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The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult long-standing disease.
J Am Acad Dermatol
Patrick M Brunner, Helen He, Ana B Pavel +11 more
Despite increasing evidence that adults with long-standing atopic dermatitis (AD) have systemic inflammation, little is known about systemic inflammation in recent-onset early pediatric AD.
Regulation of Somatostatin Receptor 2 Trafficking by C-Tail Motifs and the Retromer.
Endocrinology
Courtney Olsen, Kimiya Memarzadeh, Arzu Ulu +3 more
The Gi-coupled somatostatin receptor 2 (SST2) is a G protein-coupled receptor (GPCR) that mediates many of somatostatin's neuroendocrine actions. Upon stimulation, SST2 is rapidly internalized and transported to early endosomes before being recycled to the plasma membrane. However, little is known about the intracellular itinerary of SST2 after it moves to the early endosomal compartment or the cytoplasmic proteins that regulate its trafficking. As postsynaptic density protein/discs large 1/zonula occludens-1 (PDZ) domain interactions often regulate the trafficking and signaling potential of GPCRs, we examined the role of the SST2 PDZ ligand and additional C-terminal residues in controlling its intracellular trafficking. We determined that SST2 can recycle to the plasma membrane via multiple pathways, including a LAMP1/Rab7-positive late endosome to the trans-Golgi network (TGN) pathway. Trafficking from the late endosome to the TGN is often regulated by the retromer complex of endosomal coat proteins, and disrupting the retromer components sorting nexins 1/2 inhibits the budding of SST2 from late endosomes. Moreover, trafficking through the late endosomal/TGN pathway is dependent on an intact PDZ ligand and C-terminal tail, as truncating either the 3 or 10 C-terminal amino acids of SST2 alters the pathway through which it recycles to the plasma membrane. Moreover, addition of these amino acids to a heterologous receptor is sufficient to redirect it from a degradation pathway to a recycling itinerary. Our results demonstrate that endosomal trafficking of SST2 is dependent on numerous regulatory mechanisms controlled by its C terminus and the retromer machinery.
β1-adrenergic receptors mediate plasma acyl-ghrelin elevation and depressive-like behavior induced by chronic psychosocial stress.
Neuropsychopharmacology
Deepali Gupta, Jen-Chieh Chuang, Bharath K Mani +5 more
The ghrelin system is a key component of the mood and metabolic responses to chronic psychosocial stress. For example, circulating acyl-ghrelin rises in several rodent and human stress models, administered acyl-ghrelin induces antidepressant-like behavioral responses in mice, and mice with deleted ghrelin receptors (GHSRs) exhibit exaggerated depressive-like behaviors, changed eating behaviors, and altered metabolism in response to chronic stress. However, the mechanisms mediating stress-induced rises in ghrelin are unknown and ghrelin's antidepressant-like efficacy in the setting of chronic stress is incompletely characterized. Here, we used a pharmacological approach in combination with a 10-day chronic social defeat stress (CSDS) model in male mice to investigate whether the sympathoadrenal system is involved in the ghrelin response to stress. We also examined the antidepressant-like efficacy of administered ghrelin and the synthetic GHSR agonist GHRP-2 during and/or after CSDS. We found that administration of the β1-adrenergic receptor (β1AR) blocker atenolol during CSDS blunts the elevation of plasma acyl-ghrelin and exaggerates depressive-like behavior. Neither acute injection of acyl-ghrelin directly following CSDS nor its chronic administration during or after CSDS nor chronic delivery of GHRP-2 during and after CSDS improved stress-induced depressive-like behavior. Thus, β1ARs drive the acyl-ghrelin response to CSDS, but supplementing the natural increases in acyl-ghrelin with exogenous acyl-ghrelin or GHSR agonist does not further enhance the antidepressant-like actions of the endogenous ghrelin system in the setting of CSDS.
Protocatechuic acid attenuates angiotensin II-induced cardiac fibrosis in cardiac fibroblasts through inhibiting the NOX4/ROS/p38 signaling pathway.
Phytother Res
Hui Song, Jie Ren
Cardiac fibrosis plays a crucial role in the pathogenesis of myocardial infarction (MI). It has been found that differentiation of cardiac fibroblasts (CFs) into myofibroblasts is a major event in the process of cardiac fibrosis. In the present study, we aimed to investigate the effects of protocatechuic acid (PCA), a cardiac protective agent, on the CFs differentiation in vitro. The results showed that PCA exhibited inhibitory effects on the cell proliferation and migration in angiotensin II (Ang II)-induced CFs. PCA treatment suppressed the Ang II-induced expression of α-smooth muscle actin (α-SMA), which is a hallmark of myofibroblasts. In addition, the production of extracellular matrix (ECM) proteins, including type I collagen (Col I) and connective tissue growth factor (CTGF), were significantly decreased in the PCA-treated CFs. The Ang II-induced increased levels of matrix metalloproteinase (MMP)-2, and MMP-9 were reduced by PCA. Furthermore, PCA resulted in decrease in reactive oxygen species (ROS) generation, as well as the expressions of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme 4 (NOX4) and p-p38 in Ang II-induced CFs. These findings showed that PCA treatment prevented the Ang II-induced cardiac fibrosis by inhibiting the NOX4/ROS/p38 signaling pathway in vitro, suggesting that PCA might be a therapeutic agent for MI.
Idiopathic and isolated adrenocorticotropic hormone deficiency presenting as continuous epigastric discomfort without symptoms of hypoglycemia: a case report.
J Med Case Rep
Seizo Okauchi, Fuminori Tatsumi, Yuki Kan +11 more
Isolated adrenocorticotropic hormone deficiency is one kind of hypopituitarism and is triggered by various diseases including autoimmune disorder and/or autoimmune hypophysitis. Adrenocorticotropic hormone deficiency brings out various serious symptoms such as severe hypoglycemia, hypotensive shock, and disturbance of consciousness.
An immuno polymerase chain reaction screen for the detection of CJC-1295 and other growth-hormone-releasing hormone analogs in equine plasma.
Drug Test Anal
Mark Timms, Katherine Ganio, Grace Forbes +2 more
CJC-1295 is a 30 amino acid peptide-based drug that stimulates the release of growth hormone (GH) from the pituitary gland. It is unique among performance-enhancing peptides due to the presence of a reactive maleimidopropionic acid group that covalently links the peptide to free thiols on the surface of plasma proteins. Once conjugated, CJC-1295 remains active in the bloodstream for significantly longer than non-conjugated peptide-based drugs that are rapidly excreted. Conjugation of CJC-1295 to plasma proteins prevents its detection by top-down mass-spectrometry-based peptide screening protocols as it effectively becomes a macromolecular protein with an undefined molecular weight. Using a pair of monoclonal antibodies raised against the CJC-1295 peptide, we present an immuno-polymerase chain reaction (I-PCR) assay that is capable of detecting the CJC-1295-protein conjugate at concentrations down to 0.8 pg/mL. Detection of endogenous equine GHRH necessitated a screening threshold for CJC-1295 in equine plasma of 50 pg/mL. The effectiveness of the assay for controlling the illicit use of CJC-1295 was confirmed in equine blood samples after administration in thoroughbred race horses.
MANAGEMENT OF AMNESTIC AND BEHAVIORAL DISORDERS AFTER KETAMINE ANESTHESIA.
Georgian Med News
I Belenichev, B Burlaka, A Puzyrenko +3 more
General anesthesia may cause damage of the central nervous system and cognitive dysfunction in the postoperative period. A new intranasal form of Noopept (N-Phenylacetyl-L-prolylglycine ethyl ester) was developed by our team at the Department of the medical technology (Zaporizhzhia State Medical University, Ukraine). The objectives of this investigation were the study of neuroprotective action of Noopept and to prove using in the clinic for correction of amnestic and behavioral disorders after ketamine anesthesia. We discovered that the intranasal administration of noopept after ketamine anesthesia significantly decreases anxiety and excitability, raises the animal's activity, shows an intensive antiamnesic effects and increases animal's training ability. Noopept significantly exceeds piracetam and cerebrocurin according to neuroprotective effects.
Effect of eccentric action velocity on expression of genes related to myostatin signaling pathway in human skeletal muscle.
Biol Sport
Hamilton Roschel, Carlos Ugrinowistch, Audrei Reis Santos +4 more
The aim of this study was to investigate the effects of an acute bout of eccentric actions, performed at fast velocity (210º.s-1) and at slow velocity (20º.s-1), on the gene expression of regulatory components of the myostatin (MSTN) signalling pathway. Participants performed an acute bout of eccentric actions at either a slow or a fast velocity. Muscle biopsy samples were taken before, immediately after, and 2 h after the exercise bout. The gene expression of the components of the MSTN pathway was assessed by real-time PCR. No change was observed in MSTN, ACTRIIB, GASP-1 or FOXO-3a gene expression after either slow or fast eccentric actions (p > 0.05). However, the MSTN inhibitors follistatin (FST), FST-like-3 (FSTL3) and SMAD-7 were significantly increased 2 h after both eccentric actions (p < 0.05). No significant difference between bouts was found before, immediately after, or 2 h after the eccentric actions (slow and fast velocities, p > 0.05). The current findings indicate that a bout of eccentric actions activates the expression of MSTN inhibitors. However, no difference was observed in MSTN inhibitors' gene expression when comparing slow and fast eccentric actions. It is possible that the greater time under tension induced by slow eccentric (SE) actions might compensate the effect of the greater velocity of fast eccentric (FE) actions. Additional studies are required to address the effect of eccentric action (EA) velocities on the pathways related to muscle hypertrophy.
Somatostatin receptor pathophysiology in the neuroendocrine system.
Expert Rev Endocrinol Metab
Manuela Albertelli, Marica Arvigo, Mara Boschetti +3 more
The actions of somatostatin (SRIF) are mediated by specific G protein-coupled receptors, named SRIF receptor (SSTR) subtypes 1, 2, 3 and 5. SRIF binding to SSTR activates a series of second messenger systems, resulting in the inhibition of calcium channels and adenylate cyclase activity, ultimately leading to inhibition of hormone secretion, while stimulation of other second messengers, such as phosphotyrosine phosphatases play a role in the control of cell growth. The SSTR and dopamine receptor families share a 30% sequence homology and appear to be structurally related. The knowledge on the pathophysiology of these two families of G protein-coupled receptors in neuroendocrine tumors has progressively increased due to the new insights in receptor dimerization, internalization and trafficking. Depending on the expression of different SSTRs in tissues, their combinations and interactions affect the functionality of the subtypes expressed and the influence of the microenvironment, the response to ligands and, by consequence, the response to treatment can be very different.
[The ulm emergency algorithm for the acute treatment of drug-induced, bradykinin-mediated angioedema].
Med Klin Intensivmed Notfmed
J Hahn, B Bock, C-M Muth +4 more
Bradykinin-mediated, drug-induced edema like ACE-inhibitor-induced angioedema (ACEi AE) is almost exclusively located in the head and neck region and is potentially life threatening. To date, there are no guidelines or officially-approved treatments available for this pathology.
Characterizing the protective effects of SHLP2, a mitochondrial-derived peptide, in macular degeneration.
Sci Rep
Sonali Nashine, Pinchas Cohen, Anthony B Nesburn +2 more
Mitochondrial-derived peptides (MDPs) are rapidly emerging therapeutic targets to combat development of neurodegenerative diseases. SHLP2 (small humanin-like peptide 2) is a newly discovered MDP that is coded from the MT-RNR2 (Mitochondrially encoded 16S rRNA) gene in mitochondrial DNA (mtDNA). In the current study, we examined the biological consequences of treatment with exogenously-added SHLP2 in an in vitro human transmitochondrial age-related macular degeneration (AMD) ARPE-19 cell model. In AMD cells, we observed significant down-regulation of the MDP-coding MT-RNR2 gene, and remarkably reduced levels of all five oxidative phosphorylation (OXPHOS) complex I-V protein subunits that are involved in the electron transport chain; these results suggested mitochondrial toxicity and abnormal OXPHOS complex protein subunits' levels in AMD cells. However, treatment of AMD cells with SHLP2: (1) restored the normal levels of OXPHOS complex protein subunits, (2) prevented loss of viable cells and mitochondria, (3) increased the number of mtDNA copies, (4) induced anti-apoptotic effects, and (5) attenuated amyloid-β-induced cellular and mitochondrial toxicity. Cumulatively, our findings established the protective role of SHLP2 in AMD cells in vitro. In conclusion, this novel study supports the merit of SHLP2 in the treatment of AMD, a primary retinal disease that is a leading cause of blindness among the elderly population in the United States as well as worldwide.
Effects of noopept on cognitive functions and pubertal process in rats with diabetes.
Life Sci
Perihan Gürbüz, Halil Düzova, Azibe Yildiz +6 more
Type 1 diabetes (T1DM) is a common chronic disease in childhood. Increasing insulin resistance in puberty gives rise to higher doses of insulin usage in treatment. Of this reason new approaches in treatment are needed. Noopept researches suggest it to have anti-diabetic properties. We tried to determine the effects of noopept on pubertal diabetes.
Crystal structure of the WFIKKN2 follistatin domain reveals insight into how it inhibits growth differentiation factor 8 (GDF8) and GDF11.
J Biol Chem
Jason C McCoy, Ryan G Walker, Nathan H Murray +1 more
Growth differentiation factor 8 (GDF8; also known as myostatin) and GDF11 are closely related members of the transforming growth factor β (TGF-β) family. GDF8 strongly and negatively regulates skeletal muscle growth, and GDF11 has been implicated in various age-related pathologies such as cardiac hypertrophy. GDF8 and GDF11 signaling activities are controlled by the extracellular protein antagonists follistatin; follistatin-like 3 (FSTL3); and WAP, follistatin/kazal, immunoglobulin, Kunitz, and netrin domain-containing (WFIKKN). All of these proteins contain a follistatin domain (FSD) important for ligand binding and antagonism. Here, we investigated the structure and function of the FSD from murine WFIKKN2 and compared it with the FSDs of follistatin and FSTL3. Using native gel shift and surface plasmon resonance analyses, we determined that the WFIKKN2 FSD can interact with both GDF8 and GDF11 and block their interactions with the type II receptor activin A receptor type 2B (ActRIIB). Further, we solved the crystal structure of the WFIKKN2 FSD to 1.39 Å resolution and identified surface-exposed residues that, when substituted with alanine, reduce antagonism of GDF8 in full-length WFIKKN2. Comparison of the WFIKKN2 FSD with those of follistatin and FSTL3 revealed differences in both the FSD structure and position of residues within the domain that are important for ligand antagonism. Taken together, our results indicate that both WFIKKN and follistatin utilize their FSDs to block the type II receptor but do so via different binding interactions.
[Epigenetic Mechanisms of Peptide-Driven Regulation and Neuroprotective Protein FKBP1b].
Mol Biol (Mosk)
B I Kuznik, S O Davydov, E S Popravka +3 more
Cortexin is a clinically approved cerebral cortex polypeptide complex in calves. The mechanism of cortexin action is not understood well. Two cortexin derivatives, short peptides EDR and DS with neuroprotective activity, were synthesized. According to the data of molecular modeling, these peptides are able to bind to the histone H1.3 protein. This can affect the conformation of histone H1.3, which leads to a change in the chromatin structure in the loci of some genes, in particular Fkbp1b encoding the FK506-binding protein. Electrophysiological processes associated with the Ca^(2+) exchange are disturbed in the pyramidal neurons of the hippocampus during aging of the brain. The Fkbp1b gene encodes peptidyl-prolyl cis-trans isomerase, regulating the release of calcium ions from the sarcoplasmic and endoplasmic reticulum of neurons. The activation of the Fkbp1b gene transcription under treatment with short peptides can promote the synthesis of its protein product and the activation of the Ca^(2+) release from organelles of the sarcoplasmic and endoplasmic reticulum of neurons, which, in turn, can lead to an increase in the functional activity of neurons.
Peptide mimetic of N-terminal ghrelin enhances ghrelin-induced growth hormone secretion and c-Fos expression in mice.
J Neuroendocrinol
Mojca Lunder, Miha Vodnik, Valentina Kubale +3 more
Orexigenic peptide ghrelin and its receptor have been extensively investigated as potential therapeutic targets, primarily because of their role in feeding initiation and growth hormone (GH) release. However, no specific ghrelin targeting anti-obesity or cachexia therapeutics are available for clinical use thus far and further efforts in this direction are warranted. The present study aimed to find new peptide drug leads modulating ghrelin signal transduction. By targeting neutralising antibodies against ghrelin with phage display libraries, we aimed to identify peptides binding to the cognate receptor. Four synthetic peptides were selected and tested using calcium screening assays. The most effective competitive antagonist FSFLPPE was further tested in vivo. Administration of the peptide produced no significant effect on either food intake or GH release. Surprisingly, when co-administered with ghrelin, the peptide significantly enhanced GH secretion and c-Fos expression. The evidence obtained in the present study indicates that FSFLPPE might act as an ago-allosteric modulator.
Biophysical Investigations Elucidating the Mechanisms of Action of Antimicrobial Peptides and Their Synergism.
Biomolecules
Arnaud Marquette, Burkhard Bechinger
Biophysical and structural investigations are presented with a focus on the membrane lipid interactions of cationic linear antibiotic peptides such as magainin, PGLa, LL37, and melittin. Observations made with these peptides are distinct as seen from data obtained with the hydrophobic peptide alamethicin. The cationic amphipathic peptides predominantly adopt membrane alignments parallel to the bilayer surface; thus the distribution of polar and non-polar side chains of the amphipathic helices mirror the environmental changes at the membrane interface. Such a membrane partitioning of an amphipathic helix has been shown to cause considerable disruptions in the lipid packing arrangements, transient openings at low peptide concentration, and membrane disintegration at higher peptide-to-lipid ratios. The manifold supramolecular arrangements adopted by lipids and peptides are represented by the 'soft membranes adapt and respond, also transiently' (SMART) model. Whereas molecular dynamics simulations provide atomistic views on lipid membranes in the presence of antimicrobial peptides, the biophysical investigations reveal interesting details on a molecular and supramolecular level, and recent microscopic imaging experiments delineate interesting sequences of events when bacterial cells are exposed to such peptides. Finally, biophysical studies that aim to reveal the mechanisms of synergistic interactions of magainin 2 and PGLa are presented, including unpublished isothermal titration calorimetry (ITC), circular dichroism (CD) and dynamic light scattering (DLS) measurements that suggest that the peptides are involved in liposome agglutination by mediating intermembrane interactions. A number of structural events are presented in schematic models that relate to the antimicrobial and synergistic mechanism of amphipathic peptides when they are aligned parallel to the membrane surface.
FGF21 Prevents Angiotensin II-Induced Hypertension and Vascular Dysfunction by Activation of ACE2/Angiotensin-(1-7) Axis in Mice.
Cell Metab
Xuebo Pan, Yihui Shao, Fan Wu +16 more
Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. However, the role of FGF21 in hypertension remains elusive. Here we show that FGF21 deficiency significantly exacerbates angiotensin II-induced hypertension and vascular dysfunction, whereas such negative effects are reversed by replenishment of FGF21. Mechanistically, FGF21 acts on adipocytes and renal cells to promote induction of angiotensin-converting enzyme 2 (ACE2), which in turn converts angiotensin II to angiotensin-(1-7), then inhibits hypertension and reverses vascular damage. In addition, ACE2 deficiency strikingly abrogates these beneficial effects of FGF21 in mice, including alleviation of angiotensin II-associated hypertension and vascular damage. Otherwise, pharmaceutical inhibition of angiotensin-(1-7) attenuates the protective effect of FGF21 on angiotensin II-induced vascular dysfunction, but not on hypertension. Thus, FGF21 protects against angiotensin II-induced hypertension and vascular impairment by activation of the ACE2/angiotensin-(1-7) axis via fine-tuning the multi-organ crosstalk between liver, adipose tissue, kidney, and blood vessels.
The evolution of body composition in oncology-epidemiology, clinical trials, and the future of patient care: facts and numbers.
J Cachexia Sarcopenia Muscle
Justin C Brown, Elizabeth M Cespedes Feliciano, Bette J Caan
There is growing interest from the oncology community to understand how body composition measures can be used to improve the delivery of clinical care for the 18.1 million individuals diagnosed with cancer annually. Methods that distinguish muscle from subcutaneous and visceral adipose tissue, such as computed tomography (CT), may offer new insights of important risk factors and improved prognostication of outcomes over alternative measures such as body mass index. In a meta-analysis of 38 studies, low muscle area assessed from clinically acquired CT was observed in 27.7% of patients with cancer and associated with poorer overall survival [hazard ratio: 1.44, 95% CI: 1.32-1.56]. Therapeutic interventions such as lifestyle and pharmacotherapy that modify all aspects of body composition and reduce the incidence of poor clinical outcomes are needed in patients with cancer. In a meta-analysis of six randomized trials, resistance training exercise increased lean body mass assessed from dual-energy X-ray absorptiometry [mean difference (MD): +1.07 kg, 95% CI: 0.76-1.37; P < 0.001] and walking distance [MD: +143 m, 95% CI: 70-216; P < 0.001] compared with usual care control in patients with non-metastatic cancer. In a meta-analysis of five randomized trials, anamorelin (a ghrelin agonist) significantly increased lean body mass [MD: +1.10 kg, 95% CI: 0.35-1.85; P = 0.004] but did not improve handgrip strength [MD: 0.52 kg, 95% CI: -0.09-1.13; P = 0.09] or overall survival compared with placebo [HR: 0.99, 95% CI: 0.85-1.14; P = 0.84] in patients with advanced or metastatic cancer. Early screening to identify individuals with occult muscle loss, combined with multimodal interventions that include lifestyle therapy with resistance exercise training and dietary supplementation combined with pharmacotherapy, may be necessary to provide a sufficient stimulus to prevent or slow the cascade of tissue wasting. Rapid, cost-efficient, and feasible methods to quantify muscle and adipose tissue distribution are needed if body composition assessment is to be integrated into large-scale clinical workflows. Fully automated analysis of body composition from clinically acquired imaging is one example. The study of body composition is one of the most provocative areas in oncology that offers tremendous promise to help patients with cancer live longer and healthier lives.
Experimental Substantiation of Application of Semax as a Modulator of Immune Reaction on the Model of "Social" Stress.
Bull Exp Biol Med
M A Samotrueva, A L Yasenyavskaya, V Kh Murtalieva +4 more
We studied immunocorrecting effects of Semax (Met-Glu-His-Phe-Pro-Gly-Pro) on the model of "social" stress caused by sensory contact and intermale confrontation. Functional activity of the immune system of laboratory animals was evaluated in standard immunopharmacological tests: delayed-type hypersensitivity reaction, direct agglutination test, latex test for studying phagocytic activity of peripheral blood neutrophils, changes in differential leukocyte count, and weight of immunocompetent organs. It was found that changes in the immune response caused by "social" stress are multidirectional, which confirms the theory of stress-induced "immune imbalance". Semax acted as effective immune corrector restoring cellular and humoral immunogenesis reactions and phagocytic activity of neutrophils. This attested to the presence of immunomodulating properties in Semax and necessitates further studies in this field.
The Growth Hormone Releasing Hormone Analogue, Tesamorelin, Decreases Muscle Fat and Increases Muscle Area in Adults with HIV.
J Frailty Aging
S Adrian, A Scherzinger, A Sanyal +9 more
Tesamorelin, a growth hormone-releasing hormone analogue, decreases visceral adipose tissue in people living with HIV, however, the effects on skeletal muscle fat and area are unknown.