Locally Directed Recombinant Adeno- Associated Virus-Mediated IGF-1 Gene Therapy Enhances Osteochondral Repair and Counteracts Early Osteoarthritis In Vivo.

BACKGROUND: Restoration of osteochondral defects is critical, because osteoarthritis (OA) can arise. HYPOTHESIS: Overexpression of insulin-like growth factor 1 (IGF-1) via recombinant adeno-associated viral (rAAV) vectors (rAAV-IGF-1) would improve osteochondral repair and reduce parameters of early perifocal OA in sheep after 6 months in vivo. STUDY DESIGN: Controlled laboratory study. METHODS: Osteochondral defects were created in the femoral trochlea of adult sheep and treated with rAAV-IGF-1 or rAAV-lacZ (control) (24 defects in 6 knees per group). After 6 months in vivo, osteochondral repair and perifocal OA were assessed by well-established macroscopic, histological, and immunohistochemical scoring systems as well as biochemical and micro-computed tomography evaluations. RESULTS: Application of rAAV-IGF-1 led to prolonged (6 months) IGF-1 overexpression without adverse effects, maintaining a significantly superior overall cartilage repair, together with significantly improved defect filling, extracellular matrix staining, cellular morphology, and surface architecture compared with rAAV-lacZ. Expression of type II collagen significantly increased and that of type I collagen significantly decreased. Subchondral bone repair and tidemark formation were significantly improved, and subchondral bone plate thickness and subarticular spongiosa mineral density returned to normal. The OA parameters of perifocal structure, cell cloning, and matrix staining were significantly better preserved upon rAAV-IGF-1 compared with rAAV-lacZ. Novel mechanistic associations between parameters of osteochondral repair and OA were identified. CONCLUSION: Local rAAV-mediated IGF-1 overexpression enhanced osteochondral repair and ameliorated parameters of perifocal early OA. CLINICAL RELEVANCE: IGF-1 gene therapy may be beneficial in repair of focal osteochondral defects and prevention of perifocal OA.

IGF-1R mediates crosstalk between nasopharyngeal carcinoma cells and osteoclasts and promotes tumor bone metastasis.

BACKGROUND: Nasopharyngeal carcinoma (NPC) poses a significant health burden in specific regions of Asia, and some of NPC patients have bone metastases at the time of initial diagnosis. Bone metastasis can cause pathologic fractures and pain, reducing patients' quality of life, and is associated with worse survival. This study aims to unravel the complex role of insulin-like growth factor 1 receptor (IGF-1R) in NPC bone metastasis, offering insights into potential therapeutic targets. METHODS: We assessed IGF-1R expression in NPC cells and explored its correlation with bone metastasis. Experiments investigated the impact of osteoclast-secreted IGF-1 on the IGF-1R/AKT/S6 pathway in promoting NPC cell proliferation within the bone marrow. Additionally, the reciprocal influence of tumor-secreted Granulocyte-macrophage colony-stimulating factor (GM-CSF) on osteoclast differentiation and bone resorption was examined. The effects of IGF-1 neutralizing antibody, IGF-1R specific inhibitor (NVP-AEW541) and mTORC inhibitor (rapamycin) on nasopharyngeal carcinoma bone metastasis were also explored in animal experiments. RESULTS: Elevated IGF-1R expression in NPC cells correlated with an increased tendency for bone metastasis. IGF-1, secreted by osteoclasts, activated the IGF-1R/AKT/S6 pathway, promoting NPC cell proliferation in the bone marrow. Tumor-secreted GM-CSF further stimulated osteoclast differentiation, exacerbating bone resorption. The IGF-1 neutralizing antibody, NVP-AEW541 and rapamycin were respectively effective in slowing down the rate of bone metastasis and reducing bone destruction. CONCLUSION: The intricate interplay among IGF-1R, IGF-1, and GM-CSF highlights potential therapeutic targets for precise control of NPC bone metastasis, providing valuable insights for developing targeted interventions.

Association between serum insulin-like growth factor 1 levels and the improvements of cognitive impairments in a subgroup of schizophrenia: Preliminary findings.

BACKGROUND: Numerous studies have implicated abnormal insulin-like growth factor 1 (IGF-1) in the pathophysiology of schizophrenia, but findings have been inconsistent. METHODS: We conducted a meta-analysis to compare IGF-1 levels in schizophrenia patients with healthy controls and explored factors contributing to variability between estimates. In an independent sample (58 chronic schizophrenia patients and 30 healthy controls), we investigated differences in IGF-1 levels among schizophrenia subgroups with distinct cognitive profiles, identified using k-means clustering based on five cognitive domains from The Repeatable Battery for the Assessment of Neuropsychological Status. Associations between serum IGF-1 levels and clinical and neurocognitive improvements were also examined. RESULTS: The meta-analysis revealed significantly lower serum IGF-1 levels in schizophrenia patients compared to healthy controls, albeit with high heterogeneity. Medication status, BMI, and severity of negative symptoms were identified as potential contributors to this heterogeneity. In our independent study, antipsychotic treatment led to a significant increase in IGF-1 levels, and lower pre-treatment serum IGF-1 levels correlated with greater improvement in cognitive deficits, particularly in a subgroup with more severe cognitive symptoms. CONCLUSIONS: Our findings support the "IGF-1 deficiency hypothesis" in the pathogenesis of schizophrenia. Further research is crucial to elucidate the role of IGF-1 in the cognitive impairments associated with schizophrenia.

Pasireotide: potential treatment option for McCune-Albright-associated acromegaly.

Only 30% of patients with McCune-Albright syndrome (MAS)-associated acromegaly achieve biochemical control under first-generation somatostatin receptor ligands (fg-SRLs), while pegvisomant fails to normalize insulin-like growth factor 1 (IGF-I) in >20% of cases. Here, we report all the patients with MAS-associated acromegaly treated with pasireotide long-acting release (LAR) in our center. Pasireotide LAR 20 mg/month resulted in rapid and long-term IGF-I normalization in patients #1 and #3. Patient #3 was resistant to fg-SRLs, while patient #1 was also controlled on fg-SRLs. In patient #2, resistant to fg-SRLs and uncontrolled on pegvisomant 40 mg/day combined with cabergoline 0.5 mg/day, pegvisomant was replaced with pasireotide LAR 40 mg/month, resulting in the near normalization of IGF-I levels. All 3 patients developed intermittent impaired fasting glucose, without the need for glucose-lowering drugs. Thus, pasireotide LAR is clearly useful as third-line therapy, and potentially even as second-line therapy, in MAS-associated acromegaly.

Evaluation of Stem Cell Laden Collagen + Polycaprolactone + Multi-Walled Carbon Nano-Tubes Nano-Neural Scaffold with and Without Insulin Like Growth Factor-I For Sciatic Nerve Regeneration Post Crush Injury in Wistar Rats.

BACKGROUND/AIMS: All body functions are activated, synchronized and controlled by a substantial, complex network, the nervous system. Upon injury, pathophysiology of the nerve injury proceeds through different paths. The axon may undergo a degenerative retraction from the site of injury for a short distance unless the injury is near to the cell body, in which case it continues to the soma and undergoes retrograde neuronal degeneration. Otherwise, the distal section suffers from Wallerian degeneration, which is marked by axonal swelling, spheroids, and cytoskeleton degeneration. The objective of the study was to evaluate the potential of mesenchymal stem cell laden neural scaffold and insulin-like growth factor I (IGF-I) in nerve regeneration following sciatic nerve injury in a rat model. METHODS: The animals were anaesthetized and a cranio-lateral incision over left thigh was made. Sciatic nerve was exposed and crush injury was introduced for 90 seconds using haemostat at second locking position. The muscle and skin were sutured in routine fashion and thus the rat model of sciatic crush injury was prepared. The animal models were equally distributed into 5 different groups namely A, B, C, D and E and treated with phosphate buffer saline (PBS), carbon nanotubes based neural scaffold only, scaffold with IGF-I, stem cell laden scaffold and stem cell laden scaffold with IGF-I respectively. In vitro scaffold testing was performed. The nerve regeneration was assessed based on physico-neuronal, biochemical, histopathological examination, and relative expression of NRP-1, NRP-2 and GAP-43 and scanning electron microscopy. RESULTS: Sciatic nerve injury model with crush injury produced for 90 seconds was standardized and successfully used in this study. All the biochemical parameters were in normal range in all the groups indicating no scaffold related changes. Physico-neuronal, histopathological, relative gene expression and scanning electron microscopy observations revealed appreciable nerve regeneration in groups E and D, followed by C and B. Restricted to no regeneration was observed in group A. CONCLUSION: Carbon nanotubes based scaffold provided electro-conductivity for proper neuronal regeneration while rat bone marrow-derived mesenchymal stem cells were found to induce axonal sprouting, cellular transformation; whereas IGF-I induced stem cell differentiation, myelin synthesis, angiogenesis and muscle differentiation.

Observation of Serological Index and Efficacy of Abiraterone Hydrochloride Tablets Combined with Endocrine Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: This study reviewed and analysed the serological indexes, clinical efficacy and common clinical indexes of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with combination of abiraterone hydrochloride tablets and endocrine therapy. METHOD: This study is a retrospective analysis. A total of 133 mCRPC patients who were admitted to our hospital from January 2019 to December 2021 were selected as the study subjects. The patients were categorised into the experimental group (n = 51) and control group (n = 82) according to their treatment method. The control group was treated with docetaxel combined with endocrine therapy, whilst the experimental group was treated with combination therapy with abiraterone hydrochloride tablets. Subsequently, the clinical data of the two groups, including serum insulin-like growth factor-1 (IGF-1), human glandular kallikrein 2 (hK2), prostate specific antigen (PSA), vascular endothelial growth factor (VEGF) and serum carcinoembryonic antigen (CEA), were analysed. RESULT: The overall response rate of the experimental group (84.3%) was higher than that of the control group (72.0%). The serum levels of CEA, total prostate specific antigen, free prostate specific antigen, testosterone and androgen receptor splice variant 7 in both groups were lower than those of before treatment, and the values obtained by the experimental group were lower than those of the control group (p < 0.05). After treatment, the levels of CD3+, CD4+ and CD4+/CD8+ in both groups were higher than those before treatment, and the levels of CD8+, IGF-1, hK2, PSA and VEGF in the two groups decreased after treatment (p < 0.05). CONCLUSIONS: The use of abiraterone hydrochloride tablet combined with endocrine therapy for patients with mCRPC is effective and can improve clinical symptoms and serum cytokine levels.

Insulin Growth Factor-1 Status in Hidradenitis Suppurativa: A French Institutional Pilot Study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease of the follicles in the apocrine glands and is associated with a deficiency in the innate immunity of the skin. It is characterized by the occurrence of nodules, abscesses, fistulas, scars. OBJECTIVE: Although a relationship has already been demonstrated between HS and innate immunity, IGF-1 status in patients with HS is still unknown. The objective of this pilot study was to determine IGF-1 status in patients with HS as well as its potential relationship with the clinical profile of the disease. METHODS: This monocentric and cross-sectional study involved 39 patients hospitalized at the Dermatology Department of CHU Nantes between November 2014 and January 2018. Clinical data and IGF1 status were collected during the follow-up consultation. RESULTS: Forty-nine percent of the patients had very low levels of IGF-1. At the clinical level, these patients were young and with a short duration of disease. The major difference was that IGF1-deficient patients had a higher BMI than others. The others factors differing between the two patient groups did not reach statistical significance. CONCLUSION: This exploratory pilot study indicates that HS with a low level of IGF-1 could represent a specific phenotype of patients with HS. These preliminary results have to be confirmed with a larger cohort, as they could have practical consequences in the therapeutic care of these patients.

Challenges in the care of individuals with severe primary insulin-like growth factor-I deficiency (SPIGFD): an international, multi-stakeholder perspective.

BACKGROUND: Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care. OBJECTIVE: To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally. METHODS: An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD. RESULTS: As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing. CONCLUSIONS: To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care. Medical writing support was industry-sponsored.

3M syndrome: Evaluating the clinical and laboratory features and the response of the growth hormone treatment: Single center experience.

INTRODUCTION & OBJECTIVE: 3 M Syndrome is a rarely encountered autosomal recessive syndrome characterized by low birth weight, severe postnatal growth deficiency, and minor dysmorphic abnormalities. 3 M-related short stature has been attributed to the resistance to growth hormone (GH) to a certain extent rather than to GH deficiency. The resistance to GH, on the other hand, has been associated with impaired protein scaffolding, transport, and p53-mediated apoptosis at the IGF-1 post-receptor pathway. In this context, the objective of this study is to evaluate the clinical, laboratory, and genetic characteristics of the patients with 3 M syndrome, detect the mutations frequently observed in these patients, and assess their response to GH treatment. MATERIAL&METHODS: The sample of this single-center study consisted of patients diagnosed with 3 M syndrome based on genetic tests between 2007 and 2021. Patients' clinic, laboratory, and genetic characteristics pertaining to the time of admission and follow-up were recorded. All patients except one underwent a growth hormone stimulation test (GHST) (Levo-dopa or insulin tolerance test). Insulin-like growth factor (IGF) generation test was performed on those with sufficient GHST results (0.1 mg/kg/day for four days). RESULTS: The median age of the patients, five females and three males, was 2.8 (0.25-8.12) years at admission. All but one patient were small for gestational age (SGA). The patient with normal birth weight was the baby of a diabetic mother. Obscurin-like 1 (OBSL1) variant was detected in all cases. The median height standard deviation score (SDS) at admission was -4.94 ((-5.63)- (-3.27)) SDS, and the median midparenteral height SDS was -1.27 SDS ((-3.1)- (0.34)). All patients were prepubertal at admission. The GHST response was sufficient in five cases. IGF generation test was performed in three cases. Seven patients received GH therapy (35-57 µg/kg/day). Five of these patients discontinued GH therapy since their growth velocity (GV) fell below normal during treatment. In addition, one case discontinued GH therapy because her IGF-1 value was>2 SDS, and another case received gonadotropin-releasing hormone (GnRH) analogs together with GH therapy. The median age and height SDS of the patients were 10.1 (1.79-18) years and -5.09 SDS ((-7.11)- (2.45)), respectively, as of the last follow-up visit. The height SDS values of the two cases that reached the final height were -7.11 SDS and -3.39 SDS. There were no side effects of GH treatment. CONCLUSION: The study findings indicated a good GV during the early stages of the long-term GH treatment administered to patients with 3 M syndrome. However, response to GH therapy decreased in the following years, and the desired improvement in height SDS could not be achieved in patients who reached their final heights. Taken together with the literature data, it has been concluded that initiating GH therapy in the prepubertal period provided better outcomes than after puberty.

Administration of insulin like growth factor I (IGFI) lowers serum lipoprotein(a)-impact on atherosclerotic cardiovascular disease.

Insulin like growth factor I (IGFI) secreted by the liver upon stimulation by pituitary growth hormone (GH) acts as the most important growth stimulating hormone in children. The present review presents evidence that among its additional metabolic effects, IGF-I suppresses the synthesis of lipoprotein(a) [Lp(a)], an independent risk factor for atherosclerotic cardiovascular disease. In view of this property, it is suggested that the addition of IGF-I to the armamentarium of hyperlipoproteinemia treatment should be considered.

The effect of anamorelin (ONO-7643) on cachexia in cancer patients: Systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Cachexia is associated with increased morbidity and mortality rates in patients with cancer. This meta-analysis aims to explore the effect of anamorelin on cancer cachexia markers. METHODS: We searched MEDLINE/PubMed, SCOPUS, and WOS from their inception until 5 June 2022. A systematic search was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. We included trials investigating the effect of anamorelin on body weight, lean body mass, fat mass, insulin-like growth factor 1 (IGF-1), handgrip, quality of life insulin-like growth factor-binding protein 3 (IGFBP-3), and in patients with cancer. A random-effects model was run to pooled results. RESULTS: Five articles providing 1331 participants were analyzed in this study. Pooled analysis revealed a significant increase in body weight (weighted mean difference (WMD): 1.56 kg, 95% confidence interval (CI): 1.20, 1.92; I2= 0%), lean body mass (WMD: 1.36 kg, 95% CI: 0.85, 1.86; I2= 53.1%), fat mass (WMD: 1.02 kg, 95% CI: 0.51, 1.53; I2= 60.7%), IGF-1 (WMD: 51.16 ng/mL, 95% CI: 41.42, 60.90, I2= 0%), and IGFBP-3 (WMD: 0.43 µg/mL, 95% CI: 0.17, 0.68, I2= 98.6%). Results showed no significant increase in appetite when analysis run on all studies without considering different doses 0.29 (95% CI: -0.30, 0.89, I2= 73.8%), however, there was a significant increase in appetite without heterogeneity and inconsistency 0.59 (95% CI: 0.32, 0.86; I2= 0%) in the 100 mg/day group compared to anamorelin non-user. CONCLUSIONS: Patients with cancer who receive anamorelin as a treatment for cachexia showed a significant increase in body weight, lean body mass, fat mass, IGF-1, and IGFBP-3.

Repositioning of Anti-Diabetic Drugs against Dementia: Insight from Molecular Perspectives to Clinical Trials.

Insulin resistance as a hallmark of type 2 DM (T2DM) plays a role in dementia by promoting pathological lesions or enhancing the vulnerability of the brain. Numerous studies related to insulin/insulin-like growth factor 1 (IGF-1) signaling are linked with various types of dementia. Brain insulin resistance in dementia is linked to disturbances in Aß production and clearance, Tau hyperphosphorylation, microglial activation causing increased neuroinflammation, and the breakdown of tight junctions in the blood-brain barrier (BBB). These mechanisms have been studied primarily in Alzheimer's disease (AD), but research on other forms of dementia like vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) has also explored overlapping mechanisms. Researchers are currently trying to repurpose anti-diabetic drugs to treat dementia, which are dominated by insulin sensitizers and insulin substrates. Although it seems promising and feasible, none of the trials have succeeded in ameliorating cognitive decline in late-onset dementia. We highlight the possibility of repositioning anti-diabetic drugs as a strategy for dementia therapy by reflecting on current and previous clinical trials. We also describe the molecular perspectives of various types of dementia through the insulin/IGF-1 signaling pathway.

Insulin-like growth factor-1 replacement therapy after extremely premature birth: An opportunity to optimize lifelong lung health by preserving the natural sequence of lung development.

The past decades have seen markedly improved survival of increasingly immature preterm infants, yet major health complications persist. This is particularly true for bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, which has become the most common sequelae of prematurity and a significant predictor of respiratory morbidity throughout childhood as well as adult life, neurodevelopmental disability, cardiovascular disease, and even death. The need for novel approaches to reduce BPD and related complications of prematurity has never been more critical. Thus, despite major advances in the use of antenatal steroids, surfactant therapy, and improvements in respiratory support, there is a persistent need for developing therapeutic strategies that more specifically reflect our growing understanding of BPD in the post-surfactant age, or the "new BPD." In contrast with the severe lung injury leading to marked fibroproliferative disease from the past, the "new BPD" is primarily characterized by an arrest of lung development as related to more extreme prematurity. This distinction and the continued high incidence of BPD and related sequelae suggest the need to identify therapies that target critical mechanisms that support lung growth and maturation in conjunction with treatments to improve respiratory outcomes across the lifespan. As the prevention of BPD and its severity remains a primary goal, we highlight the concept from preclinical and early clinical observations that insulin-like growth factor 1 (IGF-1) can potentially support the natural sequence of lung growth as a replacement therapy after preterm birth. Data supporting this hypothesis are robust and include observations that low IGF-1 levels persist after extremely preterm birth in human infants and strong preclinical data from experimental models of BPD highlight the therapeutic benefit of IGF-1 in reducing disease. Importantly, phase 2a clinical data in extremely premature infants where replacement of IGF-1 with a human recombinant human IGF-1 complexed with its main IGF-1 binding protein 3, significantly reduced the most severe form of BPD, which is strongly associated with multiple morbidities that have lifelong consequences. As physiologic replacement therapy of surfactant heralded the success of reducing acute respiratory distress syndrome in preterm infants, the paradigm has the potential to become the platform for discovering the next generation of therapies like IGF-1, which becomes deficient after extremely premature birth where endogenous production by the infant is not sufficient to maintain the physiologic levels adequate to support normal organ development and maturation.

The efficacy of metformin as adjuvant to chemotherapy on IGF levels in non-diabetic female patients with progressive and non-progressive metastatic breast cancer.

OBJECTIVE: Some studies have shown that metformin inhibits the proliferation of breast cancer (BC) cells via multiple ways. One of these mechanisms is through the indirect control of the IGF-route mediated via the activation of the AMPK-LKB1 pathway in the liver, which leads to a decrease in blood glucose and insulin levels. The objective of this study was to investigate the effects of metformin as adjuvant to chemotherapy on IGF levels in female patients with progressive and non-progressive metastatic BC. PATIENTS AND METHODS: In this trial, 107 women receiving chemotherapy for metastatic breast cancer (MBC) were divided into two groups: the metformin group received 500 mg of metformin twice daily, whereas the control group did not receive any metformin. All patients received chemotherapy according to the South Egypt Cancer Institute's (SECI) established regimen. The level of IGF-1 was determined in the blood at the initiation of therapy (baseline) and at six months post treatment. RESULTS: No substantial differences were noted regarding IGF-1 levels in both groups at baseline (IGF-1 average level was 40.74 ± 36.16 vs. 32.06 ± 20.00 in the metformin and the placebo group, respectively, p = 0.462). While after six months, the mean IGF-1 level was 37.62 ± 31.35 vs. 39.12 ± 2 5.93 in the metformin and placebo groups, respectively, (p = 0.170). CONCLUSIONS: Metformin as an adjuvant to chemotherapy in MBC patients had no significant effect on reducing IGF-l levels which promotes the inhibition of the proliferation of BC cells in MBC patients.

Growth hormone secretagogues modulate inflammation and fibrosis in mdx mouse model of Duchenne muscular dystrophy.

Introduction: Growth hormone secretagogues (GHSs) exert multiple actions, being able to activate GHS-receptor 1a, control inflammation and metabolism, to enhance GH/insulin-like growth factor-1 (IGF-1)-mediated myogenesis, and to inhibit angiotensin-converting enzyme. These mechanisms are of interest for potentially targeting multiple steps of pathogenic cascade in Duchenne muscular dystrophy (DMD). Methods: Here, we aimed to provide preclinical evidence for potential benefits of GHSs in DMD, via a multidisciplinary in vivo and ex vivo comparison in mdx mice, of two ad hoc synthesized compounds (EP80317 and JMV2894), with a wide but different profile. 4-week-old mdx mice were treated for 8 weeks with EP80317 or JMV2894 (320 µg/kg/d, s.c.). Results: In vivo, both GHSs increased mice forelimb force (recovery score, RS towards WT: 20% for EP80317 and 32% for JMV2894 at week 8). In parallel, GHSs also reduced diaphragm (DIA) and gastrocnemius (GC) ultrasound echodensity, a fibrosis-related parameter (RS: ranging between 26% and 75%). Ex vivo, both drugs ameliorated DIA isometric force and calcium-related indices (e.g., RS: 40% for tetanic force). Histological analysis highlighted a relevant reduction of fibrosis in GC and DIA muscles of treated mice, paralleled by a decrease in gene expression of TGF-ß1 and Col1a1. Also, decreased levels of pro-inflammatory genes (IL-6, CD68), accompanied by an increment in Sirt-1, PGC-1α and MEF2c expression, were observed in response to treatments, suggesting an overall improvement of myofiber metabolism. No detectable transcript levels of GHS receptor-1a, nor an increase of circulating IGF-1 were found, suggesting the presence of a novel receptor-independent mechanism in skeletal muscle. Preliminary docking studies revealed a potential binding capability of JMV2894 on metalloproteases involved in extracellular matrix remodeling and cytokine production, such as ADAMTS-5 and MMP-9, overactivated in DMD. Discussion: Our results support the interest of GHSs as modulators of pathology progression in mdx mice, disclosing a direct anti-fibrotic action that may prove beneficial to contrast pathological remodeling.

Long-term opioid treatment and endocrine measures in chronic non-cancer pain patients.

BACKGROUND: The prevalence of chronic non-cancer pain (CNCP) has increased dramatically the past decades, which combined with indiscriminate use of prescribed opioids has become a public health problem. Endocrine dysfunction may be a complication of long-term opioid treatment (L-TOT), but the evidence is limited. This study aimed at investigating the associations between L-TOT and endocrine measures in CNCP patients. METHODS: Cortisol (spot and after stimulation), thyrotropin (TSH), thyroxin (T4), insulin-like growth factor 1 (IGF-1), prolactin (PRL), 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone (DHEAS), sex hormone-binding globulin (SHBG), total testosterone (TT) and free testosterone (fT) were measured. Group comparisons were done between CNCP patients in L-TOT and controls as well as between patients on high- or low-dose morphine equivalents. RESULTS: Eighty-two CNCP patients (38 in L-TOT and 44 controls not receiving opioids) were included. Low TT (p = 0.004) and fT concentrations (p < 0.001), high SHBG (p = 0.042), low DEAS (p = 0.017) and low IGF-1 (p = 0.003) in men were found when comparing those in L-TOT to controls and high PRL (p = 0.018), low IGF-1 standard deviation score (SDS) (p = 0.006) along with a lesser, but normal cortisol response to stimulation (p = 0.016; p = 0.012) were found when comparing L-TOT to controls. Finally, a correlation between low IGF-1 levels and high opioid dose was observed (p < 0.001). CONCLUSIONS: Our study not only supports previous findings but even more interestingly disclosed new associations. We recommend future studies to investigate endocrine effects of opioids in larger, longitudinal studies. In the meanwhile, we recommend monitoring endocrine function in CNCP patients when prescribing L-TOT. SIGNIFICANCE: This clinical study found associations between L-TOT, androgens, growth hormone and prolactin in patients with CNCP compared to controls. The results support previous studies as well as add new knowledge to the field, including an association between high opioid dose and low growth hormone levels. Compared to existing research this study has strict inclusion/exclusion criteria, a fixed time period for blood sample collection, and adjustments for potential confounders, which has not been done before.

IGF1 synthesis after CO2 fractional laser resurfacing (FLR): New insights in the treatment of scalp actinic keratoses.

OBJECTIVES: Actinic keratosis have a high risk of progression to a squamous cell carcinoma. Insulin-like growth factor 1 and its receptor play a relevant role in restoring repair of ultraviolet-induced cell damage. This pathway is reduced in patients older than 65 years. Ablative fractional laser resurfacing could normalize insulin-like growth factor 1 (IGF-1) secretion in elderly by recruiting new fibroblasts. The aim of the study is to evaluate restoration of IGF1 values by PCR in senescent fibroblasts after ablative fractional laser resurfacing. METHODS: We enrolled 30 male patients with multiple actinic keratosis on the scalp, equally divided into two mirror areas of up to 50 cm2 , treating only the right one. We performed one skin biopsy for each area 30 days after treatment. Real-time PCR in fibroblasts was performed to assess the change in IGF1. At baseline and after 6 months, in vivo reflectance confocal microscopy examination was performed in all patients. RESULTS: IGF1 values were increased in the treated side by about 60%. The right areas had fairly complete resolution of actinic keratosis at the last follow-up visit after 6 months with no appearance of new lesions. The mean number of actinic keratosis in the right area was reduced by more than 75% at four- and six-follow-up visits compared to the left area. The improvement in the right area was also evidenced by lower values of the mean AKASI (actinic keratosis area and severity index) score. Reflectance confocal microscopy showed a reduction of keratinocytic disarray and scales after treatment. DISCUSSION: Taken together, all the clinical, laboratory, and in vivo results of our study allowed us to confirm that ablative fractional laser resurfacing is a valuable tool for the treatment of actinic keratosis and cancerization field, both for the management of clinically evident lesions and for preventing the occurrence of squamous cell carcinoma.

Prospects for the Use of Intranasally Administered Insulin and Insulin-Like Growth Factor-1 in Cerebral Ischemia.

Current approaches to the treatment of stroke have significant limitations, and neuroprotective therapy is ineffective. In view of this, searching for effective neuroprotectors and developing new neuroprotective strategies remain a pressing topic in research of cerebral ischemia. Insulin and insulin-like growth factor-1 (IGF-1) play a key role in the brain functioning by regulating the growth, differentiation, and survival of neurons, neuronal plasticity, food intake, peripheral metabolism, and endocrine functions. Insulin and IGF-1 produce multiple effects in the brain, including neuroprotective action in cerebral ischemia and stroke. Experiments in animals and cell cultures have shown that under hypoxic conditions, insulin and IGF-1 improve energy metabolism in neurons and glial cells, promote blood microcirculation in the brain, restore nerve cell functions and neurotransmission, and produce the anti-inflammatory and antiapoptotic effects on brain cells. The intranasal route of insulin and IGF-1 administration is of particular interest in the clinical practice, since it allows controlled delivery of these hormones directly to the brain, bypassing the blood-brain barrier. Intranasally administered insulin alleviated cognitive impairments in elderly people with neurodegenerative and metabolic disorders; intranasally administered insulin and IGF-1 promoted survival of animals with ischemic stroke. The review discusses the published data and results of our own studies on the mechanisms of neuroprotective action of intranasally administered insulin and IGF-1 in cerebral ischemia, as well as the prospects of using these hormones for normalization of CNS functions and reduction of neurodegenerative changes in this pathology.

Resveratrol and Dulaglutide ameliorate adiposity and liver dysfunction in rats with diet-induced metabolic syndrome: Role of SIRT-1 / adipokines / PPARγ and IGF-1.

BACKGROUND: Adiposity and non-alcoholic fatty liver disease (NAFLD) are common characteristics of metabolic syndrome (MS). Understanding the underlying pathogenesis is crucial for the development of new remedies. Resveratrol controls obesity and glycemic disorders in patients with MS. OBJECTIVES: This study aimed to evaluate the effect of resveratrol and dulaglutide on adipose tissues and liver in rats with MS, declaring their possible mechanisms. METHODS: Rats allocated as Control, MS (induced by a high fat/ high sucrose diet for eight weeks), MS + Resveratrol (30 mg/kg/day orally), and MS + Dulaglutide (0.6 mg/kg twice weekly SC); drugs administration was in the last four weeks. Serum biochemical measurements were done. Liver and visceral fat were processed for biochemistry, histopathology, and immunohistochemistry. RESULTS: MS results demonstrated significantly increased systolic and diastolic blood pressure, anthropometric measurements, serum levels of alanine aminotransferase (ALT), glycemic indices, and lipids with decreased HDL-C. Tissue levels of leptin, malondialdehyde (MDA), and TNF-α reactivity significantly increased. Expression of adiponectin, PPARγ, and insulin growth factor-1 (IGF-1) decreased. Also, Western blotting mRNA gene expression of liver SIRT-1 was down-regulated. Resveratrol and dulaglutide significantly and effectively reversed MS complexity, ameliorating all findings, particularly NAFLD and adiposity-induced inflammation. Resveratrol significantly appears superior to dulaglutide regarding the effects on hemodynamics, lipids, adipokines, IGF-1 levels, and adipocyte size. Parallel, dulaglutide has more influence on glycemic control. CONCLUSION: Protective effects of the drugs may be through correlations between SIRT-1/adipokines/IGF-1 and PPARγ, improving the cross-talk between insulin resistance, obesity markers, liver dysfunction, and TNF-α. Promising multi-beneficial therapies of resveratrol or dulaglutide in MS are recommended clinically for this purpose. Showing the Experimental Design.

An open-label extension of a phase 2 dose-finding study of once-weekly somatrogon vs. once-daily Genotropin in children with short stature due to growth hormone deficiency: results following 5 years of treatment.

OBJECTIVES: Somatrogon is a long-acting recombinant human growth hormone (GH) employed as a once-weekly treatment for children with GH deficiency (GHD). A 12-month, phase 2 study of once-weekly somatrogon vs. once-daily GH (Genotropin®) was initiated, after which participants could enroll into an open-label extension (OLE) evaluating the safety and efficacy of long-term somatrogon treatment. METHODS: There were five study periods, Periods I and II were 6 months each while Periods III, IV, and V were 12 months each. In the main study (Periods I and II), 53 prepubertal children with GHD were randomized to once-weekly somatrogon (0.25, 0.48, or 0.66 mg/kg/week) or once-daily Genotropin (0.034 mg/kg/day); 48 continued into the OLE, consisting of Period III (original somatrogon dose; Genotropin recipients randomized to one of three somatrogon doses), Period IV (somatrogon 0.66 mg/kg/week), and Period V (prefilled somatrogon pen [0.66 mg/kg/week]). RESULTS: At the end of Period III, the mean ± SD annual height velocity (HV) for 0.25, 0.48, and 0.66 mg/kg/week somatrogon groups was 7.73 ± 1.89, 7.54 ± 1.28, and 8.81 ± 1.12 cm/year, respectively; HV was sustained during Periods IV/V. Height SD scores (SDS) showed progressive improvement throughout the OLE, regardless of initial cohort assignment, approaching the normal range (-0.69 ± SD 0.87) at the end of Period V Year 1. Mild or moderate treatment-emergent adverse events were reported in 81.3% of participants, most unrelated to study drug. CONCLUSIONS: Up to 5 years of once-weekly somatrogon was well tolerated and resulted in sustained improvement in height SDS and delta height SDS in prepubertal short children with GHD.