Effect of Aerosol Inhalation Combined With a Vibration Expectoration Machine on Sputum Volume, IGF-1, α1-AT and PDGF-B in Patients With Chronic Obstructive Pulmonary Emphysema.

Objective: Aerosol inhalation is commonly used in the treatment of chronic obstructive pulmonary emphysema (COPE). This study aimed to evaluate the effectiveness of aerosol inhalation combined with a vibration expectoration machine on COPE. Methods: From June 2019 to June 2020, 110 patients receiving COPE treatment in Linyi Central Hospital in China were included in this randomized controlled trial. All patients were randomly assigned into one of two groups using the random number table. A total of 55 patients were given aerosol inhalation combined with the use of a vibration expectoration machine in the study group, and 55 patients were given aerosol inhalation alone in the control group. The general data, clinical efficacy arterial blood gas index, pulmonary function index and serum levels of insulin-like growth factor 1 (IGF-1), alpha 1 antitrypsin (α1-AT) and platelet-derived growth factor-B (PDGF-B) were compared. Results: There was no difference in baseline characteristics between the 2 groups (P > .05). After treatment, the clinical efficacy in the study group was significantly higher than in the control group (96.36% vs 81.82%, respectively; P = .023), daily sputum production in the study group was significantly higher compared with the control group (80.92 ± 10.29 vs 58.63 ± 9.02 ml, respectively; P < .001) and hospitalization time was significantly reduced in the study group (11.87 ± 1.76 vs 17.62 ± 1.92 days, respectively; P < .001). In addition, the respiratory rate was significantly lower in the study group (17.43 ± 1.61 vs 22.08 ± 3.25, respectively; P < .001). Partial pressure of oxygen (P[O2]) was significantly higher (76.29 ± 7.34 vs 66.81 ± 7.93 mmHg, respectively; P < .001) and partial pressure of carbon dioxide (P[CO2]) was significantly lower (34.82 ± 6.02 vs 39.83 ± 6.01 mmHg respectively; P < .001) in the study group compared with the control group. In addition, forced expiratory volume in the first second (FEV1) (1.79 ± 0.36 vs 1.66 ± 0.28 L, respectively), forced vital capacity (FVC) (2.58 ± 0.28 vs 2.42 ± 0.11 L, respectively), forced expiratory volume in the first second as a percentage of the predicted value (FEV1%pred) (65.32 ± 4.03 vs 59.83 ± 4.76 L, respectively) and maximal mid-expiratory flow (MMEF) (1.51 ± 0.27% vs 1.36 ± 0.12%, respectively) were all significantly increased after treatment in the study group compared with the control group (all P < .001). The IGF-1 (104.92 ± 11.27 vs 137.83 ± 11.02 ng/mL, respectively) and PDGF-B (124.39 ± 14.29 vs 249.93 ± 33.49 ng/L, respectively) were significantly reduced in the study group after treatment (all P < .001). The α1-AT (2.82 ± 0.38 vs 2.17 ± 0.22 g/L, respectively) were significantly increased after treatment in the study group compared with the control group. Conclusion: Aerosol inhalation combined with the use of a vibration expectoration machine is worthy of clinical application, and can effectively improve outcomes in patients with COPE.

Fuzheng Jiedu Decoction Induces Apoptosis and Enhances Cisplatin Efficacy in Ovarian Cancer Cells In Vitro and In Vivo through Inhibiting the PI3K/AKT/mTOR/NF-κB Signaling Pathway.

Objectives: This study is aimed at investigating the anticancer activity of Fuzheng Jiedu decoction (FJD) alone or in combination with cisplatin in ovarian cancer (OC) models, as well as its underlying mechanisms of action. Methods: The anticancer activities of FJD, cisplatin, and the combination of the PI3K inhibitor (LY294002, LY) or activator (IGF-1) were evaluated in OC cell lines in vitro and in a SKOV3 xenograft mouse model in vivo. The cell proliferation and invasion ability were measured using MTT, EdU, and transwell assays, respectively. The cell apoptosis was examined by flow cytometry and JC-1 assays. The expression levels of the Bcl-2 family and the PI3K/AKT/mTOR/NF-κB pathway-related proteins were analyzed by Western blot. Results: The in vivo and in vitro studies showed that FJD administration could significantly inhibit cell proliferation and promote cell apoptosis in two OC cell lines SKOV3 and 3AO and partially decreased the tumor volumes and weights. In addition, FJD could significantly downregulate the protein levels of p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, NF-κB, p38, and Bcl-2 and upregulate the Bax, Cyt-C, and cleaved caspase-3 in OC tumor tissues and cells. FJD cotreatment increased the efficacy of cisplatin, including inhibiting OC cell proliferation and invasion, promoting cell apoptosis, and inhibiting the PI3K/AKT/mTOR signaling pathway, while this enhancement was suppressed by IGF-1. Similarly, LY also enhanced the anticancer efficacy of cisplatin. Conclusions: This study indicated that FJD could improve the efficacy of cisplatin by inhibiting the PI3K/AKT/mTOR/NF-κB signaling pathway. It is suggested that FJD may be a valuable adjuvant drug for the treatment of OC.

Pretreatment with mechano growth factor E peptide attenuates osteoarthritis through improving cell proliferation and extracellular matrix synthesis in chondrocytes under severe hypoxia.

Osteoarthritis (OA) is characterized by pain and declining gait function associated with degeneration of cartilage. A severe hypoxic environment occurs due to tissue injury in the joint cavity and may aggravate the development of OA. In this study, the effects of severe hypoxia and treatment with mechano growth factor (MGF) E peptide on metabolism of the extracellular matrix (ECM) during the progression of OA were determined. The results showed that cell viability, cell proliferation, and type II collagen expression in chondrocytes were significantly inhibited by cobalt chloride (CoCl2)-simulated severe hypoxia, whereas cell apoptosis and expression levels of hypoxia inducible factor 1 alpha, type I collagen, and matrix metalloproteinases 1/13 were clearly induced. Pretreatment with MGF E peptide reduced the abovementioned adverse effects induced by CoCl2-simulated severe hypoxia in chondrocytes. Pretreatment also upregulated the proliferation of chondrocytes under severe hypoxia through the PI3K-Akt and MEK-ERK1/2 signaling pathways. In a rat model of monosodium iodoacetate (MIA)-induced OA. MIA treatment induced tissue necrosis and cartilage degeneration, and histological score was significantly decreased. The levels of type II collagen and aggrecan were reduced after MIA treatment for 4 or 6 weeks, and abnormal distribution of ECM occurred in the inner epicondyle after 6 weeks. MGF E peptide also reduced the progression of MIA-induced OA by retarding cartilage degeneration, upregulating type II collagen synthesis, and improving ECM distribution after 4 or 6 weeks. Our findings suggest that MGF attenuates the progression of OA, and thus may be applied for the treatment of OA in the clinic.

Somatotropic Axis Dysfunction in Non-Alcoholic Fatty Liver Disease: Beneficial Hepatic and Systemic Effects of Hormone Supplementation.

BACKGROUND: Somatotropic axis dysfunction associated with non-alcoholic fatty liver disease (NAFLD) has potential multisystemic detrimental effects. Here, we analysed the effects of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) supplementation on liver histology, adipokine profile and muscle function in an NAFLD model. METHODS: C57BL/6 mice were fed with a high fat diet (HFD) for 12 weeks and were separated into three groups treated for 4 weeks with: (1) High fat diet (HFD) (n = 10); (2) HFD + GH 9 μg/g/d (n = 10); (3) HFD + IGF-1 0.02 µg/g/d (n = 9). A control group fed a chow diet was included (n = 6). Liver histology, liver triglycerides content, serum alanine aminotransferase (ALT) activity, adiponectin and leptin serum levels, in vivo muscle strength, tetanic force and muscle fibre cross-sectional area (CSA) were measured. RESULTS: HFD + GH and HFD + IGF-1 groups showed significantly lower ALT activity compared to HFD (p < 0.01). Liver triglyceride content in HFD + GH was decreased compared to HFD (p < 0.01). Histologic steatosis score was increased in HFD and HFD + GH group (p < 0.01), whereas HFD + IGF-1 presented no difference compared to the chow group (p = 0.3). HFD + GH group presented lower serum leptin and adiponectin levels compared to HFD. GH and IGF-1 supplementation therapy reverted HFD-induced reduction in muscle strength and CSA (sarcopenia). CONCLUSIONS: GH and IGF-1 supplementation induced significant improvement in liver steatosis, aminotransferases and sarcopenia in a diet-induced NAFLD model.

Positive effect of IGF-1 injection on gastrocnemius of rat during distraction osteogenesis.

Distraction osteogenesis (DO) is used to form new bone between bone segments to lengthen the callus. Skeletal muscles frequently fail to adapt to distraction, which causes complications. Insulin-like growth factor-1 (IGF-1) has been implicated as a central regulator of muscle repair. We hypothesized that IGF-1 injection could reduce muscle complications in DO. A total of 102 Sprague-Dawley rats received DO or did not were randomly assigned into saline, IGF-1 and normal groups. On the day before the distraction, the rats in the IGF-1 group were injected with IGF-1. The gastrocnemius muscles of the rats were harvested at the 0, 1st, 4th, 7th, and 10th days of distraction. The weight of the muscles, cross-sectional area (CSA) of the muscle fibers, collagen volume fraction (CVF), maximum limit load (MLL), maximum contraction forces, and gene expression of Akt, MyoD, myogenin, myostatin, and collagen I were analyzed. The results indicated that IGF-1 injection had increased the weights, CSA of the muscle fibers, MLL and force generation of the gastrocnemius. Also, Akt, MyoD, and myogenin were upregulated, and myostatin was downregulated in the IGF-1 group. Injection of IGF-1 could attenuate the gastrocnemius atrophy, prevent fibrosis, increase MLL, and regulate the related mRNA.

Enriched early life experiences reduce adult anxiety-like behavior in rats: a role for insulin-like growth factor 1.

Early life experiences can affect brain development, contributing to shape interindividual differences in stress vulnerability and anxiety-like behavior. In rodents, high levels of maternal care have long-lasting positive effects on the behavior of the offspring and stress response; post-weaning rearing in an enriched environment (EE) or massage counteract the negative effects of maternal separation or prenatal stressors. We recently found that insulin-like growth factor 1 (IGF-1) is a key mediator of early EE or massage on brain development. Whether early enrichment of experience can induce long-lasting effects on anxiety-like behavior and whether IGF-1 is involved in these effects is not known. We assessed anxiety-like behavior by means of the elevated plus maze in control adult rats and in adult rats subjected to early EE or to massage. We found that both EE and massage reduced adult anxiety-like behavior. Early IGF-1 systemic injections in rat pups reared in standard condition mimic the effects of EE and massage, reducing anxiety-like behavior in the adult; blocking early IGF-1 action in massaged and EE animals prevents massage and EE effects. In EE and IGF-1-treated animals, we assessed the hippocampal expression of glucocorticoid receptors (GRs) at postnatal day 12 (P12) and P60, finding a significantly higher GR expression at P60 for both treatments. These results suggest that IGF-1 could be involved in mediating the long-lasting effects of early life experiences on vulnerability/resilience to stress in adults.

Hyperglycemia in stroke and possible treatments.

Hyperglycemia affects approximately one-third of acute ischemic stroke patients and is associated with poor clinical outcomes. In experimental and clinical stroke studies, hyperglycemia has been shown to be detrimental to the penumbral tissue for several reasons. First, hyperglycemia exacerbates both calcium imbalance and the accumulation of reactive oxygen species (ROS) in neurons, leading to increased apoptosis. Second, hyperglycemia fuels anaerobic energy production, causing lactic acidosis, which further stresses neurons in the penumbral regions. Third, hyperglycemia decreases blood perfusion after ischemic stroke by lowering the availability of nitric oxide (NO), which is a crucial mediator of vasodilation. Lastly, hyperglycemia intensifies the inflammatory response after stroke, causing edema, and hemorrhage through disruption of the blood brain barrier and degradation of white matter, which leads to a worsening of functional outcomes. Many neuroprotective treatments addressing hyperglycemia in stroke have been implemented in the past decade. Early clinical use of insulin provided mixed results due to insufficiently controlled glucose levels and heterogeneity of patient population. Recently, however, the latest Stroke Hyperglycemia Insulin Network Effort trial has addressed the shortcomings of insulin therapy. While glucagon-like protein-1 administration, hyperbaric oxygen preconditioning, and ethanol therapy appear promising, these treatments remain in their infancy and more research is needed to better understand the mechanisms underlying hyperglycemia-induced injuries. Elucidation of these mechanistic pathways could lead to the development of rational treatments that reduce hyperglycemia-associated injuries and improve functional outcomes for ischemic stroke patients.

Insulin-like growth factor-1 and its derivatives: potential pharmaceutical application for treating neurological conditions.

Ischemic brain damage remains a major cause of disability at all ages. This review examines the efficacy, mode of action and mechanisms of insulin-like growth factor (IGF)-1 and its derivatives in animal models of acute brain injury and neurodegenerative conditions, their potential in pharmaceutical developments. IGF-1 reduces cell loss and improves long-term neurological function in animal models. IGF-1 needs to be given within a few hours of the insult. However, the therapeutic window can be extended by mild hypothermia, likely by delaying apoptosis. Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential limit clinical translation. Thus, recent studies have examined related compounds. For example, intravenous infusion of the N-terminal tripeptide of IGF-1 (glycine- proline-glutamate, GPE) can alleviate brain injury and improve long-term function in rats, with a broad effective dose range and a 3-7 hour therapeutic window, but has a short half-life. G-2meth-PE(G-2mPE), a GPE analogue with a longer half-life, is also neuroprotective. GPE/G-2mPE do not interact with IGF receptors and may act by modulating postinjury inflammation, astrogliosis and vascular remodeling. Cyclo-glycyl-proline (cGP), an endogenous diketopiperazine possibly derived from GPE is also neuroprotective. An analogue, cyclo-L-glycyl-L-2-allylproline (NNZ-2591) improves long-term somatosensory-motor function and histology after ischemic injury. Treatment with NNZ-2591 after 6-hypdroxydopamine injection in adult rats improves neurogenesis and long-term motor function. Further, oral administration of NNZ-2591 also prevents scopolamine-induced acute memory impairment. These beneficial effects may mediated by improved neuroplasticity. This review is an updated version of a previous publication in Recent Pat CNS Drug Discov.

Reconstruct large osteochondral defects of the knee with hIGF-1 gene enhanced Mosaicplasty.

OBJECTIVE: To investigate a compound technique including gene therapy, injectable tissue engineering and Mosaicplasty to reconstruct large osteochondral defect. METHODS: Plasmid vector containing hIGF-1 cDNA was created and transfected into BMSCs in vitro with FuGene6. After gene expression determination, cells were mixed with calcium alginate gel. Osteochondral defects were created on the femoral condyle of goats in a diameter of 6mm. Osteochondral plugs were harvested from the intertrochlea groove and pressed into the recipient sites in a mosaic mode. Gene modified BMSCs-scaffold complex was applied to fill the residual defects. Control groups were also set up. At 4 and 16 weeks, specimens were investigated in gross and under microscopy, electromicroscopy and MRI detection. RESULTS: hIGF-I gene was expressed effectively with the peak concentration at 34.75 ng/ml. Subchondral bone and cartilage were integrated well in gene enhanced Mosaicplasty group. The reconstructed tissue filled up the gaps between columns, which appeared better than other groups. The regenerated cartilage was integrated with neighbor tightly in regular arrange. Extracellular matrix distributed evenly and deeply stained by alcian blue. Quantitative histologic assessments showed higher score in gene enhanced Mosaicplasty group. Glycosaminoglycan assay revealed no difference between groups involving Mosaicplasty. MRI analysis demonstrated the healing process between the subchondral bone other than control groups. CONCLUSIONS: hIGF-I gene enhanced tissue engineering can modify the outcome of Mosaicplasty to reconstruct large osteochondral defects in weight-bearing region.

Controlled release of IGF-I from a biodegradable matrix improves functional recovery of skeletal muscle from ischemia/reperfusion.

Ischemia/reperfusion (I/R) injury is a considerable insult to skeletal muscle, often resulting in prolonged functional deficits. The purpose of the current study was to evaluate the controlled release of the pro-regenerative growth factor, insulin-like growth factor-I (IGF-I), from a biodegradable polyethylene glycol (PEG)ylated fibrin gel matrix and the subsequent recovery of skeletal muscle from I/R. To accomplish this, the hind limbs of male Sprague-Dawley rats were subjected to 2-h tourniquet-induced I/R then treated with saline, bolus IGF-I (bIGF), PEGylated fibrin gel (PEG-Fib), or IGF-I conjugated PEGylated fibrin gel (PEG-Fib-IGF). Functional and histological evaluations were performed following 14 days of reperfusion, and muscles from 4-day reperfusion animals were analyzed by Western blotting and histological assessments. There was no difference in functional recovery between saline, bIGF, or PEG-Fib groups. However, PEG-Fib-IGF treatment resulted in significant improvement of muscle function and structure, as observed histologically. Activation of the PI3K/Akt pathway was significantly elevated in PEG-Fib-IGF muscles, compared to PEG-Fib treatment, at 4 days of reperfusion, suggesting involvement of the pathway PI3K/Akt as a mediator of the improved function. Surprisingly, myoblast activity was not evident as a result of PEG-Fib-IGF treatment. Taken together, these data give evidence for a protective role for the delivered IGF. These results indicate that PEG-Fib-IGF is a viable therapeutic technique in the treatment of skeletal muscle I/R injury.

Treatment of subchondral cystic lesions of the medial femoral condyle of mature horses with growth factor enhanced chondrocyte grafts: a retrospective study of 49 cases.

REASONS FOR PERFORMING STUDY: To evaluate the long-term clinical outcome after allogeneic chondrocyte and insulin-like growth factor-I (IGF-I) grafting of subchondral cystic lesions (SCLs) of the femoral condyle in horses. OBJECTIVE: To test the hypothesis that chondrocyte and IGF-I grafts will improve the long-term clinical outcome in arthroscopically debrided SCLs. METHODS: Medical records of 49 horses with SCLs of the femoral condyle treated by debridement and implantation of chondrocytes and IGF-I were reviewed. Preoperative radiographs were obtained, and caudocranial radiographic projections were used to establish a ratio between cyst and femoral condyle size. Arthroscopic cyst debridement followed by filling of the bone void with autologous cancellous bone (45 horses) or tricalcium phosphate granules (4 horses) was performed. A paired syringe containing a fibrinogen and chondrocyte mixture in one syringe and calcium-activated bovine thrombin with IGF-I in the other was used to cover the surface. A successful outcome was defined as a horse that performed to its intended use without lameness. RESULTS: A successful outcome was achieved in 36 of 49 horses (74%). Preoperative radiography was performed in all horses, with 33 horses having unilateral SCLs of the medial femoral condyle, 15 horses having bilateral SCLs of the medial femoral condyle, and one horse having bilateral SCLs of the lateral femoral condyle. Median age of the horses was 3.3 years. Fifteen horses had preoperative radiographic and arthroscopic evidence of osteoarthritis (OA). A successful outcome was not influenced by age of horse, presence of pre-existing osteoarthritis or preoperative size of the subchondral cyst. Grafting resulted in success for 80% of horses >3 years old, and in 80% of horses with OA. CONCLUSIONS: Implantation of allogeneic chondrocytes supplemented with IGF-I is an effective treatment for horses with SCLs of the femoral condyle, and particularly for older horses and horses with pre-existing osteoarthritis. POTENTIAL RELEVANCE: Chondrocyte implantation may offer a greater chance of long-term success in older horses and horses with osteoarthritis than has been previously reported with cyst debridement alone.

[Pharmacological treatment for retinopathy of prematurity]. / Pharmakologische Therapie der Frühgeborenenretinopathie.

Mandatory screening performed by an experience ophthalmologist remains the most important pillar in the management of retinopathy of prematurity (ROP). The current gold standard for treatment of proliferative ROP is still panretinal laser photocoagulation, depending on severity, in combination with vitreoretinal surgery if necessary. The first case series of off-label intravitreal anti-VEGF treatment are encouraging. In addition to intravitreal anti-VEGF therapy, other treatment concepts such as supplementation with IGF-1 or omega-3 fatty acids also represent interesting pharmacological approaches to the management of ROP. However, larger controlled trials are required to validate the benefits and safety of these systemic treatment approaches.

Investigational anabolic therapies for osteoporosis.

IMPORTANCE OF THE FIELD: Anabolic therapy, or stimulating the function of bone-forming osteoblasts, is the preferred pharmacological intervention for osteoporosis. AREAS COVERED IN THIS REVIEW: We reviewed bone anabolic agents currently under active investigation. The bone anabolic potential of IGF-I and parathyroid hormone-related protein is discussed in the light of animal data and human studies. We also discuss the use of antagonists of the calcium-sensing receptor (calcilytics) as orally administered small molecules capable of transiently elevating serum parathyroid hormone (PTH). Further, we reviewed novel anabolic agents targeting members of the wingless tail (Wnt) signaling family that regulate bone formation including DKK-1, sclerostin, Thp1, and glycogen synthase kinase 3beta. We have also followed up on the promise shown by beta-blockers in modulating the activity of sympathetic nervous system, thus affecting bone anabolism. We give critical consideration to neutralizing the activity of activin A, a negative regulator of bone mass by soluble activin receptor IIA, as a strategy to promote bone formation. WHAT THE READER WILL GAIN: Update on various strategies to promote osteoblast function currently under evaluation. TAKE HOME MESSAGE: In spite of favorable results in experimental models, none of these strategies has yet achieved the ultimate goal of providing an alternative to injectable PTH, the sole anabolic therapy in clinical use.

[Adjunctive therapies to glycaemic control of type 1 diabetes mellitus]. / Adjuvantes no tratamento da hiperglicemia do diabetes melito tipo 1.

Since Diabetes Control and Complications Trial (DCCT), intensive therapy has been directed at achieving glucose and glycosylated hemoglobin (HbA1c) values as close to normal as possible regarding safety issues. However, hyperglycemia (especially postprandial hyperglycemia) and hypoglicemia continue to be problematic in the management of type 1 diabetes. The objective of associating other drugs to insulin therapy is to achieve better metabolic control lowering postprandial blood glucose levels. Adjunctive therapies can be divided in four categories based on their mechanism of action: enhancement of insulin action (e.g. the biguanides and thiazolidinediones), alteration of gastrointestinal nutrient delivery (e.g. acarbose and amylin) and other targets of action (e.g. pirenzepine, insulin-like growth factor I and glucagon-like peptide-1). Many of these agents have been found to be effective in short-term studies with decreases in HbA1c of 0.5-1%, lowering postprandial blood glucose levels and decreasing daily insulin doses.

Adjuvantes no tratamento da hiperglicemia do diabetes melito tipo 1: [revisão] / Adjunctive therapies to glycaemic control of type 1 diabetes mellitus: [review]

Desde o Diabetes Control and Complications Trial (DCCT), a terapia insulínica intensiva tem sido direcionada para alcançar valores de glicemia e hemoglobina glicada (HbA1c) tão próximos do normal quanto a segurança permita. Entretanto, a hiperglicemia (especialmente a hiperglicemia pós-prandial) e a hipoglicemia continuam a ser um problema no manejo do diabetes tipo 1. O objetivo de associar outras drogas à terapia insulínica é diminuir a glicemia pós-prandial. A terapia adjunta pode ser dividida em três grupos, conforme seu mecanismo de ação: 1. Aumento da ação da insulina (metformina e tiazolidinedionas); 2. Alteração da liberação de nutrientes no trato gastrintestinal (acarbose e amilina); 3. Outros modos de ação [pirenzepina, fator de crescimento insulina-símile (IGF-1) e peptídeo semelhante ao glucagon 1 (GLP-1). Muitos desses agentes mostraram, em estudos de curto prazo, diminuição de 0,5 por cento a 1 por cento na HbA1c, diminuir a hiperglicemia pós-prandial e as doses diárias de insulina.

Since Diabetes Control and Complications Trial (DCCT), intensive therapy has been directed at achieving glucose and glycosylated hemoglobin (HbA1c) values as close to normal as possible regarding safety issues. However, hyperglycemia (especially postprandial hyperglycemia) and hypoglicemia continue to be problematic in the management of type 1 diabetes. The objective of associating other drugs to insulin therapy is to achieve better metabolic control lowering postprandial blood glucose levels. Adjunctive therapies can be divided in four categories based on their mechanism of action: enhancement of insulin action (e.g. the biguanides and thiazolidinediones), alteration of gastrointestinal nutrient delivery (e.g. acarbose and amylin) and other targets of action (e.g. pirenzepine, insulin-like growth factor I and glucagon-like peptide-1). Many of these agents have been found to be effective in short-term studies with decreases in HbA1c of 0.5-1 percent, lowering postprandial blood glucose levels and decreasing daily insulin doses.

Strategic approaches to developing drug treatments for ALS.

Significant progress in understanding the cellular mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has not been matched with the development of therapeutic strategies to prevent disease progression. The multiple potential causes and relative rarity of the disease are two significant factors that make drug development and assessment in clinical trials extremely difficult. We review recent progress in promoting therapeutics into clinical trials and highlight the value of moderate throughput screening for the acceleration and improvement of drug design.

Contribution of insulin-like growth factor I to the healing of colonic anastomoses in rats.

The aim of this experimental study was to investigate the contribution of insulin-like growth factor I (IGF)-I in the colonic healing process when injected intraperitoneally after colon resection. Forty male Wistar rats were used. Rats in the control group were injected with 3 mL of a solution of 0.9% NaCl intraperitoneally after the operation and on postoperative day 2, 4, and 6. Rats in the IGF-I group received recombinant human IGF-I in a dose of 2 mg/kg body weight intraperitoneally, immediately after the colonic anastomosis was performed and on postoperative day 2, 4, and 6. All rats were killed on postoperative day 7. The hydroxyproline tissue content was significantly higher in the IGF-1 group than in the control group. The bursting pressures were also significantly higher in IGF-1 group than in the control group. The weight change between the groups differed significantly; in the control group the average weight decreased about 5% postoperatively, while in the IGF-1 group the average weight increased about 6%. The average inflammatory cell infiltration score was significantly higher in the control group. Neoagiogenesis did not differ significantly between the two groups. The fibroblast activity differed significantly between the two groups, as the control group had significantly less fibroblasts compared to the IGF-1 group. In conclusion, IGF-I when given intraperitoneally stimulates the healing of colonic anastomoses in the rats. Further studies are required in order to determine whether this effect is dose related.

Systemic IGF-I treatment inhibits cell death in diabetic rat retina.

Diabetic retinopathy can result in apoptotic cell death of retinal neurons, as well as significant visual loss. It is further known that insulin-like growth factor (IGF) levels are reduced in diabetes and that IGF-I can prevent cell death in many cell types. In this study, we tested the hypothesis that systemic treatment with IGF-I could inhibit death of neuroretinal cells in diabetic rats by examining the expression of proapoptotic markers. In diabetic rat retina, the number of TUNEL-immunoreactive cells increased approximately sixfold in the photoreceptor layer (P<.001) and eightfold in the inner nuclear layer (INL; P<.001); phospho-Akt (p-Akt; Thr 308) immunoreactivity increased eightfold in the ganglion cell layer (GCL; P<.001) and threefold in the INL (P<.01). Subcutaneous IGF-I treatment significantly reduced the number of TUNEL (P<.001) and p-Akt immunoreactive retinal cells (P<.05) in diabetic rats approximately to the level of the nondiabetic group. Qualitative results showed that caspase-3 and BAD immunoreactivities were also elevated in diabetes and reduced in IGF-I-treated animals. Elevated TUNEL and p-Akt immunoreactivities were localized to distinct cell layers in the retina of diabetic rats. Early intervention with systemic IGF-I reduced the presence of proapoptotic markers indicative of neuroretinal cell death, despite ongoing hyperglycemia and weight loss. The eye is a special sensory organ, and these data show that cell loss in the nervous system, even in uncontrolled diabetes, can be prevented by IGF-I administration.

Hormonal adjuvants for the treatment of renal anaemia.

Hormonal adjuvants, besides being erythropoietic agents, broaden the spectrum of therapeutic options for the treatment of the anaemia of chronic kidney disease (CKD). Lowering elevated parathyroid hormone levels by oral calcium supplementation and phosphate restriction, by varying dialysate calcium concentrations, by administration of vitamin D3 derivatives and, in the near future, by treatment with calcimimetics may prove efficient in some patients to fight extensive requirements of erythropoietic agents. Clinical evidence for a principal role of secondary hyperparathyroidism in resistance to erythropoietin, however, is lacking. Active vitamin D3 derivatives, in addition to their beneficial effects on secondary hyperparathyroidism, appear to exert a direct, stimulatory action on erythroid precursor cells and possibly also an inhibitory action on collagen synthesis by bone marrow stromal cells. Growth hormone (GH) induces insulin-like growth factor (IGF)-1, which in turn counteracts apoptosis similarly to erythropoietin, and fosters proliferation of burst- and colony-forming units-erythroid (BFU-E, CFU-E). If erythropoietic agents improve survival of CKD patients, a similar benefit should apply for strategies that increase synthesis and bioavailabilty of IGF-1. The latter appears to be reduced in CKD patients, and zinc supplementation potentially enhances it via an increase in free IGF-1. Finally, androgens also exert anti-anaemic effects. Nandrolone decanoate constitutes the only androgen currently applicable for selected male dialysis patients over the age of 50 years. It should not be given to women, however, because of serious side effects. Collectively, hormonal interventions offer the potential to reduce requirements of erythropoietic agents, and some may also improve physical performance.