Combination of blockade of endothelin signalling and compensation of IGF1 expression protects the retina from degeneration.

Retinitis pigmentosa (RP) and macular dystrophy (MD) cause severe retinal dysfunction, affecting 1 in 4000 people worldwide. This disease is currently assumed to be intractable, because effective therapeutic methods have not been established, regardless of genetic or sporadic traits. Here, we examined a RP mouse model in which the Prominin-1 (Prom1) gene was deficient and investigated the molecular events occurring at the outset of retinal dysfunction. We extracted the Prom1-deficient retina subjected to light exposure for a short time, conducted single-cell expression profiling, and compared the gene expression with and without stimuli. We identified the cells and genes whose expression levels change directly in response to light stimuli. Among the genes altered by light stimulation, Igf1 was decreased in rod photoreceptor cells and astrocytes under the light-stimulated condition. Consistently, the insulin-like growth factor (IGF) signal was weakened in light-stimulated photoreceptor cells. The recovery of Igf1 expression with the adeno-associated virus (AAV) prevented photoreceptor cell death, and its treatment in combination with the endothelin receptor antagonist led to the blockade of abnormal glial activation and the promotion of glycolysis, thereby resulting in the improvement of retinal functions, as assayed by electroretinography. We additionally demonstrated that the attenuation of mammalian/mechanistic target of rapamycin (mTOR), which mediates IGF signalling, leads to complications in maintaining retinal homeostasis. Together, we propose that combinatorial manipulation of distinct mechanisms is useful for the maintenance of the retinal condition.

Cellular Energy Sensor Sirt1 Augments Mapk Signaling to Promote Hypoxia/Reoxygenation-Induced Catch-up Growth in Zebrafish Embryo.

Animal growth is blunted in adverse environments where catabolic metabolism dominates; however, when the adversity disappears, stunted animals rapidly catch up to age-equivalent body size. This phenomenon is called catch-up growth, which we observe in various animals. Since growth retardation and catch-up growth are sequential processes, catabolism or stress response molecules may remain active, especially immediately after growth resumes. Sirtuins (Sirt1-7) deacetylate target proteins in a nicotinamide adenine dinucleotide-dependent manner, and these enzymes govern diverse alleys of cellular functions. Here, we investigated the roles of Sirt1 and its close paralog Sirt2 in the hypoxia/reoxygenation-induced catch-up growth model using zebrafish embryos. Temporal blockade of Sirt1/2 significantly reduced the growth rate of the embryos in reoxygenation, but it was not evident in constant normoxia. Subsequent gene knockdown and chemical inhibition experiments demonstrated that Sirt1, but not Sirt2, was required for the catchup growth. Inhibition of Sirt1 significantly reduced the activity of mitogen-activated kinase (Mapk) of embryos in the reoxygenation condition. In addition, co-inhibition of Sirt1- and Igf-signaling did not further reduce the body growth or Mapk activation compared to those of the Igf-signaling-alone-inhibited embryos. Furthermore, in the reoxygenation condition, Sirt1- or Igf-signaling inhibition similarly blunted Mapk activity, especially in anterior tissues and trunk muscle, where the sirt1 expression was evident in the catching-up embryos. These results suggest that the catch-up growth requires Sirt1 action to activate the somatotropic Mapk pathway, likely by modifying the Igf-signaling.

Genomic structures of insulin-like growth factor from golden pompano (Trachinotus ovatus) and their expression responses to the feed types.

Golden pompano is an important aquaculture product in the coastal regions of southern China, which is highly dependent on insulin-like growth factor (IGF) for various biological processes. The cDNAs of ToIGF1, ToIGF2, and ToIGF3 are 1718 bp, 1658 bp, and 2272 bp in length, respectively, with corresponding amino acid sequences of 185 aa, 215 aa, and 194 aa. These sequences consist of 5 parts, including the signal peptide, the B domain, the C domain, the A domain, the D domain, and the E domain, which are also found in other species. While ToIGF1 has no SSR polymorphism, ToIGF2 and ToIGF3 have 3 and 1 SSR polymorphism sites, respectively. In terms of tissue expression, ToIGF1 is predominantly expressed in the liver, ToIGF2 shows its highest expression in the gills, and ToIGF3 also shows its highest expression in the gills, but no expression in the liver and spleen. These tissue distribution results suggest that ToIGFs are not only present in growth-related tissues such as the brain, muscle, and liver, but also in reproductive tissues, tissues that regulate osmotic pressure, and tissues related to food intake. This observation is consistent with other bony fish species and highlights the extensive biological functions of ToIGFs that need to be further explored and exploited. In addition, the expression levels of ToIGFs were found to be different in the different dietary groups, including the pelleted food group, the frozen squid group, and the frozen fish group. In the pelleted diet group, ToIGF1 and ToIGF2 were highly expressed in the liver and intestinal tissues, followed by the frozen fish group. These results suggest that the type of diet can affect the body's energy metabolism by influencing tissue expression of growth-related genes, which in turn affects individual growth.

Trends of correlations between serum levels of growth hormone and insulin-like growth factor-I in general practice.

Serum levels of growth hormone (GH) and insulin-like growth factor (IGF)-I are crucial in the diagnosis and management of GH-related diseases. However, these levels are affected by nutritional and metabolic status. To elucidate the correlations between GH and IGF-I in various conditions, a retrospective analysis was performed for adult patients in which GH levels were examined by general practitioners during the period from January 2019 to December 2021. Of 642 patients, 33 patients were diagnosed with acromegaly, 21 were diagnosed with GH deficiency (GHD), and 588 were diagnosed with non-GH-related diseases (NGRD). In contrast to the positive correlations found between the levels of GH and IGF-I in patients with acromegaly (R=0.50; P<0.001) and patients with GHD (R=0.39; P=0.08), a negative correlation was found in the NGRD group (R=-0.23; P<0.001). In that group, the results of multivariable analysis showed that GH levels were predominantly influenced by gender and body mass index (BMI), whereas IGF-I levels were modulated by albumin in addition to age and GH. Of note, in the NGRD group, there was an enhanced negative correlation between GH and IGF-I under conditions of BMI < 22 and albumin < 4.0 g/dL (R=-0.45; P<0.001), and the negative correlation between GH and IGF-I was reinforced by excluding patients with other pituitary diseases and patients taking oral steroids (R=-0.51; P<0.001 and R=-0.59; P<0.001, respectively). Collectively, the results indicate that attention should be given to the presence of a negative correlation between serum levels of GH and IGF-I, especially in lean and low-nutritious conditions.

Prediabetes: A Benign Intermediate Stage or a Risk Factor in Itself?

Prediabetes is a condition when the blood glucose levels are above the normal range but below the threshold for defining diabetes. Previously considered benign, it is now recognized to be associated with various macrovascular and microvascular complications, with increases in the risk of cardiovascular events, nephropathy neuropathy, and retinopathy. Early identification of prediabetics may help detect the risk for these future complications at an earlier stage. Moreover, therapeutic options for prediabetes are available, which can retard its progression to diabetes and the subsequent development of complications. Hence, we make a case for the early identification of prediabetes through screening methods and appropriate institution of management strategies.

Signaling Pathways Involved in Manganese-Induced Neurotoxicity.

Manganese (Mn) is an essential trace element, but insufficient or excessive bodily amounts can induce neurotoxicity. Mn can directly increase neuronal insulin and activate insulin-like growth factor (IGF) receptors. As an important cofactor, Mn regulates signaling pathways involved in various enzymes. The IGF signaling pathway plays a protective role in the neurotoxicity of Mn, reducing apoptosis in neurons and motor deficits by regulating its downstream protein kinase B (Akt), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR). In recent years, some new mechanisms related to neuroinflammation have been shown to also play an important role in Mn-induced neurotoxicity. For example, DNA-sensing receptor cyclic GMP-AMP synthase (cCAS) and its downstream signal efficient interferon gene stimulator (STING), NOD-like receptor family pyrin domain containing 3(NLRP3)-pro-caspase1, cleaves to the active form capase1 (CASP1), nuclear factor κB (NF-κB), sirtuin (SIRT), and Janus kinase (JAK) and signal transducers and activators of the transcription (STAT) signaling pathway. Moreover, autophagy, as an important downstream protein degradation pathway, determines the fate of neurons and is regulated by these upstream signals. Interestingly, the role of autophagy in Mn-induced neurotoxicity is bidirectional. This review summarizes the molecular signaling pathways of Mn-induced neurotoxicity, providing insight for further understanding of the mechanisms of Mn.

Evaluación del ffecto modulador del factor de cecimiento similar a la insulinaa tipo i (igf-i) en linfocitos t de bazo de ratas sometidas a estrés nutricional / Evaluation of the modulating effect of type-i insulin-like growthfactor (igf-i) in rat spleen-t lymphocytes under nutritional stress / Avaliacáo doefeiito modulador do factor de cescimento similar a insulina tiipo i (igf-i) em linfócitos t de baço de ratos submetidos a stress nutricional

En este trabajo se estudió el papel del factor de crecimiento similar a la insulina tipo I (IGF-I) como factormodulador del estrés inducido por una restricción proteica en la dieta, en linfocitos T de bazo de rata. Se encontró que la restricción proteica disminuye el peso corporal en un 15%, el peso del bazo en un 32% y la población total de linfocitos T en un 42%. Igualmente, se observó en la población restringida un incremento en los porcentajes de las subpoblaciones T-CD4, T-CD8 y linfocitos B, y una relación T-CD4/T-CD8 disminuida, lo que sugiere una función inmune afectada por la malnutrición. También se halló que los cultivos de linfocitos provenientes de bazo de ratas en restricción proteica presentanmenor proliferación que los provenientes de ratas bien alimentadas; dicha proliferación se incrementa al adicionar IGF-I de manera dependiente de la dosis. Esta respuesta depende, también, del contenido de proteína en la dieta, observándose una mayor y más pronta respuesta a IGF-I en el grupo bien nutrido. La concanavalina A incrementó, igualmente, la proliferación en ambos grupos de animales, y al combinarla con IGF-I se presentó un sinergismo en la respuesta. En este trabajo se encontró, también, que la restricción proteica incrementa la apoptosis de los linfocitos T, y que la adición de IGF-I logra proteger dichas células de la apoptosis soportando el papel inmunomodulador de esta hormona en estrés nutricional.

In this work we studied the role of Insulin- like Growth Factor-I (IGF-I) as stress modulator in spleen T-lymphocytes from protein restricted rats. In protein restriction we found 15% lowered body weight, 32% lowered spleen weight and a reduction of 42% in total T-cell population. Also, increased percentages of T-CD4, T-CD8 and B cell populations and lowered T-CD4/T-CD8 ratio was observed, suggesting an impaired immune function due to malnutrition. Cultures of spleen T-lymphocytes from protein restricted rats showed less proliferation than the ones from well fed rats, this proliferation was increased after the addition of IGF-I in a dose depending manner. This answer depends, also, from the protein content of the diet, since the well fed animals showed a higher and faster answer. Concanavaline A, also, increased proliferation in both groups of rats and when combined with IGF-I a synergistic answer was found. In this work we also found that protein restriction increased apoptosis of T-lymphocytes, and the addition of IGF-I helped in the recovery of those cells supporting the immunomodulator role of IGF-I in nutritional stress.

Neste trabalho foi estudado o papel de Factor de Crescimento Similar à Insulina Tipo I (IGF-I) como factor modulador do stress induzido por uma restrição proteica em linfócitos T de baço de rato. Encontrou- se que a restrição proteica diminui o peso corporal em 15%, o peso do baço dos animais em 32% e a população total de linfócitos T em 42%. Igualmente, se observou uma alteração nas percentagens das subpopulações T-CD4, T-CD8 e linfócitos B, e uma relação T-CD4/T-CD8 diminuída que sugere uma função imune afectada pela má nutrição. Foi encontrado que os cultivos de linfócitos provenientes do baço de rato em restrição proteica apresentam menor proliferação que os provenientes de ratos bem alimentados; dita proliferação incrementa ao adicionar IGF-I de maneira dependente da dose. Esta resposta depende, também, do conteúdo de proteína na dieta, observando- se uma maior e mais rápida resposta a IGF-I no grupo bem nutrido. A concavalina A incrementou, igualmente, a proliferação em ambos grupos de animais, e ao combiná-la com IGF-I apresentou-se um sinergismo na resposta. Nesta investigação também foi encontrado que a restrição proteica incrementa a apoptose dos linfócitos T e que a adição de IGF-I permite proteger estas células da apoptose dando suporte ao papel imunomodulador desta hormona em stress nutricional.