed to investigate the biology of CFTR modulation and systemic effects of CFTR restoration by examining changes in circulating measurements of inflammation and growth and novel proteins with ivacaftor treatment. Blood samples from 64 CF subjects with G551D-CFTR were analyzed for inflammatory and growth-related proteins at baseline, 1 and 6 months after ivacaftor initiation. In 30 subjects, plasma was assayed for 1,322 proteins using the SomaScan proteomic platform at baseline and 6 months post-ivacaftor. Correlations with clinical outcomes were assessed. Significant reductions in high mobility group box-1 protein (HMGB-1), calprotectin, serum amyloid A, and granulocyte colony-stimulating factor (G-CSF), and an increase in insulin-like growth factor (IGF-1) occurred 1 month after ivacaftor. This treatment effect was sustained at 6 months for HMGB-1 and calprotectin. Correcting for multiple comparisons in the proteomic analysis, 9 proteins (albumin, afamin, leptin, trypsin, pancreatic stone protein [PSP], pituitary adenylate cyclase-activating polypeptide-38, repulsive guidance molecule A [RGMA], calreticulin, GTPase KRas) changed significantly with ivacaftor. Proteins changing with treatment are involved in lipid digestion and transport and extracellular matrix organization biological processes. Reductions in calprotectin and G-CSF and increases in calreticulin, and RGMA correlated with improved lung function, while increasing IGF-1, leptin and afamin and decreasing PSP correlated with increased weight. Ivacaftor led to changes in inflammatory, lipid digestion, and extracellular matrix proteins, lending insights into the extrapulmonary effects of CFTR modulation.

Neutrophil-to-Lymphocyte, Platelet-to-Lymphocyte Ratios, and Systemic Immune-Inflammation Index as Potential Biomarkers of Chronic Inflammation in Patients with Newly Diagnosed Acromegaly: A Single-Centre Study

Acromegaly is a rare disease caused by overproduction of growth hormone (GH) by a pituitary adenoma, and consequently increased insulin-like growth factor 1 (IGF-1) concentration. The GH/IGF-1 axis and immune cells interactions are hypothesized to be involved in subclinical inflammation. This retrospective study aimed to investigate the differences in neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR) ratios, and systemic immune-inflammation index (SII) in GH-secreting adenomas compared with non-functioning pituitary adenomas (NFPAs) concerning clinical and radiological findings. After evaluation of 665 patients with pituitary tumors, 62 individuals with newly diagnosed acromegaly and 134 with NFPAs were enrolled in the analysis. The control group consisted of 120 healthy individuals. Fifty-eight patients with acromegaly were re-evaluated after medical or surgical therapies. NLR, PLR, SII values, and neutrophil count were significantly higher (p ≤ 0.001), whereas lymphocyte count was lower in acromegaly than in NFPAs (p = 0.001). No significant differences between NFPAs and controls were observed in analyzed ratios. Higher preoperative NLR, PLR, SII values were found in patients who failed to achieve a cure with surgery (p < 0.05). Although NLR, PLR, and SII values were significantly higher in acromegaly, these indices cannot be used to discriminate GH-secreting pituitary tumors from NFPAs. Treatment of acromegaly decreased the value of NLR and SII, but it requires further studies to consolidate the real clinical role of these inflammation-related ratios.