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Cancer is a global health concern influenced by genetics, environment and lifestyle choices. Recent research shows that a ketogenic diet (KD) might ease cancer symptoms and reduce tumour size. We hypothesised that the KD could result in improvements in cancer‐related variables. Therefore, this study aims to perform a systematic review and meta‐analysis to assess the KD's efficacy for patients with cancer. The databases PubMed (MEDLINE), Web of Science, CINAHL and Open Grey were utilised for conducting a systematic review and meta‐analysis. The analysis was limited to randomised controlled trials with adult participants aged 18 years and above. Levels of glucose, cholesterol, insulin‐like growth factor 1, weight and quality of life were evaluated following the KD. After identifying 596 articles in the initial search, eight studies, lasting between 4 and 16 weeks, were included in the systematic review and seven in the meta‐analysis. The KD led to decreased glucose levels in patients with cancer but did not show significant improvements in cholesterol, insulin‐like growth factor 1, weight or quality of life. Based on the results of this systematic review and meta‐analysis, there is insufficient evidence to establish a definitive link between the KD and cancer‐related parameters. While some studies suggest potential benefits in terms of some outcomes and tumour size reduction, further research is required to fully comprehend the effects of this diet. [ABSTRACT FROM AUTHOR]

The article discusses the need for reliable biomarkers to detect pulmonary congestion in patients with heart failure (HF) in order to prevent hospitalizations and improve patient outcomes. The current biomarkers used in clinical practice, B-type natriuretic peptides (NPs), have limitations such as being affected by comorbidities and having inconsistent measurement intervals. The article presents the BioMEMS study, which aims to identify alternative biomarkers that accurately reflect worsening congestion and can be easily measured. The study collects blood samples from HF patients and analyzes them using the Olink Cardiovascular III panel to evaluate the relationship between biomarkers and pulmonary artery pressures. The ultimate goal is to develop a biomarker-based management strategy for HF patients that is decentralized, manageable, and economically sustainable. [Extracted from the article]

Background and Purpose: Excessive fibrogenesis is associated with adverse cardiac remodelling and heart failure. The myofibroblast, primarily derived from resident fibroblast, is the effector cell type in cardiac fibrosis. Megakaryocytic leukaemia 1 (MKL1) is considered the master regulator of fibroblast–myofibroblast transition (FMyT). The underlying transcriptional mechanism is not completely understood. Our goal was to identify novel transcriptional targets of MKL1 that might regulate FMyT and contribute to cardiac fibrosis. Experimental Approach: RNA sequencing (RNA‐seq) performed in primary cardiac fibroblasts identified insulin‐like growth factor binding protein 5 (IGFBP5) as one of the genes most significantly up‐regulated by constitutively active (CA) MKL1 over‐expression. IGFBP5 expression was detected in heart failure tissues using RT‐qPCR and western blots. Key Results: Once activated, IGFBP5 translocated to the nucleus to elicit a pro‐FMyT transcriptional programme. Consistently, IGFBP5 knockdown blocked FMyT in vitro and dampened cardiac fibrosis in mice. Of interest, IGFBP5 interacted with nuclear factor of activated T‐cell 4 (NFAT4) to stimulate the transcription of microfibril‐associated protein 5 (MFAP5). MFAP5 contributed to FMyT and cardiac fibrosis by enabling sterol response element binding protein 2 (SREBP2)‐dependent cholesterol synthesis. Conclusions and Implications: Our data unveil a previously unrecognized transcriptional cascade, initiated by IGFBP5, that promotes FMyT and cardiac fibrosis. Screening for small‐molecule compounds that target this axis could yield potential therapeutics against adverse cardiac remodelling. [ABSTRACT FROM AUTHOR]

The circadian system regulates 24‐h time‐of‐day patterns of cardiovascular physiology, with circadian misalignment resulting in adverse cardiovascular risk. Although many proteins in the coagulation‐fibrinolysis axis show 24‐h time‐of‐day patterns, it is not understood if these temporal patterns are regulated by circadian or behavioral (e.g., sleep and food intake) cycles, or how circadian misalignment influences these patterns. Thus, we utilized a night shiftwork protocol to analyze circadian versus behavioral cycle regulation of 238 plasma proteins linked to cardiovascular physiology. Six healthy men aged 26.2 ± 5.6 years (mean ± SD) completed the protocol involving two baseline days with 8‐h nighttime sleep opportunities (circadian alignment), a transition to shiftwork day, followed by 2 days of simulated night shiftwork with 8‐h daytime sleep opportunities (circadian misalignment). Plasma was collected for proteomics every 4 h across 24 h during baseline and during daytime sleep and the second night shift. Cosinor analyses identified proteins with circadian or behavioral cycle‐regulated 24‐h time‐of‐day patterns. Five proteins were circadian regulated (plasminogen activator inhibitor‐1, angiopoietin‐2, insulin‐like growth factor binding protein‐4, follistatin‐related protein‐3, and endoplasmic reticulum resident protein‐29). No cardiovascular‐related proteins showed regulation by behavioral cycles. Within the coagulation pathway, circadian misalignment decreased tissue factor pathway inhibitor, increased tissue factor, and induced a 24‐h time‐of‐day pattern in coagulation factor VII (all FDR < 0.10). Such changes in protein abundance are consistent with changes observed in hypercoagulable states. Our analyses identify circadian regulation of proteins involved in cardiovascular physiology and indicate that acute circadian misalignment could promote a hypercoagulable state, possibly contributing to elevated cardiovascular disease risk among shift workers. [ABSTRACT FROM AUTHOR]

Background and Purpose Methods Results Conclusions Parkinson's disease (PD) is an age‐related condition characterized by substantial phenotypic variability. Consequently, pathways and proteins involved in biological aging, such as the central aging pathway comprising insulin‐like growth factor 1–α‐Klotho–sirtuin 1–forkhead box O3–peroxisome proliferator‐activated receptor γ, may potentially influence disease progression.Cerebrospinal fluid (CSF) levels of α‐Klotho in 471 PD patients were examined. Of the 471 patients, 96 carried a GBA1 variant (PD GBA1), whilst the 375 non‐carriers were classified as PD wild‐type (PD WT). Each patient was stratified into a CSF α‐Klotho tertile group based on the individual level. Kaplan–Meier survival curves and Cox regression analysis stratified by tertile groups were conducted. These longitudinal data were available for 255 patients. Follow‐up times reached from 8.4 to 12.4 years. The stratification into PD WT and PD GBA1 was undertaken to evaluate potential continuum patterns, particularly in relation to CSF levels.Higher CSF levels of α‐Klotho were associated with a significant later onset of cognitive impairment. Elevated levels of α‐Klotho in CSF were linked to higher Montreal Cognitive Assessment scores in male PD patients with GBA1 mutations.Our results indicate that higher CSF levels of α‐Klotho are associated with a delayed cognitive decline in PD. Notably, this correlation is more prominently observed in PD patients with GBA1 mutations, potentially reflecting the accelerated biological aging profile characteristic of individuals harboring GBA1 variants. [ABSTRACT FROM AUTHOR]

Background: Active surveillance (AS) is increasingly used to monitor patients with lower risk prostate cancer (PCa). The Prostate Cancer Active Lifestyle Study (PALS) was a randomized controlled trial to determine whether weight loss improves obesity biomarkers on the causal pathway to progression in patients with PCa on AS. Methods: Overweight/obese men (body mass index >25 kg/m2) diagnosed with PCa who elected AS were recruited. The intervention was a 6‐month, individually delivered, structured diet and exercise program adapted from the Diabetes Prevention Program with a 7% weight loss goal from baseline. Control participants attended one session reviewing the US Dietary and Physical Activity Guidelines. The primary outcome was change in glucose regulation from baseline to the end of the 6‐month intervention, which was measured by fasting plasma glucose, C‐peptide, insulin, insulin‐like growth factor 1, insulin‐like growth factor binding protein‐3, adiponectin, and homeostatic model assessment for insulin resistance. Results: Among 117 men who were randomized, 100 completed the trial. The mean percentage weight loss was 7.1% and 1.8% in the intervention and control arms, respectively (adjusted between‐group mean difference, −6.0 kg; 95% confidence interval, −8.0, −4.0). Mean percentage changes from baseline for insulin, C‐peptide, and homeostatic model assessment for insulin resistance in the intervention arm were −23%, −16%, and −25%, respectively, compared with +6.9%, +7.5%, and +6.4%, respectively, in the control arm (all p for intervention effects ≤.003). No significant between‐arm differences were detected for the other biomarkers. Conclusions: Overweight/obese men with PCa undergoing AS who participated in a lifestyle‐based weight loss intervention successfully met weight loss goals with this reproducible lifestyle intervention and experienced improvements in glucose‐regulation biomarkers associated with PCa progression. The Prostate Cancer Active Lifestyle Study was a randomized controlled trial to determine whether weight loss improves obesity biomarkers on the causal pathway to progression in patients with prostate cancer undergoing active surveillance. Overweight/obese men with prostate cancer on active surveillance who participated in a lifestyle‐based weight loss intervention successfully met weight loss goals and experienced improvements in glucose‐regulation biomarkers associated with prostate cancer progression. [ABSTRACT FROM AUTHOR]

Background: Berberine (BBR), an isoquinoline alkaloid from Coptidis rhizoma, has been found to have powerful activities against various human malignancies, including breast cancer. However, the underlying antitumor mechanisms of BBR in breast cancer remain poorly understood. Methods: Breast cancer cells were cultured and treated with different doses (0, 20, 40, and 60 μM) of BBR for 48 h. Cell viability, proliferation, apoptosis, invasion, and migration were assessed using 3‐(4, 5‐dimethyl‐2‐thiazolyl)‐2, 5‐diphenyl‐2H‐tetrazolium bromide (MTT), 5‐ethynyl‐2′‐deoxyuridine (EdU), flow cytometry, transwell, and wound healing assays. Fibroblast growth factor 7 (FGF7), methyltransferase‐like 3 (METTL3), and insulin‐like growth factor‐2 mRNA‐binding protein 3 (IGF2BP3) mRNA levels and protein levels were measured using real‐time quantitative polymerase chain reaction (RT‐qPCR) and western blot. Interaction between METTL3 and FGF7 m6A was assessed using methylated RNA immunoprecipitation (MeRIP)‐qPCR and RNA immunoprecipitation (RIP) assay. Binding ability between IGF2BP3 and FGF7 mRNA was analyzed using RIP assay. Results: BBR treatment hindered breast cancer cell proliferation, invasion, migration, and induced apoptosis. FGF7 expression was upregulated in breast cancer tissues, while its level was reduced in BBR‐treated tumor cells. FGF7 upregulation relieved the repression of BBR on breast cancer cell malignant behaviors. In mechanism, METTL3 stabilized FGF7 mRNA through the m6A‐IGF2BP3‐dependent mechanism and naturally improved FGF7 expression. BBR treatment inhibited breast cancer growth in vivo. Conclusion: BBR treatment blocked breast cancer cell growth and metastasis partly by regulating METTL3‐mediated m6A modification of FGF7 mRNA, providing a promising therapeutic target for breast cancer treatment. [ABSTRACT FROM AUTHOR]

Aim: To investigate the effect of cholecalciferol supplementation on hand grip strength, walking speed, and expression of vitamin D receptor (VDR), interleukine‐6 (IL‐6) and insulin‐like growth factor‐1 (IGF‐1) in monocyte in pre‐frail older adults. Methods: We conducted a randomized double‐blinded placebo‐controlled clinical trial for 12 weeks, involving 120 pre‐frail older adults who were randomized to the cholecalciferol group (cholecalciferol 4000 IU/day) or the placebo group. All subjects were given calcium lactate 500 mg/day. Hand grip strength and walking speed, as primary outcomes, were analyzed using intention‐to‐treat analysis. The expression of VDR, IGF‐1 and IL‐6 in monocytes, as secondary outcomes, were analyzed using per‐protocol analysis. Results: After a 12‐week intervention, there was a significant increase in serum 25(OH)D levels in both groups, with the increase being higher in the cholecalciferol group than in the placebo group (49.05 vs. 24.01 ng/mL; P < 0.001). No statistically significant differences were observed in hand grip strength (P = 0.228) and walking speed (P = 0.734) between the groups. There were no differences in the expression of VDR (P = 0.513), IL‐6 (P = 0.509), and IGF‐1 (P = 0.503) monocytes between the groups. Conclusions: Cholecalciferol supplementation for 12 weeks increased serum 25(OH)D levels among pre‐frail older adults. However, it did not improve hand grip strength and walking speed, and nor did it change the expression of VDR, IL‐6, and IGF‐1 in monocytes. Geriatr Gerontol Int 2024; 24: 554–562. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis is critical for forming new blood vessels from antedating vascular vessels. The endothelium is essential for angiogenesis, vascular remodelling and minimisation of functional deficits following ischaemia. The insulin‐like growth factor (IGF) family is crucial for angiogenesis. Insulin‐like growth factor‐binding protein 5 (IGFBP5), a binding protein of the IGF family, may have places in angiogenesis, but the mechanisms are not yet completely understood. We sought to probe whether IGFBP5 is involved in pathological angiogenesis and uncover the molecular mechanisms behind it. Methods and results: IGFBP5 expression was elevated in the vascular endothelium of gastrocnemius muscle from critical limb ischaemia patients and hindlimb ischaemic (HLI) mice and hypoxic human umbilical vein endothelial cells (HUVECs). In vivo, loss of endothelial IGFBP5 (IGFBP5EKO) facilitated the recovery of blood vessel function and limb necrosis in HLI mice. Moreover, skin damage healing and aortic ring sprouting were faster in IGFBP5EKO mice than in control mice. In vitro, the genetic inhibition of IGFBP5 in HUVECs significantly promoted tube formation, cell proliferation and migration by mediating the phosphorylation of IGF1R, Erk1/2 and Akt. Intriguingly, pharmacological treatment of HUVECs with recombinant human IGFBP5 ensued a contrasting effect on angiogenesis by inhibiting the IGF1 or IGF2 function. Genetic inhibition of IGFBP5 promoted cellular oxygen consumption and extracellular acidification rates via IGF1R‐mediated glycolytic adenosine triphosphate (ATP) metabolism. Mechanistically, IGFBP5 exerted its role via E3 ubiquitin ligase Von Hippel‐Lindau (VHL)‐regulated HIF1α stability. Furthermore, the knockdown of the endothelial IGF1R partially abolished the reformative effect of IGFBP5EKO mice post‐HLI. Conclusion: Our findings demonstrate that IGFBP5 ablation enhances angiogenesis by promoting ATP metabolism and stabilising HIF1α, implying IGFBP5 is a novel therapeutic target for treating abnormal angiogenesis‐related conditions. [ABSTRACT FROM AUTHOR]

This study evaluated the effect of bovine somatotropin (bST) on pregnancy rate (PR) and size of the dominant follicle (DF) on the day of intravaginal progesterone (P4) removal in protocols for fixed‐time artificial insemination (FTAI). Bos indicus (Nellore) females (n = 392) were distributed into three groups. The control group (CG; n = 92) received an intravaginal P4 device + estradiol benzoate on day (d)0; prostaglandin F2α on d7 (first application); removal of P4 + estradiol cypionate (EC) + PGF2α (second application) + ultrasound (US) of the DF on d9; the FTAI was performed on d11; and pregnancy diagnosis (PD) was performed on d45. The bST group (bSTG; n = 142) underwent the same protocol as the CG, except that the animals received 125 mg of bST on d7. The equine chorionic gonadotropin (eCG) group (eCGG; n = 158) underwent the same protocol as the CG, except that the animals received 300 IU of eCG on d9. The PRs of the bSTG, eCGG, and CG were 48%, 48%, and 35%, respectively (p <.05); the bSTG and eCGG showed greater PRs, with follicles 6–7.9 mm (p <.05) and 8–8.9 mm in diameter, respectively. The bSTG exhibited a greater dimension of the DF on d9 of the protocol (p <.05). The eCGG had higher PRs with a body condition score (BCS) of 2.5, and the bSTG had a BCS of 3.0 (p <.05). It was concluded that bST increased PR, bST showed better performance in smaller DF and larger follicular diameter on d9 of the protocol, eCG acted better on animals with lower BCSs, and bST can be used in FTAI. [ABSTRACT FROM AUTHOR]

This study aims to investigate the relationship between metabolic parameters and the number of embryos produced in superovulated cows with high genetic characteristics in milk yield. Eighteen Holstein donors were treated with classic superovulation protocols, AI and flushing. During superovulation, decreasing doses of FSH (follicle‐stimulating hormone) were administered at 12‐h intervals for 4 days. Plasma insulin‐like growth factor (IGF1), glucose (GLU), beta‐hydroxybutyric acid (BHB), non‐esterified fatty acid (NEFA), blood urea nitrogen (BUN) and total protein (TP) levels were determined by using an autoanalyzer. The mixed model analysis of variance was used for statistical analysis. As a result, plasma IGF1, BHB and BUN had significant interactions with both groups and days (p <.05). Additionally, plasma TP–days interactions were significant (p <.05). Furthermore, there was a negative correlation between the number of embryos and plasma BHB levels (p <.05). In conclusion, under appropriate environmental conditions, metabolic profile control of donors can contribute to the embryo production process and to the studies on the metabolic infrastructure. [ABSTRACT FROM AUTHOR]

Adult stem cells occupy a niche that contributes to their function, but how stem cells rebuild their microenvironment after injury remains an open‐ended question. Herein, biomaterial‐based systems and metabolic labeling are utilized to evaluate how skeletal muscle stem cells deposit extracellular matrix. Muscle stem cells and committed myoblasts are observed to generate less nascent matrix than muscle resident fibro‐adipogenic progenitors. When cultured on substrates that matched the stiffness of physiological uninjured and injured muscles, muscle stem cells increased nascent matrix deposition with activation kinetics. Reducing the ability to deposit nascent matrix by an inhibitor of vesicle trafficking (Exo‐1) attenuated muscle stem cell function and mimicked impairments observed from muscle stem cells isolated from old muscles. Old muscle stem cells are observed to deposit less nascent matrix than young muscle stem cells, which is rescued with therapeutic supplementation of insulin‐like growth factors. These results highlight the role of nascent matrix production with muscle stem cell activation. [ABSTRACT FROM AUTHOR]

Aims: High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables. Methods and results: In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m2). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population‐based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m2). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase‐2 (MMP‐2), insulin‐like growth factor binding protein‐2 (IGFBP‐2) and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP‐2 and NT‐proBNP, regardless of baseline LAVi (pinteraction > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C‐terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (pinteraction > 0.10). Conclusion: In individuals without heart failure, LAVi was associated with MMP‐2, IGFBP‐2 and NT‐proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size. [ABSTRACT FROM AUTHOR]

Background: Thymic atrophy is characterized by loss of thymocytes, destruction of thymic architecture, and a subsequent decrease in naïve T cells with compromised immunity. Thymic atrophy occurs during aging. Environmental factors including alcohol misuse also induce thymic atrophy. Despite the link between alcohol misuse and thymic atrophy, the underlying mechanism is understudied. We aimed to identify molecules and signaling pathways that underly alcohol‐induced thymic atrophy during aging. Methods: F344 rats were given 3‐day binge‐ethanol (4.8 g/kg/day; 52% w/v; i.g.) and the thymus was collected and weighed. Molecular mechanisms underlying ethanol‐induced thymic atrophy were investigated by network meta‐analysis using the QIAGEN Ingenuity Pathway Analysis (IPA). The molecules associated with ethanol were identified from the QIAGEN Knowledge Base (QKB) and those associated with thymic atrophy were identified from QKB and Mouse Genome Informatics (MGI). Aging‐mediated Differential Expression Genes (DEGs) from mouse thymocytes were obtained from the Gene Expression Omnibus (GEO) database (GSE132136). The relationship between the molecules and associated signaling pathways were studied using IPA. Results: Binge‐ethanol decreased thymic weight in F344 rats. Our meta‐analysis using IPA identified molecules commonly shared by ethanol and thymic atrophy through which simulation with ethanol increased thymic atrophy. We then obtained aging‐mediated DEGs from the atrophied thymocytes. We found that ethanol contributed to thymic atrophy through modulation of the aging‐mediated DEGs. Our network meta‐analysis suggests that ethanol may augment thymic atrophy through increased expression of cytokines (e.g., IL‐6, IL‐17A and IL‐33) along with their regulators (e.g., STAT1 and STAT3). Conclusions: Exposure to alcohol may augment thymic atrophy by altering the activity of key inflammatory mediators, such as STAT family members and inflammatory cytokines. These findings provide insights into the signaling pathways and upstream regulators that underly alcohol‐induced thymic atrophy during aging, suggesting that alcohol consumption could prepone thymic atrophy. [ABSTRACT FROM AUTHOR]

Aims: Insulin‐like growth factor binding protein‐7 (IGFBP7) is a biomarker of tissue senescence with a role in cardio‐renal pathophysiology. The role of IGFBP7 as a prognostic biomarker across the full ejection fraction (EF) spectrum of heart failure (HF) remains less well understood. We examined associations between IGFBP7 and risk of cardio‐renal outcomes regardless of EF and the effect of empagliflozin treatment on IGFBP7 concentrations among individuals with HF. Methods and results: IGFBP7 was measured in 1125 study participants from the EMPEROR‐Reduced and EMPEROR‐Preserved trials. Cox regression was used to study associations with outcomes. Study participants with IGFBP7 levels in the highest tertile had a higher‐risk clinical profile. In Cox proportional hazards models adjusted for clinical variables, N‐terminal pro‐B‐type natriuretic peptide and high‐sensitivity cardiac troponin T, baseline IGFBP7 values in the highest tertile predicted an increased risk of HF hospitalization or cardiovascular death (hazard ratio [HR] 2.00, 95% confidence interval [CI] 1.28–3.10, p = 0.002, p for trend <0.001) and higher risk of the renal composite endpoint (HR 4.66, 95% CI 1.61–13.53, p = 0.005, p for trend = 0.001), regardless of EF. Empagliflozin reduced risk for cardiovascular death/HF hospitalization irrespective of baseline IGFBP7 (p for trend across IGFBP7 tertiles = 0.26). Empagliflozin treatment was not associated with meaningful change in IGFBP7 at 12 or 52 weeks. Conclusion: Across the entire left ventricular EF spectrum in the EMPEROR Programme, concentrations of the senescence‐associated biomarker IGFBP7 were associated with higher risk clinical status and predicted adverse cardio‐renal outcomes even in models adjusted for conventional biomarkers. Empagliflozin did not significantly affect IGFBP7 levels over time. [ABSTRACT FROM AUTHOR]

Oral mucosa is an ideal model for studying scarless wound healing. Researchers have shown that the key factors which promote scarless wound healing already exist in basal state of oral mucosa. Thus, to identify the other potential factors in basal state of oral mucosa will benefit to skin wound healing. In this study, we identified eight gene modules enriched in wound healing stages of human skin and oral mucosa through co‐expression analysis, among which the module M8 was only module enriched in basal state of oral mucosa, indicating that the genes in module M8 may have key factors mediating scarless wound healing. Through bioinformatic analysis of genes in module M8, we found IGF2 may be the key factor mediating scarless wound healing of oral mucosa. Then, we purified IGF2 protein by prokaryotic expression, and we found that IGF2 could promote the proliferation and migration of HaCaT cells. Moreover, IGF2 promoted wound re‐epithelialization and accelerated wound healing in a full‐thickness skin wound model. Our findings identified IGF2 as a factor to promote skin wound healing which provide a potential target for wound healing therapy in clinic. [ABSTRACT FROM AUTHOR]

Refractory wounds present complex and serious clinical dilemmas in plastic and reconstructive surgeries. Currently, there are no standard guidelines for the treatment of refractory wounds. To observe the clinical effects of ultraviolet (UV) therapy combined with autologous platelet‐rich plasma (PRP) on chronic refractory wounds. Between January 2021 and December 2022, 60 inpatients with chronic refractory wounds were enrolled. Twenty patients were assigned to each of control groups 1 and 2 and treatment group according to whether they received PRP or UV treatment. All the patients underwent thorough debridement. Control group 2 received UV radiation. The treatment group underwent UV radiation combined with PRP gel covering the wound. Control group 1 underwent routine dressing changes after surgery, followed by skin grafting or skin key transfer if needed. One month later, we observed the wound healing in the two groups. After 2—4 PRP gel treatments, the wounds of patients in the treatment group healed. The healing time was 25.25 ± 4.93 days, and the dressings were changed 4.15 ± 3.30 times, both of which were better outcomes than in both control groups. In the treatment group, epidermal growth factor (EGF), insulin‐like growth factor (IGF), platelet‐derived growth factor (PGF), and transforming growth factor β (TGF‐β) were slightly higher, and the concentration of vascular endothelial growth factor (VEGF) was significantly higher than in the control group (p < 0.05). PRP combined with UV therapy significantly increased the concentration of wound growth factors, accelerated wound healing, shortened treatment time, reduced treatment costs, and alleviated pain in patients. [ABSTRACT FROM AUTHOR]

This article discusses the potential use of insulin-like growth factor binding protein-7 (IGFBP7) as a biomarker for heart failure (HF). The study conducted by Ferreira et al. examined the association between IGFBP7 levels and outcomes in HF patients. The results showed that higher levels of IGFBP7 were associated with a greater risk of cardiovascular events and renal outcomes. The study also found that changes in IGFBP7 levels over time were prognostically significant. However, further research is needed to determine how to translate the prognostic value of IGFBP7 into clinical practice and leverage it for therapeutic innovation. The article emphasizes the importance of incorporating biomarkers into clinical settings and exploring potential therapeutic targets indicated by these biomarkers. [Extracted from the article]

This article provides an update on contemporary insulin therapy. Despite advances in oral antidiabetic drugs, insulin injection remains the main treatment for various conditions, including type 1 diabetes, type 2 diabetes with impaired renal function, pregnant women, and hospitalized patients. Insulin therapy is also necessary for individuals who do not respond to oral antidiabetic drugs. Different types of insulin are available, with insulin glargine and insulin degludec considered the most useful basal insulin. Studies have shown that insulin degludec has reduced occurrences of severe hypoglycemia compared to insulin glargine. Combined injectable therapy, such as adding a glucagon-like peptide-1 receptor agonist, can be considered if basal insulin alone is not sufficient. Newer basal insulin options, such as insulin icodec and basal insulin-Fc, are being developed for weekly subcutaneous administration. The article also discusses the use of insulin treatment devices and continuous glucose monitoring to improve diabetes control. However, there are concerns about insulin allergy, anti-insulin antibodies, and the potential risk of neoplastic consequences. Further research is needed to confirm these findings. Overall, this article emphasizes the importance of long-acting insulin in the treatment of diabetes and the need for ongoing research to improve insulin regimens and ensure patient safety. [Extracted from the article]

Recurrent spontaneous abortion (RSA) is a serious condition that adversely affects women's health. Differentially expressed proteins (DEPs) in plasma of patients experiencing RSA is helpful to find new therapeutic targets and identified with mass spectrometry. In 57 DEPs, 21 were upregulated and 36 were downregulated in RSA. Gene ontology analyses indicated that identified DEPs were associated with cell proliferation, including significantly downregulated insulin‐like growth factor binding protein 2 (IGFBP2). Immunohistochemical result using clinical decidual tissues also showed that IGFBP2 expression was significantly decreased in RSA trophoblasts. Cell proliferation assay indicated that IGFBP2 treatment increased the proliferation and mRNA expressions of PCNA and Ki67 in trophoblast cells. Transcriptome sequencing experiments and Kyoto Encyclopedia of Genes and Genomes analyses revealed that gene expression for components in PI3K‐Akt pathway in trophoblasts was significantly upregulated following IGFBP2 treatment. To confirm bioinformatics findings, we did cell‐based experiments and found that treatment of inhibitors for insulin‐like growth factor (IGF)‐1 receptor‐PI3K‐Akt pathway significantly reduced IGFBP2‐induced trophoblast cell proliferation and mRNA expressions of PCNA and Ki67. Our findings suggest that IGFBP2 may increase trophoblast proliferation through the PI3K‐Akt signaling pathway to affect pregnancy outcomes and that IGFBP2 may be a new target for future research and treatment of RSA. [ABSTRACT FROM AUTHOR]

Overexpression of pathogenic membrane proteins drives abnormal proliferation and invasion of tumor cells. Various strategies to durably knockdown membrane proteins with heterobifunctional degraders have been successfully developed, including LYTAC, KineTAC, and AbTAC. However, challenges including complicated synthetic procedures and the inability to simultaneously degrade multiple pathogenic proteins still exist. Herein, we developed insulin‐like growth factor 2 (IGF2)‐tagged aptamer chimeras (ITACs) that link the cell‐surface lysosome‐targeting receptor IGF2R and membrane proteins of interest (POIs) based on specific recognition of aptamers to the POIs and high‐affinity binding of IGF2 to IGF2R. We demonstrated that ITACs exhibit robust degradation efficiency of various membrane proteins in multiple cell lines. Furthermore, systematic studies revealed that a moderate cell‐surface IGF2R level is responsible for the excellent degradation performance of ITACs. Importantly, we further established a modular assembly strategy that allows assembly of one IGF2 with two aptamers with precise stoichiometry (dITACs), enabling cooperative and simultaneous degradation of two membrane proteins. This work provides an efficient and facile target membrane protein degradation platform and will shed light on the treatment of diseases related to the overexpression of membrane proteins. [ABSTRACT FROM AUTHOR]

Aims: Growth differentiation factor‐15 (GDF‐15) is upregulated in part in response to cardiomyocyte stretch and stress, and it exerts a protective role that is mediated by its action to suppress signalling through insulin‐like growth factor (IGF) and enhance signalling through adenosine monophosphate‐activated protein kinase (AMPK). Sodium–glucose cotransporter 2 (SGLT2) inhibitors improve outcomes in heart failure, which has been experimentally linked to AMPK. This study aimed at evaluating the associations of GDF‐15 with baseline characteristics, the prognostic significance of GDF‐15, and the effect of empagliflozin on GDF‐15 in patients with heart failure with a reduced and preserved ejection fraction. Methods and results: Growth differentiation factor‐15 was determined in serum samples from the EMPEROR‐Reduced and EMPEROR‐Preserved trials. Cox regression and mixed models for repeated measures were used to study the association with outcomes and the effect of empagliflozin on GDF‐15, respectively. We studied 1124 patients (560 placebo and 564 empagliflozin) with median GDF‐15 levels at baseline of 2442 (interquartile range 1603–3780) pg/ml. Patients with higher GDF‐15 levels were typically older men with more severe symptoms, higher N‐terminal pro‐B‐type natriuretic peptide levels, worse kidney function and who were prescribed metformin. Baseline levels of GDF‐15 were well correlated with levels of IGF‐binding protein 7 (rho = 0.64). Higher levels of GDF‐15 were independently associated with an increased risk of cardiovascular death, heart failure hospitalizations, and worse kidney outcomes. When considered as a continuous variable, for each doubling in GDF‐15, the adjusted hazard ratio for cardiovascular death or heart failure hospitalization was 1.40 (95% confidence interval 1.15–1.71; p < 0.001). The relative effect of empagliflozin on cardiovascular death and hospitalization for heart failure was most pronounced in patients with higher baseline levels of GDF‐15 (interaction p‐trend = 0.031). At week 52, when compared with placebo, empagliflozin increased GDF‐15 by an additional 8% (p = 0.020), an effect that was primarily seen in patients not receiving metformin, a known AMPK activator. Conclusions: Growth differentiation factor‐15 is a marker of worse heart failure severity, is an independent predictor of major heart failure outcomes and may be associated with more pronounced benefits of empagliflozin. GDF‐15 is increased among metformin users, and empagliflozin was associated with an increase in GDF‐15 levels, primarily in patients not receiving metformin. [ABSTRACT FROM AUTHOR]

Developmental scientists have adopted numerous biomarkers in their research to better understand the biological underpinnings of development, environmental exposures, and variation in long‐term health. Yet, adoption patterns merit investigation given the substantial resources used to collect, analyse, and train to use biomarkers in research with infants and children. We document trends in use of 90 biomarkers between 2000 and 2020 from approximately 430,000 publications indexed by the Web of Science. We provide a tool for researchers to examine each of these biomarkers individually using a data‐driven approach to estimate the biomarker growth trajectory based on yearly publication number, publication growth rate, number of author affiliations, National Institutes of Health dedicated funding resources, journal impact factor, and years since the first publication. Results indicate that most biomarkers fit a "learning curve" trajectory (i.e., experience rapid growth followed by a plateau), though a small subset decline in use over time. [ABSTRACT FROM AUTHOR]

Background: Chronic uncontrolled hyperglycemia, a precursor to chronic low‐grade inflammation, is a leading cause of coronary artery disease (CAD) due to plaque buildup in type‐1 diabetes (T1D) patients. We evaluated levels of 22 inflammatory markers in cross‐sectional serum samples from 1222 subjects to evaluate their potential as risk factors for CAD in T1D patients. Hypothesis: Circulating levels of markers of inflammation may be the risk factors for incident CAD. Methods: The T1D subjects were divided into two groups: those without CAD (n = 1107) and with CAD (n = 115). Serum levels of proteins were assayed using multiplex immunoassays on a Luminex Platform. Differences between the two groups were made by univariate analysis. Multivariate logistic regression was used to ascertain the potential of proteins as risk factors for CAD. Influence of age, duration of diabetes, sex, hypertension, and dyslipidemia was determined in a stepwise manner. Serum levels of 22 proteins were combined into a composite score using Ridge regression for risk‐based stratification. Results: Mean levels of CRP, IGFBP1, IGFBP2, insulin‐like growth factors binding protein‐6 (IGFBP6), MMP1, SAA, sTNFRI, and sTNFRII were elevated in CAD patients (n = 115) compared to T1D patients without CAD (nCAD, n = 1107). After adjusting for age, duration of diabetes, sex, hypertension, and dyslipidemia, higher levels of sTNFRI (odds ratio [OR] = 2.18, 1.1 × 10−3), sTNFRII (OR = 1.52, 1 × 10−2), and IGFBP6 (OR = 3.62, 1.8 × 10−3) were significantly associated with CAD. The composite score based on Ridge regression, was able to stratify CAD patients into low, medium, and high‐risk groups. Conclusions: The results show activation of the TNF pathway in CAD patients. Evaluating these markers in serum can be a potential tool for identifying high‐risk T1D patients for intensive anti‐inflammatory therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Optimizing patient selection for neoadjuvant chemotherapy in patients with breast cancer remains an unmet clinical need. Quantitative features from medical imaging were reported to be predictive of treatment responses. However, the biologic meaning of these latent features is poorly understood, preventing the clinical use of such noninvasive imaging markers. The study aimed to develop a deep learning signature (DLS) from pretreatment magnetic resonance imaging (MRI) for predicting responses to neoadjuvant chemotherapy in patients with breast cancer and to further investigate the biologic meaning of the DLS by identifying its underlying pathways using paired MRI and proteomic sequencing data. Methods: MRI‐based DLS was constructed (radiogenomic training dataset, n = 105) and validated (radiogenomic validation dataset, n = 26) for the prediction of pathologic complete response (pCR) to neoadjuvant chemotherapy. Proteomic sequencing revealed biological functions facilitating pCR (n = 139). Their associations with DLS were uncovered by radiogenomic analysis. Results: The DLS achieved a prediction accuracy of 0.923 with an AUC of 0.958, higher than the performance of the model trained by transfer learning. Cellular membrane formation, endocytosis, insulin‐like growth factor binding, protein localization to membranes, and cytoskeleton‐dependent trafficking were differentially regulated in patients showing pCR. Oncogenic signaling pathways, features correlated with human phenotypes, and features correlated with general biological processes were significantly correlated with DLS in both training and validation dataset (p.adj < 0.05). Conclusions: Our study offers a biologically interpretable DLS for the prediction of pCR to neoadjuvant chemotherapy in patients with breast cancer, which may guide personalized medication. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effects of in ovo injection of soy isoflavones (ISF) on hatchability, body weight, antioxidant status and intestinal development of newly hatched broiler chicks. One hundred and eighty fertile eggs were divided as follows: the control group, 3 mg/egg ISF (low dose) and 6 mg/egg ISF (high dose) on the 18th day of incubation. The results demonstrated that in ovo inclusion of 6 mg of ISF significantly increased hatchability and hatch weight. Both doses of ISF inclusion elevated the serum glutathione peroxidase and slightly decreased malondialdehyde compared to the control group. The high dose of ISF brings higher villus height and a higher villus/crypt ratio in chicks. Moreover, the mRNA levels of tumour necrosis factor‐ α and interferon‐gamma in the spleen were significantly decreased. The ISF treatments showed an improvement in intestinal enzyme expression levels of sucrose isomaltase and mucin 2 as well as tight junction protein (TJ) mRNA expression of claudin‐1 at high doses of ISF (p < 0.05) when compared with the other groups. Furthermore, the mRNA level of IGF‐1 was increased in the high doses of ISF compared to the control. Overall, these findings indicate that in ovo administration of ISF on the 18th day of incubation enhances hatchability, antioxidant status and intestinal morphometrics in hatched chicks and modulates the expression of proinflammatory cytokines, TJs and insulin‐like growth factor. In addition, the sustainability of antioxidants and other positive effects of ISF may increase chick viability and growth performance. [ABSTRACT FROM AUTHOR]

Tendon injury healing is a complex process that involves the participation of a significant number of molecules and cells, including growth factors molecules in a key role. Numerous studies have demonstrated the function of growth factors in tendon healing, and the recent emergence of EV has also provided a new visual field for promoting tendon healing. This review examines the tendon structure, growth, and development, as well as the physiological process of its healing after injury. The review assesses the role of six substances in tendon healing: insulin‐like growth factor‐I (IGF‐I), transforming growth factor β (TGFβ), vascular endothelial growth factor (VEGF), platelet‐derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and EV. Different growth factors are active at various stages of healing and exhibit separate physiological activities. IGF‐1 is expressed immediately after injury and stimulates the mitosis of various cells while suppressing the response to inflammation. VEGF, which is also active immediately after injury, accelerates local metabolism by promoting vascular network formation and positively impacts the activities of other growth factors. However, VEGF's protracted action could be harmful to tendon healing. PDGF, the earliest discovered cytokine to influence tendon healing, has a powerful cell chemotaxis and promotes cell proliferation, but it can equally accelerate the response to inflammation and relieve local adhesions. Also useful for relieving tendon adhesion is TGF‐ β, which is active almost during the entire phase of tendon healing. As a powerful active substance, in addition to its participation in the field of cardiovascular and cerebrovascular vessels, tumour and chronic wounds, TGF‐ β reportedly plays a role in promoting cell proliferation, activating growth factors, and inhibiting inflammatory response during tendon healing. [ABSTRACT FROM AUTHOR]

Objective: Hyperintensity signal in T2‐weighted magnetic resonance imaging (MRI) has been related to better therapeutic response during pasireotide treatment in acromegaly. The aim of the study was to evaluate T2 MRI signal intensity and its relation with pasireotide therapeutic effectiveness in real‐life clinical practice. Design, Patients and Measurements: Retrospective multicentre study including acromegaly patients treated with pasireotide. Adenoma T2‐weighted MRI signal at diagnosis was qualitatively classified as iso‐hyperintense or hypointense. Insulin‐like growth factor (IGF‐I), growth hormone (GH) and tumour volume reduction were assessed after 6 and 12 months of treatment and its effectiveness evaluated according to baseline MRI signal. Hormonal response was considered 'complete' when normalization of IGF‐I levels was achieved. Significant tumour shrinkage was defined as a volume reduction of ≥25% from baseline. Results: Eighty‐one patients were included (48% women, 50 ± 1.5 years); 93% had previously received somatostatin receptor ligands (SRLs) treatment. MRI signal was hypointense in 25 (31%) and hyperintense in 56 (69%) cases. At 12 months of follow‐up, 42/73 cases (58%) showed normalization of IGF‐I and 37% both GH and IGF‐I. MRI signal intensity was not associated with hormonal control. 19/51 cases (37%) presented a significant tumour volume shrinkage, 16 (41%) from the hyperintense group and 3 (25%) from the hypointense. Conclusions: T2‐signal hyperintensity was more frequently observed in pasireotide treated patients. Almost 60% of SRLs resistant patients showed a complete normalization of IGF‐I after 1 year of pasireotide treatment, regardless of the MRI signal. There was also no difference in the percentage tumour shrinkage over basal residual volume between the two groups. [ABSTRACT FROM AUTHOR]

Tissue‐specific decellularized extracellular matrix recapitulates the complexity of natural ECMs, creating an organ‐specific microenvironment based on its intrinsic characteristics. Here, hydrogels containing uterus‐derived decellularized extracellular matrix (UdECMs) from the endometrium‐specific layer or the entire uterus are developed. UdECMs serve as effective organ‐specific biomaterials, displaying that intrauterine UdECM administration induces endometrial regeneration and fertility enhancement. Moreover, UdECM administration alters the profile of natural killer cell subpopulations to exhibit more mature and less cytotoxic features, providing a favorable uterine environment for successful implantation and decidualization. Interestingly, insulin‐like growth factor 1 and insulin‐like growth factor‐binding protein 3 as key regulatory factors that contribute to UdECM‐mediated endometrial regeneration are discovered. Furthermore, ex vivo culture of human uterine tissues reveals that UdECMs of different origins exhibit distinct therapeutic effects based on the endometrial conditions of patients, suggesting their uses as a therapeutic intervention providing personalized regenerative medicine for infertile patients with a poor uterine environment. [ABSTRACT FROM AUTHOR]

Aims: Stanniocalcin‐2 (STC2) has recently been implicated in human muscle mass variability by genetic analysis. Biochemically, STC2 inhibits the proteolytic activity of the metalloproteinase PAPP‐A, which promotes muscle growth by upregulating the insulin‐like growth factor (IGF) axis. The aim was to examine if STC2 affects skeletal muscle mass and to assess how the IGF axis mediates muscle hypertrophy induced by functional overload. Methods: We compared muscle mass and muscle fiber morphology between Stc2−/− (n = 21) and wild‐type (n = 15) mice. We then quantified IGF1, IGF2, IGF binding proteins −4 and −5 (IGFBP‐4, IGFBP‐5), PAPP‐A and STC2 in plantaris muscles of wild‐type mice subjected to 4‐week unilateral overload (n = 14). Results: Stc2−/− mice showed up to 10% larger muscle mass compared with wild‐type mice. This increase was mediated by greater cross‐sectional area of muscle fibers. Overload increased plantaris mass and components of the IGF axis, including quantities of IGF1 (by 2.41‐fold, p = 0.0117), IGF2 (1.70‐fold, p = 0.0461), IGFBP‐4 (1.48‐fold, p = 0.0268), PAPP‐A (1.30‐fold, p = 0.0154) and STC2 (1.28‐fold, p = 0.019). Conclusion: Here we provide evidence that STC2 is an inhibitor of muscle growth upregulated, along with other components of the IGF axis, during overload‐induced muscle hypertrophy. [ABSTRACT FROM AUTHOR]

Objective: Attributable to the insulin‐like growth factor (IGF) axis involvement in fetal growth regulation, possible contribution of the maternal IGF axis to antenatal fetal macrosomia diagnosis is a subject of particular interest in diabetic pregnancy. Methods: A total of 130 women were prospectively enrolled in a longitudinal single‐center cohort study. The four study groups were: type 1 diabetes (n = 40), type 2 diabetes (n = 35), gestational diabetes (n = 40), and control (n = 15). IGF‐1 and IGF‐2 and insulin‐like growth factor‐binding protein (IGFBP) 1, 3, 6, and 7 serum levels were analyzed in 11‐ to 14‐week and 30‐ to 34‐week samples with a specific immunoassay. Results: In mothers of large‐for‐gestational‐age neonates (90th percentile), higher (median test) first‐trimester IGF‐1 (P = 0.007) and lower IGFBP‐1 (P = 0.035) were observed. The IGF‐1/IGFBP‐1 ratio was positively associated with neonatal weight (r = 0.434, P < 0.001). Receiver operating characteristic analysis revealed an association between large for gestational age and the first‐trimester IGF‐1 (area under the curve [AUC] = 0.747, P < 0.001), IGFBP‐1 (AUC = 0.334, P = 0.011), and IGF‐1/IGFBP‐1 ratio (AUC = 0.750, P < 0.001). IGF‐1/IGFBP‐1 ratio had better performance for prediction of birth weight over 4000 g (AUC = 0.822, P < 0.001). Conclusion: The authors detected different first‐trimester IGF‐1 and IGF‐1/IGFBP‐1 thresholds applicable for either supposition or rejection of macrosomia diagnosis. Further investigation is needed to determine how the maternal IGF axis can contribute to fetal macrosomia prediction. Synopsis: Maternal levels of insulin‐like growth factors, insulin‐like growth factor–binding proteins, and insulin‐like growth factor 1/insulin‐like growth factor–binding protein 1 ratio can contribute to prenatal macrosomia diagnosis, but further investigation is required. [ABSTRACT FROM AUTHOR]

The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. Although controversial, this is supported by firm evidence that semelparous species display evolutionarily programmed ageing in response to reproductive and environmental cues. Parabiosis experiments reveal that ageing is orchestrated systemically through the circulation, accompanied by programmed changes in hormone levels across a lifetime. This implies that, like the circadian and circannual clocks, there is a master 'clock of age' (circavital clock) located in the limbic brain of mammals that modulates systemic changes in growth factor and hormone secretion over the lifespan, as well as systemic alterations in gene expression as revealed by genomic methylation analysis. Studies on accelerated ageing in mice, as well as human longevity genes, converge on evolutionarily conserved fibroblast growth factors (FGFs) and their receptors, including KLOTHO, as well as insulin‐like growth factors (IGFs) and steroid hormones, as key players mediating the systemic effects of ageing. Age‐related changes in these and multiple other factors are inferred to cause a progressive decline in tissue maintenance through failure of stem cell replenishment. This most severely affects the immune system, which requires constant renewal from bone marrow stem cells. Age‐related immune decline increases risk of infection whereas lifespan can be extended in germfree animals. This and other evidence suggests that infection is the major cause of death in higher organisms. Immune decline is also associated with age‐related diseases. Taking the example of Alzheimer's disease (AD), we assess the evidence that AD is caused by immunosenescence and infection. The signature protein of AD brain, Aβ, is now known to be an antimicrobial peptide, and Aβ deposits in AD brain may be a response to infection rather than a cause of disease. Because some cognitively normal elderly individuals show extensive neuropathology, we argue that the location of the pathology is crucial – specifically, lesions to limbic brain are likely to accentuate immunosenescence, and could thus underlie a vicious cycle of accelerated immune decline and microbial proliferation that culminates in AD. This general model may extend to other age‐related diseases, and we propose a general paradigm of organismal senescence in which declining stem cell proliferation leads to programmed immunosenescence and mortality. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have shown that the insulin‐like growth factor (IGF) pathway is highly associated with tumor initial and progression in several tumors. However, compared with IGF1/1R and IGF2/2R, insufficient studies have focused on IGF‐binding proteins (IGFBPs). Methods: The GDC TCGA and GTEx data of 33 cancers, TCGA pan‐cancer immune phenotypes, tumor mutation burdens, and the copy number alterations of IGFBPs were extracted. Next, the prognostic value of IGFBPs was analyzed based on a univariate Cox analysis. Additionally, the ESTIMATE algorithm was used to calculate stromal and immune scores and tumor purity, and the CIBERSORT algorithm was used to estimate tumor‐infiltrating immunocyte levels. Ultimately, the correlation between IGFBP expression and cancer hallmark pathways was estimated with a Spearman analysis. Results: The expression of IGFBPs was differentially expressed and correlated with prognosis in specific cancers. IGFBPs may operate as biological markers for carcinogenesis and progression and as prognostic biomarkers. Additionally, IGFBP5 has been proved that promotes the invasion and migration of ovarian cancer. Conclusions: In general, IGFBPs can serve as predictable biomarkers and potential therapeutic targets for specific tumors. Our results could provide underlying targets for the design of laboratory experiments to elucidate the mechanism of IGFBPs in cancers and identify IGFBP5 as a prognostic factor in ovarian cancers. [ABSTRACT FROM AUTHOR]

Background: The overall survival of IDH‐wildtype glioblastoma patients is poor despite best available treatments. There is an urgent need for new biomarkers to inform more precise disease stratification. Previous studies have identified insulin‐like growth factor binding protein‐2 (IGFBP‐2) as a potential biomarker for glioblastoma diagnosis and therapeutic targeting. Other studies have indicated links between the insulin‐like growth factor (IGF) axis and tumorigenic functions of a molecular chaperone glucose related protein of 78 kDa (GRP78). We aimed to interrogate the oncogenic effects of IGFBP‐2 and GRP78 in our glioma stem cell (GSC) lines and clinical cohort. Methods: Immunoblotting, reverse transcription quantitative real‐time PCR were used to quantify protein and mRNA levels derived from GSCs and non‐malignant neural stem cells (NSCs). Microarray analysis was used to compare the differences in IGFBP‐2 (IGFBP‐2) and GRP78 (HSPA5) transcript expression between NSCs, GSCs and adult human cortex samples. Immunohistochemistry was used to quantify IGFBP‐2 and GRP78 expression in IDH‐wildtype glioblastoma tissue sections (n = 92) and clinical implications assessed using survival analysis. Finally, the relationship between IGFBP‐2 and GRP78 was further explored molecularly using coimmunoprecipitation. Results: Here, we demonstrate that IGFBP‐2 and HSPA5 mRNA is overexpressed in GSCs and NSCs in comparison to non‐malignant brain tissue. We also determined a relationship in which G144 and G26 GSCs expressed higher IGFBP‐2 protein and mRNA than GRP78, and this was reversed in mRNA isolated from adult human cortex samples. Clinical cohort analysis revealed that Glioblastomas with high IGFBP‐2 protein expression paired with low GRP78 protein expression were significantly associated with a much shorter survival time (Median = 4 months, p = 0.019) compared with 12‐14 months for any other combination of high/low protein expression. Conclusions: Inverse levels of IGFBP‐2 and GRP78 may be adverse clinical prognostic markers in IDH‐wildtype glioblastoma. Further interrogation of the mechanistic link between IGFBP‐2 and GRP78 may be important for rationalisation of their potential as biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

The epidemic spread of obesity is nowadays recognized as a global health and economic burden, arising great interest in the scientific community. The rate of adult obesity steadily increases concomitantly with the cancer incidence. As has been comprehensively reported, obesity is included among the multiple cancer risk factors and can progressively cause and/or exacerbate certain cancer types, as colorectal and breast cancers. The term adiponcosis was forged precisely to emphasize the interconnection between obesity and cancer onset and progression. The underlying mechanisms of adiponcosis have not been fully elucidated yet, may vary on cancer type, and depend on body fat distribution. It has been proposed that insulin resistance and related chronic hyperinsulinemia, increased insulin‐like growth factors production, chronic inflammation or increased bioavailability of steroid hormones could be responsible of cancer hallmarks. Additionally, it has been suggested that adipose tissue‐derived hormones, cytokines and adipokines, such as leptin, adiponectin and inflammatory markers, may reflect mechanisms linked to tumorigenesis. This review summarizes the current evidence on pathways, hormones, cytokines and low‐chronic inflammation subtending adiponconsis, focusing on breast and colorectal cancers. In addition, we analyzed the lifestyle interventions that could attenuate the driving forces of obesity‐related cancer incidence and progression. Moreover, current targets and drugs, their pros and cons, as well as new mechanisms and targets with promising therapeutic potential in cancer are discussed. Depicting this complex interconnection will provide insights for establishing new therapeutic approaches to halt the obesity impacts and thwart cancer onset and progression. [ABSTRACT FROM AUTHOR]

Objectives: Postoperative delirium (POD) is a common postsurgical complication. The early identification of its risk factors is the first step toward reducing POD. The predictive factors for POD in patients after major abdominal surgery remain obscure. Therefore, this meta‐analysis aimed to comprehensively summarize the risk factors of POD after major abdominal surgery. Methods: POD studies published between January, 1900 and June 2022 were obtained by searching PubMed, Cochrane Library, Web of Science, Embase, and Medline. Two authors independently reviewed the studies to extract the risk factors and assessed the quality of related articles using the Newcastle‐Ottawa Scale. Data were recorded, and a meta‐analysis was performed using Review Manager version 5.4.1. Results: Ten studies including total 2900 patients undergoing major abdominal surgery, were eligible for analysis, 608 of whom developed POD, for a cumulative incidence of 21%. This pooled analysis suggested the statistically significant risk factors for POD were age, higher American Society of Anesthesiologists grade, lower preoperative Mini‐Mental State Examination score, cognitive impairment, preoperative Katz‐ADL score <6, preoperative and postoperative hypoalbuminemia, lower preoperative insulin‐like growth factor‐1 levels, and longer duration of anesthesia. Conclusion: POD is common in patients undergoing major abdominal surgery. This meta‐analysis identified risk factors that may aid the early detection of POD and play a prominent role in preventing POD. Key points: Our report was the first to comprehensively summarize the related risk factors for postoperative delirium (POD) after major abdominal surgery; the results of this pooled analysis suggested the statistically significant risk factors for POD were age, higher American Society of Anesthesiologists grade, lower preoperative Mini‐Mental State Examination score, cognitive impairment, preoperative Katz‐ADL score <6, preoperative and postoperative hypoalbuminemia, lower preoperative insulin‐like growth factor‐1 levels, and longer durations of anesthesia, which may better predict the risk of POD. [ABSTRACT FROM AUTHOR]

Aim: Multiple sclerosis (MS) is an autoimmune disease, and its typical characteristics are neuroinflammation and the demyelination of neurons in the central nervous system (CNS). Sterile alpha and TIR motif containing 1 (SARM1) is an essential factor mediating axonal degeneration and SARM1 deletion reduces the neuroinflammation in spinal cord injury. This study aimed to explore the roles of SARM1 and its underlying mechanisms in MS. Methods: Experimental autoimmune encephalomyelitis (EAE, a model of MS) model was established. Immunostaining, western blot, electron microscope, and HE staining were used to examine the pathological manifestations such as inflammation, demyelination, and neuronal death in SARM1f/f EAE mice and SARM1Nestin‐CKO EAE mice. In addition, RNA‐seq, real‐time PCR and double‐immunostaining were used to examine the underlying mechanism of SARM1 in EAE mice. Results: SARM1 was upregulated in neurons of the spinal cords of EAE mice. SARM1 knockout in CNS ameliorated EAE with less neuroinflammation, demyelination, and dead neurons. Mechanically, SARM1 knockout resulted in the reduction of insulin‐like growth factor (IGF)‐binding protein 2 (IGFBP2) in neurons of EAE mice, which might inhibit the neuroinflammation through inhibiting NF‐κB signaling. Finally, activation of NF‐κB partially aggravated the neuroinflammation and demyelination deficits of SARM1Nestin‐CKO EAE mice. Conclusions: These results identified the unknown role of SARM1 in the promotion of neuroinflammation and demyelination and revealed a novel drug target pathway of SARM1/IGFBP2/NF‐κB for MS. [ABSTRACT FROM AUTHOR]

Objective: Anorexia nervosa (AN) is an eating disorder characterised by voluntary dietary restriction leading to severe undernutrition. Hypoglycaemia is mostly described through severe case reports and is always evaluated by fasting or post‐meal blood glucose, showing nothing about hypoglycaemia's length or duration. The interest of continuous interstitial glucose monitoring (CGM), largely used in diabetes mellitus, has never been evaluated in AN patients. Method: Glycaemia cycles in AN patients were assessed using CGM over 5 days and then analysed according to food intake. Results: Mean glycaemia was within normal range. 91% of the patients presented with at least one episode with glycaemia under 70 mg/dl. Within the 24 h, the percentage of time spent with a glycaemia under 70 mg/dl was of 20.82 ± 3.90% with a maximum of 52%. We found 2.52 ± 0.33 hypoglycaemia events per 24 h, including 21.11 ± 3.76% at night. CGM parameters correlated with cortisol and IGF1 plasma levels. Comparison with estimated carbohydrate intakes discriminated concordant and non‐concordant estimations depending on patient. Conclusions: AN patients display chronic prolonged mild hypoglycaemia all over the nycthemeron despite normal fasting glycaemia. Associated adaptive increased counter‐regulatory hormones might protect AN patients from deeper hypoglycaemia. CGM allowed testing food intake self‐estimation reliability of AN patients and could be a very useful biofeedback tool. Highlights: Anorexia nervosa (AN) patients display chronic prolonged mild hypoglycaemia all over the 24 h.chronic prolonged mild hypoglycaemia in AN patients is associated with adaptive higher counter‐regulatory hormones that might protect them from deeper hypoglycaemia.Data from Continuous Glucose Monitoring confronted with food intake self‐estimation may become a reliable biofeedback tool during nutrition therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Neurotrophic factors and cardiorespiratory fitness are both considered important in developmental trajectories but their link to brain health remains poorly understood. The aims of the study were to examine whether levels of plasma-derived neurotrophic factors were associated with brain health indicators in children with overweight or obesity; and to test whether these associations were moderated by cardiorespiratory fitness. 100 children (41% girls) were included in this analysis. Plasma levels of brain-derived neurotrophic factor, insulin-like growth factor-1, vascular endothelial growth factor A, and epidermal growth factor were determined by XMap technology. Academic performance and executive function were assessed using validated neuropsychological tests. Hippocampal volume was measured using magnetic resonance imaging. Cardiorespiratory fitness was assessed using the 20-m Shuttle Run Test. Insulin-like growth factor-1 was positively associated with cognitive flexibility. Stratified analyses by fitness categories (i.e. unfit vs. fit) showed that brain-derived neurotrophic factor was positively associated with right posterior hippocampal volume in fit children, and epidermal growth factor was negatively associated with right hippocampal, and right anterior hippocampal volumes in their unfit peers, with a moderating role of cardiorespiratory fitness in these associations. However, all these significant associations disappeared after correction for multiple comparisons. The association between neurotrophic factors and brain health indicators in children with overweight/obesity was neither strong nor consistent. These results could help enhance our understanding of determinants of brain health in children with overweight/obesity. Highlights This study provides novel findings on the associations between neurotrophic factors and a wide range of brain health indicators in children. This study additionally explored the role of cardiorespiratory fitness in these associations. The association between neurotrophic factors and brain health in children with overweight/obesity was neither strong nor consistent. Cardiorespiratory fitness moderated the associations of brain-derived neurotrophic factor and epidermal growth factor with right hippocampal volume. [ABSTRACT FROM AUTHOR]

Biomineralization‐controlled exo‐/endoskeleton growth contributes to body growth and body size diversity. Molluscan shells undergo ectopic biomineralization to form the exoskeleton and biocalcified "pearl" involved in invading defence. Notably, exo‐/endoskeletons have a common ancestral origin, but their regulation and body growth are largely unknown. This study employed the pearl oyster, Pinctada fucata marntensii, a widely used experimental model for biomineralization in invertebrates, to perform whole‐genome resequencing of 878 individuals from wild and breeding populations. This study characterized the genetic architecture of biomineralization‐controlled growth and ectopic biomineralization. The insulin‐like growth factor (IGF) endocrine signal interacted with ancient single‐copy transcription factors to form the regulatory network. Moreover, the "cross‐phylum" regulation of key long noncoding RNA (lncRNA) in bivalves and mammals indicated the conserved genetic and epigenetic regulation in exo‐/endoskeleton growth. Thyroid hormone signal and apoptosis regulation in pearl oysters affected ectopic biomineralization in pearl oyster. These findings provide insights into the mechanism underlying the evolution and regulation of biomineralization in exo‐/endoskeleton animals and ectopic biomineralization. [ABSTRACT FROM AUTHOR]

Proteomic analysis of patients with pulmonary arterial hypertension (PAH) has demonstrated significant abnormalities in the insulin-like growth factor axis (IGF). This study proposed to establish associations between a specific binding protein, insulin-like growth factor binding protein 4 (IGFBP4), and PAH severity as well as survival across varying study cohorts. In all cohorts studied, serum IGFBP4 levels were significantly elevated in PAH compared to controls (p < 0.0001). IGFBP4 concentration was also highest in the connective tissue-associated PAH (CTD-PAH) and idiopathic PAH subtypes (876 and 784 ng/mL, median, respectively). After adjustment for age and sex, IGFBP4 was significantly associated with worse PAH severity as defined by a decreased 6-min walk distance (6MWD), New York heart association functional class (NYHA-FC), REVEAL 2.0 score and higher right atrial pressures. In longitudinal analysis provided by one of the study cohorts, IGFBP4 was prospectively significantly associated with a shorter 6MWD, worse NYHA-FC classification, and decreased survival. Cox multivariable analysis demonstrated higher serum IGFBP4 as an independent predictor of survival in the overall PAHB cohort. Therefore, this study established that higher circulating IGFBP4 levels were significantly associated with worse PAH severity, decreased survival and disease progression. Dysregulation of IGF metabolism/growth axis may play a significant role in PAH cardio-pulmonary pathobiology. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common cancers worldwide. The tumor microenvironment exerts crucial effects in driving CRC progression. Cancer‐associated fibroblasts (CAFs) serve as one of the most important tumor microenvironment components promoting CRC progression. This study aimed to elucidate the novel molecular mechanisms of CAF‐secreted insulin‐like growth factor (IGF) 2 in colorectal carcinogenesis. Our results indicated that IGF2 was a prominent factor upregulated in CAFs compared with normal fibroblasts. CAF‐derived conditioned media (CM) promoted tumor growth, migration, and invasion of HCT 116 and DLD‐1 cells. IGF1R expression is significantly increased in CRC, serving as a potent receptor in response to IGF2 stimulation and predicting unfavorable outcomes for CRC patients. Apart from the PI3K–AKT pathway, RNA‐seq analysis revealed that the YAP1‐target signature serves as a prominent downstream effector to mediate the oncogenic signaling of IGF2–IGF1R. By single‐cell RNA sequencing (scRNA‐seq) and immunohistochemical validation, IGF2 was found to be predominantly secreted by CAFs, whereas IGF1R was expressed mainly by cancer cells. IGF2 triggers the nuclear accumulation of YAP1 and upregulates YAP1 target signatures; however, these effects were abolished by either IGF1R knockdown or inhibition with picropodophyllin (PPP), an IGF1R inhibitor. Using CRC organoid and in vivo studies, we found that cotargeting IGF1R and YAP1 with PPP and verteporfin (VP), a YAP1 inhibitor, enhanced antitumor effects compared with PPP treatment alone. In conclusion, this study revealed a novel molecular mechanism by which CAFs promote CRC progression. The findings highlight the translational potential of the IGF2–IGF1R–YAP1 axis as a prognostic biomarker and therapeutic target for CRC. © 2022 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

This study analyzed the expression of growth‐related genes of olive flounder, Paralichthys olivaceus, fed a low‐fish meal (FM) diet to investigate the replacement of the FM diet in the field. The expression of growth hormone (GH)/insulin‐like growth factor (IGF) axis genes in the brain/pituitary/liver and plasma hormone concentrations were measured. A basal experimental diet was formulated using 63% FM and 12% soybean meal as the primary protein sources, and then two other diets were made by replacing 20% and 30% of the FM with soy protein concentrate, tankage meal, and poultry by‐products meal. Each diet was fed to duplicate groups of juvenile flounder (150 ± 3.0 g) twice a day. After 20 weeks, the plasma growth‐related hormone concentrations were similar between the control and FM20 groups. Moreover, GH/IGF axis gene mRNA expression in the brain/pituitary/liver was similar between the control and FM20 groups. Immunoblotting of muscle and liver showed the same pattern. This study showed the utility of replacing 20% of the FM diet and supports the possibility of field application. [ABSTRACT FROM AUTHOR]

The aim of the present study was to examine the applicability of several hormonal indexes for early prediction of puberty and reproductive state in pigs. For this purpose, we have compared the level of hormones leptin, estradiol, progesterone, and IGF‐I in the blood of gilts at 150 days of age and their indexes of puberty and ovarian state at the age of 200 days. The association between blood leptin, estradiol, progesterone, and IGF‐I and indexes of future reproductive state has been demonstrated. High blood concentrations of leptin and IGF‐I levels were associated with relatively low reproductive traits, while high levels of estradiol and progesterone were associated with future high reproductive indexes. These observations are the first demonstration of the applicability of these endocrine indexes for prediction of porcine reproductive traits. [ABSTRACT FROM AUTHOR]

Inadequate diet and frequent symptomatic infections are considered major causes of growth stunting in low‐income countries, but interventions targeting these risk factors have achieved limited success. Asymptomatic infections can restrict growth, but little is known about their role in global stunting prevalence. We investigated factors related to length‐for‐age Z‐score (LAZ) at 24 months by constructing an interconnected network of various infections, biomarkers of inflammation (as assessed by alpha‐1‐acid glycoprotein [AGP]), and growth (insulin‐like growth factor 1 [IGF‐1] and collagen X biomarker [CXM]) at 18 months, as well as other children, maternal, and household level factors. Among 604 children, there was a continuous decline in mean LAZ and increased mean length deficit from birth to 24 months. At 18 months of age, the percentage of asymptomatic children who carried each pathogen was: 84.5% enterovirus, 15.5% parechovirus, 7.7% norovirus, 4.6% rhinovirus, 0.6% rotavirus, 69.6% Campylobacter, 53.8% Giardia lamblia, 11.9% malaria parasites, 10.2% Shigella, and 2.7% Cryptosporidium. The mean plasma IGF‐1 concentration was 12.5 ng/ml and 68% of the children had systemic inflammation (plasma AGP concentration >1 g/L). Shigella infection was associated with lower LAZ at 24 months through both direct and indirect pathways, whereas enterovirus, norovirus, Campylobacter, Cryptosporidium, and malaria infections were associated with lower LAZ at 24 months indirectly, predominantly through increased systemic inflammation and reduced plasma IGF‐1 and CXM concentration at 18 months. Key messages: Asymptomatic infections are common in apparently healthy children in rural Malawi.Asymptomatic infections are associated with reduced linear growth, mainly through systemic inflammation and reduced plasma concentration of insulin‐like growth factor 1 hormone.For achieving healthy growth at the population level, adequate nutrition programs may need to be complemented with comprehensive infection prevention and management. [ABSTRACT FROM AUTHOR]

Keywords: acne; IGF-1; lipogenesis; sebocytes; YAP EN acne IGF-1 lipogenesis sebocytes YAP 996 998 3 07/14/23 20230701 NES 230701 Acne is a chronic inflammatory disorder of the pilosebaceous unit. From these results, we determined that IGF-1 increased YAP activity in sebocytes and YAP inhibition attenuated IGF-1-induced lipid production by preventing IGFR-mTOR signalling pathway. To investigate the mechanism of YAP inhibition on IGF-1-induced lipogenesis, we evaluated the protein expression of important transcription factors related to lipid production. [Extracted from the article]

Mesenchymal stem cell‐derived conditioned medium (MSC‐CM) improves cardiac function after myocardial infarction; however, this cardioprotective effect is moderate and transient. Lipopolysaccharide (LPS) pretreatment partially improves MSC‐CM‐mediated cardioprotective effects owing to the presence of paracrine factors. However, the mechanism underlying these improved effects remains unknown. To study the effect of LPS‐pretreated MSC‐CM on hypoxia/reoxygenation (H/R)‐induced injury, MSCs were treated with or without LPS (400 ng/mL) for 48 h, and the supernatant was collected (MSC‐CM). Subsequently, H9c2 cells were co‐cultured with Nor‐CM (CM derived from LPS‐untreated MSCs) and LPS‐CM (CM derived from LPS‐pretreated MSCs) for 24 h and subjected to H/R. MSC‐CM inhibited the progression of H/R‐induced injury in H9c2 cells, and this protective effect was enhanced via LPS pretreatment as evidenced by the improved apoptosis assessment index (i.e. caspase‐3 and B‐cell lymphoma‐2 [Bcl‐2] expression) and decreased levels of lactic dehydrogenase (LDH) and cardiac troponin (cTn). In addition, the results of haematoxylin–eosin staining (H&E), transmission electron microscopy (TEM) and TdT‐mediated dUTP nick‐end labelling (TUNEL) validated that MSC‐CM inhibited H/R‐induced injury in H9c2 cardiomyocytes. LPS pretreatment downregulated the expression of high mobility group box‐1 (HMGB1) and BTB and CNC homology‐1 (Bach1) proteins in MSCs but upregulated the expression of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and insulin‐like growth factor (IGF). HMGB1 knockdown (MSC/siHMGB1‐CM) significantly decreased the expression of Bach1 and increased the expression of VEGF, HGF and IGF. Bach1 knockdown (MSC/siBach1‐CM) did not alter the production of HMGB1 but increased the expression of VEGF and IGF. LPS pretreatment did not alter the expression of the paracrine factors VEGF and HGF in the MSC/siHMGB1 group but increased their expression in the MSC/siBach1 group. The myocyte anti‐apoptotic effects of MSCs/siBach1‐CM were similar to those of untreated MSCs, which were not enhanced by LPS. LPS‐pretreated MSC‐CM protects H9c2 cells against H/R‐induced injury partly through the HMGB1/Bach1 signalling pathway. [ABSTRACT FROM AUTHOR]

Cerebral hemorrhage is a fatal disease that causes severe damage to local nerve function. The purpose of this research is to analyze the effect of kurarinone on hemin‐induced neuroinflammation and neurotoxicity. In our study, according to the results of bioinformatics analysis, we hypothesized that kurarinone might modulate cerebral hemorrhage advancement via the insulin‐like growth factor 1/phosphoinositide 3‐kinase/protein kinase B (IGF1/PI3K/Akt) signaling. Kurarinone promoted M2 microglia polarization, and curbed M1 polarization and inflammation in human microglial cells (HMC3) cells with hemin treatment. Besides, kurarinone upregulated IGF1 expression and activated the PI3K/Akt signaling pathway in hemin‐treated HMC3 cells. In addition, downregulation of IGF1 or inhibition of the PI3K/Akt signaling weakened the effects of kurarinone on microglia polarization and inflammation in HMC3 cells with hemin treatment. Kurarinone alleviated apoptosis and oxidative damage of SH‐SY5Y cells co‐cultured with hemin‐treated HMC3 cells. In conclusion, kurarinone lessened hemin‐induced neuroinflammation and microglia‐mediated neurotoxicity by regulating microglial polarization through modulating the IGF1/PI3K/Akt signaling. These results delivered a new prospective therapeutic drug for the treatment of cerebral hemorrhage. [ABSTRACT FROM AUTHOR]