Estetrol Inhibits the Prostate Cancer Tumor Stimulators FSH and IGF-1.

Background: The co-treatment of androgen deprivation therapy (ADT) for advanced prostate cancer (PCa) with the fetal estrogen estetrol (E4) may further inhibit endocrine PCa tumor stimulators. We previously reported the suppression of follicle-stimulating hormone (FSH), total and free testosterone, and prostate-specific antigen by ADT+E4. Here, we provide more detailed data on FSH suppression by E4 and present new findings on the effect of ADT+E4 on insulin-like growth factor-1 (IGF-1). Methods: A Phase II, double-blind, randomized, placebo-controlled study (the PCombi study) was conducted in advanced PCa patients treated with ADT. The study assessed the effect of E4 co-treatment with LHRH agonist ADT on tumor stimulators, including FSH and IGF-1. Patients starting ADT were randomized 2:1 to receive either 40 mg E4 (n = 41) or placebo (n = 21) for 24 weeks. Non-parametric analyses were performed on the per-protocol population (PP) and individual changes were visualized. Results: The PP included 57 patients (37 ADT+E4; 20 ADT+placebo). ADT+E4 almost completely suppressed FSH in all patients (98% versus 37%; p < 0.0001). IGF-1 levels decreased by 41% with ADT+E4 versus an increase of 10% with ADT+placebo (p < 0.0001). Conclusions: The almost complete suppression of the tumor stimulator FSH using ADT plus E4 observed in all individual patients in this study, along with the augmented suppression of IGF-1 versus an increase by ADT only, may be clinically relevant and suggest the enhanced anti-cancer treatment efficacy of E4 in addition to the previously reported additional suppression of total and free T and PSA.

Characterisation of IGF-1 (rs7136446) and IL-6 (rs1800795) polymorphisms among breast cancer patients in western Algeria.

Breast cancer (BC) is the most frequently diagnosed cancer among women worldwide, including Algeria. Certain single nucleotide polymorphisms (SNPs) have been linked to higher risk of BC. Several studies have been performed on the insulin- like growth factor 1 (IGF-1) T > C (rs7136446) and the interleukin 6 (IL-6) 174 G > C (rs1800795) SNPs to explore their role in BC. The aim of this study is to investigate the association between the 2 SNPs, IL-6 (rs1800795) and IGF-1 (rs7136446) with BC in the population of western Algeria. This study was carried out for the first time among the Algerian population. This case-control study included 109 BC patients and 112 healthy controls. Genomic DNA was extracted from peripheral blood samples. DNA concentration was determined using the Qubit 2.0 fluorometer. The genotyping of selected SNPs was performed by real-time polymerase chain reaction followed by statistical analysis to assess genotypic frequencies and genetic association with BC. The results showed that IGF-1 rs7136446 was positively associated with BC (p = 0.00001) and that the distribution of genotype frequencies of rs7136446 showed a statistically difference between human epidermal growth factor receptor 2 (HER-2) positive and HER-2 negative BC (p = 0.04), but this association did not last after the correction of Bonferroni. No association was found in genotype distribution of the IL-6 (rs1800795) among controls and BC patients or with clinicopathological parameters including HER-2 status in BC (p > 0.05). In summary, our findings indicate that IGF-1 rs7136446 is associated with BC in our population of western Algeria.

Decoding the Role of Insulin-like Growth Factor 1 and Its Isoforms in Breast Cancer.

Insulin-like Growth Factor-1 (IGF-1) is a crucial mitogenic factor with important functions in the mammary gland, mainly through its interaction with the IGF-1 receptor (IGF-1R). This interaction activates a complex signaling network that promotes cell proliferation, epithelial to mesenchymal transition (EMT) and inhibits apoptosis. Despite extensive research, the precise molecular pathways and intracellular mechanisms activated by IGF-1, in cancer, remain poorly understood. Recent evidence highlights the essential roles of IGF-1 and its isoforms in breast cancer (BC) development, progression, and metastasis. The peptides that define the IGF-1 isoforms-IGF-1Ea, IGF-1Eb, and IGF-1Ec-act as key points of convergence for various signaling pathways that influence the growth, metastasis and survival of BC cells. The aim of this review is to provide a detailed exami-nation of the role of the mature IGF-1 and its isoforms in BC biology and their potential use as possible therapeutical targets.

Message Transmission Between Adipocyte and Macrophage in Obesity.

Obesity is characterized by the chronic low-grade activation of the innate immune system. In this respect, macrophage-elicited metabolic inflammation and adipocyte-macrophage interaction have primary importance in obesity. Large quantity of macrophages is accumulated by different mechanisms in obese adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway promotes more macrophage accumulation into the obese adipose tissue. However, obesity-induced changes in adipose tissue macrophage density are mainly dependent on increases in the triple-positive cluster of differentiation (CD)11b+ F4/80+ CD11c+ adipose tissue macrophage subpopulation. As epigenetic regulators, microRNAs (miRNAs) are one of the most important mediators of obesity. miRNAs are expressed by adipocytes as well as macrophages and regulate inflammation with the expression of target genes. A paracrine loop involving free fatty acids and tumor necrosis factor-alpha (TNF-α) between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-1beta (IL-1ß) by macrophages; both adipocyte and macrophage induction by toll-like receptor-4 (TLR4) through nuclear factor-kappaB (NF-κB) activation; free fatty acid-induced and TLR-mediated activation of c-Jun N-terminal kinase (JNK)-related pro-inflammatory pathways in CD11c+ immune cells; are effective in mutual message transmission between adipocyte and macrophage and in the development of adipose tissue inflammation. Thus, the metabolic status of adipocytes and their released exosomes are important determinants of macrophage inflammatory output. However, old adipocytes are removed by macrophages through trogocytosis or sending an "eat me" signal. As a single miRNA can be able to regulate a variety of target genes and signaling pathways, reciprocal transfer of miRNAs between adipocytes and macrophages via miRNA-loaded exosomes reorganizes the different stages of obesity. Changes in the expression of circulating miRNAs because of obesity progression or anti-obesity treatment indicate that miRNAs could be used as potential biomarkers. Therefore, it is believed that targeting macrophage-associated miRNAs with anti-obesity miRNA-loaded nano-carriers may be successful in the attenuation of both obesity and adipose tissue inflammation in clinical practice. Moreover, miRNA-containing exosomes and transferable mitochondria between the adipocyte and macrophage are investigated as new therapeutic targets for obesity-related metabolic disorders.

Growth Hormone Receptor Antagonist Markedly Improves Gemcitabine Response in a Mouse Xenograft Model of Human Pancreatic Cancer.

Chemotherapy treatment against pancreatic ductal adenocarcinoma (PDAC) is thwarted by tumoral activation of multiple therapy resistance pathways. The growth hormone (GH)-GH receptor (GHR) pair is a covert driver of multimodal therapy resistance in cancer and is overexpressed in PDAC tumors, yet the therapeutic potential of targeting the same has not been explored. Here, we report that GHR expression is a negative prognostic factor in patients with PDAC. Combinations of gemcitabine with different GHR antagonists (GHRAs) markedly improve therapeutic outcomes in nude mice xenografts. Employing cultured cells, mouse xenografts, and analyses of the human PDAC transcriptome, we identified that attenuation of the multidrug transporter and epithelial-to-mesenchymal transition programs in the tumors underlie the observed augmentation of chemotherapy efficacy by GHRAs. Moreover, in human PDAC patients, GHR expression strongly correlates with a gene signature of tumor promotion and immune evasion, which corroborate with that in syngeneic tumors in wild-type vs. GH transgenic mice. Overall, we found that GH action in PDAC promoted a therapy-refractory gene signature in vivo, which can be effectively attenuated by GHR antagonism. Our results collectively present a proof of concept toward considering GHR antagonists to improve chemotherapeutic outcomes in the highly chemoresistant PDAC.

Biomimetic Supramolecular Assembly with IGF-1C Delivery Ameliorates Inflammatory Bowel Disease (IBD) by Restoring Intestinal Barrier Integrity.

The management of dysfunctional intestinal epithelium by promoting mucosal healing and modulating the gut microbiota represents a novel therapeutic strategy for inflammatory bowel disease (IBD). As a convenient and well-tolerated method of drug delivery, intrarectal administration may represent a viable alternative to oral administration for the treatment of IBD. Here, a biomimetic supramolecular assembly of hyaluronic acid (HA) and ß-cyclodextrin (HA-ß-CD) for the delivery of the C domain peptide of insulin-like growth factor-1 (IGF-1C), which gradually releases IGF-1C, is developed. It is identified that the supramolecular assembly of HA-ß-CD enhances the stability and prolongs the release of IGF-1C. Furthermore, this biomimetic supramolecular assembly potently inhibits the inflammatory response, thereby restoring intestinal barrier integrity. Following HA-ß-CD-IGF-1C administration, 16S rDNA sequencing reveals a significant increase in the abundance of the probiotic Akkermansia, suggesting enhanced intestinal microbiome homeostasis. In conclusion, the findings demonstrate the promise of the HA-based mimicking peptide delivery platform as a therapeutic approach for IBD. This biomimetic supramolecular assembly effectively ameliorates intestinal barrier function and intestinal microbiome homeostasis, suggesting its potential for treating IBD.

Composition of the microbiota in patients with growth hormone deficiency before and after treatment with growth hormone.

INTRODUCTION: Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have modulatory effects on bowel function and its microbiota. Our aim was to investigate whether low levels of GH and IGF-1 in patients with GH deficiency are associated with changes in gut physiology/integrity as well as in the composition of the gut microbiota. MATERIALS AND METHODS: We conducted a case-control study in 21 patients with GH deficiency, at baseline and after 6 months of GH treatment, and in 20 healthy controls. We analysed changes in anthropometric and laboratory characteristics and bacterial translocation and studied the composition of the microbiome by means of massive 16S rRNA gene sequencing. RESULTS: Growth hormone deficiency was accompanied by a significant increase in serum levels of sCD14, a marker of bacterial translocation (P < .01). This increase was reversed by GH treatment. We did not find any differences in the composition or α- or ß-diversity of the gut microbiota after treatment or between cases and controls. CONCLUSIONS: Our work is the first to demonstrate that the presence of GH deficiency is not associated with differences in gut microbiota composition in comparison with healthy controls, and changes in microbiota composition are also not found after 6 months of treatment. However, GH deficiency and low IGF-1 levels were associated with an increase in bacterial translocation, which had reversed after treatment.

Acromegaly in humans and cats: Pathophysiological, clinical and management resemblances and differences.

OBJECTIVE: Acromegaly is a disorder associated with excessive levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). In general, GH/IGF-1 excess leads to morphologic craniofacial and acral changes as well as cardiometabolic complications, but the phenotypic changes and clinical presentation of acromegaly differ across species. Here, we review the pathophysiology, clinical presentation and management of acromegaly in humans and cats, and we provide a systematic comparison between this disease across these different species. DESIGN: A comprehensive literature review of pathophysiology, clinical features, diagnosis and management of acromegaly in humans and in cats was performed. RESULTS: Acromegaly is associated with prominent craniofacial changes in both species: frontal bossing, enlarged nose, ears and lips, and protuberant cheekbones are typically encountered in humans, whereas increased width of the head and skull enlargement are commonly found in cats. Malocclusion, prognathism, dental diastema and upper airway obstruction by soft tissue enlargement are reported in both species, as well as continuous growth and widening of extremities resulting in osteoarticular compromise. Increase of articular joint cartilage thickness, vertebral fractures and spine malalignment is more evident in humans, while arthropathy and spondylosis deformans may also occur in cats. Generalized organomegaly is equally observed in both species. Other similarities between humans and cats with acromegaly include heart failure, ventricular hypertrophy, diabetes mellitus, and an overall increased cardiometabolic risk. In GH-secreting pituitary tumours, local compressive effects and behavioral changes are mostly observed in humans, but also present in cats. Cutis verticis gyrata and skin tags are exclusively found in humans, while palmigrade/plantigrade stance may occur in some acromegalic cats. Serum IGF-1 is used for acromegaly diagnosis in both species, but an oral glucose tolerance test with GH measurement is only useful in humans, as glucose load does not inhibit GH secretion in cats. Imaging studies are regularly performed in both species after biochemical diagnosis of acromegaly. Hypophysectomy is the first line treatment for humans and cats, although not always available in veterinary medicine. CONCLUSION: Acromegaly in humans and cats has substantial similarities, as a result of common pathophysiological mechanisms, however species-specific features may be found.

IGF-1 rs6218 polymorphisms modulate the susceptibility to age-related cataract.

Background: Single nucleotide polymorphisms (SNPs), as the most abundant form of DNA variation in the human genome, contribute to age-related cataracts (ARC) development. Apoptosis of lens epithelial cells (LECs) is closely related to ARC formation. Insulin-like growth factor 1 (IGF1) contributes to cell apoptosis regulation. Moreover, IGF1 was indicated to exhibit a close association with cataract formation. Afterward, an investigation was conducted to examine the correlation between polymorphisms in IGF1 and the susceptibility to ARC. Methods: The present investigation was a case-control study. Venous blood draws were collected from the participants for DNA genotyping. Lens capsule samples were collected to detect mRNA and apoptosis. TaqMan RT-PCR was used to detect IGF1 polymorphism genotypes and qRT PCR was used to detect IGF1 mRNA levels in LECs. LEC apoptosis was evaluated through flow cytometry. The chi-square test was used to compare differences between ARCs and controls of each SNP. Results: We found that the G allele frequency in the IGF1-rs6218 was higher in the ARCs than in the controls. Furthermore, it was observed that the rs6218 GG genotype exhibited a positive correlation to elevated levels of IGF1 mRNA in LECs. The IGF1 mRNA in the LECs and the apoptosis of LECs in nuclear type of ARCs (ARNC) was higher than the controls. Conclusion: The susceptibility to ARC was related to IGF1-rs6218 polymorphism, and this polymorphism is associated with IGF1 expression at the mRNA level. Moreover, apoptosis in LECs of ARNCs was found to be increased.

Identification of IGF-1 Effects on White Adipose Tissue and Hippocampus in Alzheimer's Disease Mice via Transcriptomic and Cellular Analysis.

Alzheimer's disease (AD) stands as the most prevalent neurodegenerative disorder, characterized by a multitude of pathological manifestations, prominently marked by the aggregation of amyloid beta. Recent investigations have revealed a compelling association between excessive adiposity and glial activation, further correlating with cognitive impairments. Additionally, alterations in levels of insulin-like growth factor 1 (IGF-1) have been reported in individuals with metabolic conditions accompanied by memory dysfunction. Hence, our research endeavors to comprehensively explore the impact of IGF-1 on the hippocampus and adipose tissue in the context of Alzheimer's disease. To address this, we have conducted an in-depth analysis utilizing APP/PS2 transgenic mice, recognized as a well-established mouse model for Alzheimer's disease. Upon administering IGF-1 injections to the APP/PS2 mice, we observed notable alterations in their behavioral patterns, prompting us to undertake a comprehensive transcriptomic analysis of both the hippocampal and adipose tissues. Our data unveiled significant modifications in the functional profiles of these tissues. Specifically, in the hippocampus, we identified changes associated with synaptic activity and neuroinflammation. Concurrently, the adipose tissue displayed shifts in processes related to fat browning and cell death signaling. In addition to these findings, our analysis enabled the identification of a collection of long non-coding RNAs and circular RNAs that exhibited significant changes in expression subsequent to the administration of IGF-1 injections. Furthermore, we endeavored to predict the potential roles of these identified RNA molecules within the context of our study. In summary, our study offers valuable transcriptome data for hippocampal and adipose tissues within an Alzheimer's disease model and posits a significant role for IGF-1 within both the hippocampus and adipose tissue.

Detection rate of IGF-1 variants and their implication to protein binding: study of over 240,000 patients.

OBJECTIVES: To determine the detection rate of IGF-1 variants in a clinical population and assess their implications. METHODS: IGF-1 variants were detected based on their predicted mass-to-charge ratios. Most variants were distinguished by their isotopic distribution and relative retention times. A67T and A70T were distinguished with MS/MS. Patient specimens with a detected variant were de-identified for DNA sequencing to confirm the polymorphism. RESULTS: Of the 243,808 patients screened, 1,099 patients containing IGF-1 variants were identified (0.45 %, or 4,508 occurrences per million). Seven patients were identified as homozygous or double heterozygous. Majority of variants (98 %) had amino acid substitutions located at the C-terminus (A62T, P66A, A67S, A67V, A67T, A70T). Isobaric variants A38V and A67V were detected more frequently in children than in adults. Six previously unreported variants were identified: Y31H, S33P, T41I, R50Q, R56K, and A62T. Compared with the overall population, z-score distribution of patients with IGF-1 variants was shifted toward negative levels (median z-score -1.4); however, it resembled the overall population when corrected for heterozygosity. Chromatographic peak area of some variants differed from that of the WT IGF-1 present in the same patient. CONCLUSIONS: In the IGF-1 test reports by LC-MS, the concentrations only account for half the total IGF-1 for patients with heterozygous IGF-1 variants. An IGF-1 variant may change the binding to its receptor and/or its binding proteins, affecting its activity and half-life in circulation. Variants located in or close to the C-domain may be pathogenic. Cross-species sequence comparison indicates that A38V and A70T may have some degree of pathogenicity.

Mechanism of NO2-induced migraine in rats: The exploration of the role of miR-653-3p/IGF1 axis.

Migraine is a severely disabling primary neurological disorder. Although some studies have confirmed that nitrogen dioxide (NO2) pollution increases the risk of migraine, and our previous study demonstrated the role of the channel protein transient receptor potential cation channel subfamily V member 1 (TRPV1) in NO2-induced migraine, the underlying mechanisms have not been fully elucidated. This study aimed to explore the intrinsic toxicity mechanism of NO2-induced migraines using transcriptome sequencing. First, the differentially expressed genes in NO2-induced migraine, insulin-like growth factor 1 (IGF1) and miRNA miR-653-3p were identified using RNA and small RNA sequencing, and a protein interaction network was constructed using STRING to explore the possible mechanisms. Next, the targeting relationship between miR-653-3p and IGF1 was determined. NO2-induced migraine was verified by silencing miR-653-3p and IGF1, independently or in combination to regulate the protein kinase B (AKT)/TRPV1 signalling pathway through the miR-653-3p/IGF1 axis. These results indicate that the key molecular mechanism of NO2-induced migraine may be that the miR-653-3p/IGF1 axis regulates the AKT/TRPV1 signalling pathway to induce migraine. The findings of this study will further elucidate the neurotoxic mechanism of NO2-induced migraines and lay a new experimental foundation for implementing migraine-related preventive and therapeutic control measures.

Insulin-like growth factors and aging: lessons from Laron syndrome.

The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway emerged in recent years as a key determinant of aging and longevity. Disruption of this network in different animal species, including flies, nematodes and mouse, was consistently associated with an extended lifespan. Epidemiological analyses have shown that patients with Laron syndrome (LS), the best-characterized disease under the umbrella of the congenital IGF1 deficiencies, seem to be protected from cancer. While aging and cancer, as a rule, are considered diametrically opposite processes, modern lines of evidence reinforce the notion that aging and cancer might, as a matter of fact, be regarded as divergent manifestations of identical biochemical and cellular underlying processes. While the effect of individual mutations on lifespan and health span is very difficult to assess, genome-wide screenings identified a number of differentially represented aging- and longevity-associated genes in patients with LS. The present review summarizes recent data that emerged from comprehensive analyses of LS patients and portrays a number of previously unrecognized targets for GH-IGF1 action. Our article sheds light on complex aging and longevity processes, with a particular emphasis on the role of the GH-IGF1 network in these mechanisms.

Effects of insulin-like growth factor-1 on the mRNA expression of estradiol receptors, steroidogenic enzymes, and steroid production in bovine follicles.

Insulin-like growth factor-1 (IGF-1) plays a crucial role in follicular growth and stimulates steroid hormone production in bovine follicles. Steroid hormones are synthesized through the actions of steroidogenic enzymes, specifically STAR, CYP11A1, HSD3B, and CYP19A1 in both theca cells (TCs) and granulosa cells (GCs), under the influence of gonadotropins. Particularly, estradiol 17ß (E2) assumes a central role in follicular development and selection by activating estrogen receptors ß (ESR2) in GCs. We assessed ESR2 mRNA expression in GCs of developing follicles and investigated the impact of IGF-1 on the mRNA expression of ESR2, CYP19A1, FSHR, and LHCGR, STAR, CYP11A1, and HSD17B in cultured GCs and TCs, respectively. Additionally, we assessed the influence of IGF-1 on androstenedione (A4), progesterone (P4), and testosterone (T) production in TCs. Small-sized follicles (< 6 mm) exhibited the highest levels of ESR2 mRNA expression, whereas medium-sized follicles (7-8 mm) displayed higher levels than large-sized follicles (≥ 9 mm) (P < 0.05). IGF-1 increased the mRNA expression of ESR2, CYP19A1, and FSHR in GCs of follicles of both sizes, except for FSHR mRNA in medium-sized follicles (P < 0.05). IGF-1 significantly elevated mRNA expression of LHCGR, STAR, CYP11A1, and CYP17B in TCs of small- and medium-sized follicles (P < 0.05). Moreover, IGF-1 augmented the production of A4 and P4 but had no impact on T production in TCs of small- and medium-sized follicles. Taken together, our findings indicate that IGF-1 upregulates steroidogenic enzymes and steroid hormone production, underscoring the crucial role of IGF-1 in follicle development and selection.

The IGF1 Signaling Pathway: From Basic Concepts to Therapeutic Opportunities.

Insulin-like growth factor 1 (IGF1) is a peptide growth factor with important functions in multiple aspects of growth, development and metabolism. The biological actions of IGF1 are mediated by the IGF1 receptor (IGF1R), a cell-surface protein that is evolutionarily related to the insulin receptor (InsR). The effects of IGF1 are moderated by a group of binding proteins (IGFBPs) that bind and transport the ligand in the circulation and extracellular fluids. In mechanistic terms, IGF1R function is linked to the MAPK and PI3K signaling pathways. Furthermore, IGF1R has been shown to migrate to cell nucleus, where it functions as a transcriptional activator. The co-localization of IGF1R and MAPK in the nucleus is of major interest as it suggests novel mechanistic paradigms for the IGF1R-MAPK network. Given its potent anti-apoptotic and pro-survival roles, and in view of its almost universal pattern of expression in most types of cancer, IGF1R has emerged as a promising molecular target in oncology. The present review article provides a concise overview of key scientific developments in the research area of IGF and highlights a number of more recent findings, including its nuclear migration and its interaction with oncogenes and tumor suppressors.

The effect of acromegaly on thyroid disease.

Long-term stimulation of thyroid follicular epithelium by high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in patients with acromegaly can lead to thyroid dysfunction, goiter, thyroid nodules, and even thyroid cancer and thyroid-associated ophthalmopathy (TAO). Excessive GH/IGF-1 promotes goiter and thyroid nodule formation, which can be reversed by normalizing the IGF-1 levels with surgery or medical treatment. Whether patients with acromegaly have an increased risk of thyroid cancer remains controversial, and routine thyroid ultrasonography and regular cancer screening are recommended in such cases, especially when the nodules possess malignant propensity. TAO is an autoimmune disease and newer treatments are being discovered against it. Recent studies have reported that the IGF-1 receptor (IGF-1R) plays an important role in the pathogenesis of TAO, and the IGF-1R inhibitor teprotumumab involves significantly improved disease endpoints in patients with active TAO. Thyroid-stimulating hormone (TSH) receptor (TSHR) and IGF-1R co-immunoprecipitate in orbital and thyroid tissues to form a functional complex; thus, combined therapy targeting TSHR and IGF-1R may be more effective than single therapy.

Combined use of microbubbles of various sizes and single-transducer dual-frequency ultrasound for safe and efficient inner ear drug delivery.

We have previously applied ultrasound (US) with microbubbles (MBs) to enhance inner ear drug delivery, with most experiments conducted using single-frequency, high-power density US, and multiple treatments. In the present study, the treatment efficacy was enhanced and safety concerns were addressed using a combination of low-power-density, single-transducer, dual-frequency US (I SPTA = 213 mW/cm2) and MBs of different sizes coated with insulin-like growth factor 1 (IGF-1). This study is the first to investigate the drug-coating capacity of human serum albumin (HSA) MBs of different particle sizes and their drug delivery efficiency. The concentration of HSA was adjusted to produce different MB sizes. The drug-coating efficiency was significantly higher for large-sized MBs than for smaller MBs. In vitro Franz diffusion experiments showed that the combination of dual-frequency US and large MB size delivered the most IGF-1 (24.3 ± 0.47 ng/cm2) to the receptor side at the second hour of treatment. In an in vivo guinea pig experiment, the efficiency of IGF-1 delivery into the inner ear was 15.9 times greater in animals treated with the combination of dual-frequency US and large MBs (D-USMB) than in control animals treated with round window soaking (RWS). The IGF-1 delivery efficiency was 10.15 times greater with the combination of single-frequency US and large size MBs (S-USMB) than with RWS. Confocal microscopy of the cochlea showed a stronger distribution of IGF-1 in the basal turn in the D-USMB and S-USMB groups than in the RWS group. In the second and third turns, the D-USMB group showed the greatest IGF-1 distribution. Hearing assessments revealed no significant differences among the D-USMB, S-USMB, and RWS groups. In conclusion, the combination of single-transducer dual-frequency US and suitably sized MBs can significantly reduce US power density while enhancing the delivery of large molecular weight drugs, such as IGF-1, to the inner ear.

Understanding Patterns of Life History Trait Covariation in an Untapped Resource, the Lab Mouse.

AbstractThrough artificial selection and inbreeding, strains of laboratory mice have been developed that vary in the expression of a single or suite of desired traits valuable to biomedical research. In addition to the selected trait(s), these strains also display variation in pelage color, body size, physiology, and life history. This article exploits the broad phenotypic variation across lab mouse strains to evaluate the relationships between life history and metabolism. Life history variation tends to exist along a fast-slow continuum. There has been considerable interest in understanding the ecological and evolutionary factors underlying life history variation and the physiological and metabolic processes that support them. Yet it remains unclear how these key traits scale across hierarchical levels, as ambiguous empirical support has been garnered at the intraspecific level. Within-species investigations have been thwarted by methodological constraints and environmental factors that obscure the genetic architecture underlying the hypothesized functional integration of life history and metabolic traits. In this analysis, we used the publicly available Mouse Phenome Database by the Jackson Laboratory to investigate the relationships among life history traits (e.g., body size, reproduction, and life span) and metabolic traits (e.g., daily energy expenditure and insulin-like growth factor 1 concentration). Our findings revealed significant variation in reproductive characteristics across strains of mice as well as relationships among life history and metabolic traits. We found evidence of variation along the fast-slow life history continuum, though the direction of some relationships among these traits deviated from interspecific predictions laid out in previous literature. Furthermore, our results suggest that the strength of these relationships are strongest earlier in life.

Effects and potential mechanisms of IGF1/IGF1R in the liver fibrosis: A review.

Liver fibrosis is a wound-healing response due to persistent liver damage and it may progress to cirrhosis and even liver cancer if no intervention is given. In the current cognition, liver fibrosis is reversible. So, it is of great significance to explore the related gene targets or biomarker for anti-fibrosis of liver. Insulin like growth factor 1 (IGF1) and IGF1 receptor (IGF1R) are mainly expressed in the liver tissues and play critical roles in the liver function. The present review summarized the role of IGF1/IGF1R and its signaling system in liver fibrosis and illustrated the potential mechanisms including DNA damage repair, cell senescence, lipid metabolism and oxidative stress that may be involved in this process according to the studies on the fibrosis of liver or other organs. In particular, the roles of IGF1 and IGF1R in DNA damage repair were elaborated, including membrane-localized and nucleus-localized IGF1R. In addition, for each of the potential mechanism in anti-fibrosis of liver, the signaling pathways of the IGF1/IGF1R mediated and the cell species in liver acted by IGF1 and IGF1R under different conditions were included. The data in this review will support for the study about the effect of IGF1/IGF1R on liver fibrosis induced by various factors, meanwhile, provide a basis for the study of liver fibrosis to focus on the communications between the different kinds of liver cells.