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Cervicovaginal natural antimicrobial expression in pregnancy and association with spontaneous preterm birth.
Sci Rep
Natasha L Hezelgrave, Paul T Seed, Evonne C Chin-Smith +3 more
There is much interest in the role of innate immune system proteins (antimicrobial peptides) in the inflammatory process associated with spontaneous preterm birth (sPTB). After promising pilot work, we aimed to validate the association between the antimicrobial peptides/proteins elafin and cathelicidin and sPTB. An observational cohort study of 405 women at high-risk, and 214 women at low-risk of sPTB. Protein concentrations of elafin and cathelicidin, and the enzyme human neutrophil elastase (HNE) were measured in over 1,000 cervicovaginal fluid (CVF) samples (10 to 24 weeks' gestation). Adjusted CVF cathelicidin and HNE concentrations (but not elafin) were raised in high-risk women who developed cervical shortening and who delivered prematurely and were predictive of sPTB < 37 weeks, with an area under the curve (AUC) of 0.75 (95% CI 0.68 to 0.81) for cathelicidin concentration at 14 to 15+6 weeks. Elafin concentrations were affected by gestation, body mass index and smoking. CVF elafin in early pregnancy was modestly predictive of sPTB < 34 weeks (AUC 0.63, 0.56-0.70). Alterations in innate immune response proteins in early pregnancy are predictive of sPTB. Further investigation is warranted to understand the drivers for this, and their potential to contribute towards clinically useful prediction techniques.
The ADNP Syndrome and CP201 (NAP) Potential and Hope.
Front Neurol
Illana Gozes
Activity-dependent neuroprotective protein (ADNP) syndrome, also known as Helsmoortel-Van Der Aa syndrome, is a rare condition, which is diagnosed in children exhibiting signs of autism. Specifically, the disease is suspected when a child is suffering from developmental delay and/or intellectual disability. The syndrome occurs when one of the two copies of the ADNP gene carries a pathogenic sequence variant, mostly a de novo mutation resulting in loss of normal functions. Original data showed that Adnp +/- mice suffer from learning and memory deficiencies, muscle weakness, and communication problems. Further studies showed that the ADNP microtubule-interacting fragment NAP (called here CP201) resolves, in part, Adnp deficiencies and protects against ADNP pathogenic sequence variant abnormalities. With a clean toxicology and positive human adult experience, CP201 is planned for future clinical trials in the ADNP syndrome.
Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells.
Bull Exp Biol Med
V Kh Khavinson, N S Linkova, I M Kvetnoy +4 more
Thymalin is a polypeptide complex isolated from the thymus and regulating the functions of the immune system. Thymalin is effective in therapy of acute respiratory syndrome, chronic obstructive bronchitis, and other immunopathology. Thymalin increases functional activity of T lymphocytes, but the targeted molecular mechanism of its biological activity requires further study. We studied the influence of thymalin on differentiation of human hematopoietic stem cells (HSC) and expression of CD28 molecule involved in the implementation of antiviral immunity in COVID-19 infection. It was found that thymalin reduced the expression of CD44 (stem cell marker) and CD117 (molecule of the intermediate stage of HSC differentiation) by 2-3 times and increased the expression of CD28 (marker of mature T lymphocytes) by 6.8 times. This indirectly indicates that thymalin stimulated differentiation of CD117+ cells into mature CD28+T lymphocytes. It is known that in patients with severe COVID-19, the number of CD28+, CD4+, CD8+T lymphocytes in the blood decreased, which attested to a pronounced suppression of immunity. It is possible that the antiviral effect of thymalin consists in compensatory stimulation of HSC differentiation into CD28+T lymphocytes at the stage of immunity suppression in unfavorable course of viral infection. Thymalin can be considered as an immunoprotective peptide drug for the prevention of COVID-19.
Serelaxin Improves Regional Myocardial Function in Experimental Heart Failure: An In Vivo Cardiac Magnetic Resonance Study.
J Am Heart Assoc
Tomas Lapinskas, Sebastian Kelle, Jana Grune +9 more
Background Animal studies demonstrated that serelaxin lessens fibrosis in heart failure. This study assessed its effect on myocardial deformation using cardiac magnetic resonance and elucidated its relationship to gene regulation and histology in a mouse heart failure model. Methods and Results C57BL/6J mice were subjected to SHAM (n=4) or transverse aortic constriction (TAC). At week 10, TAC mice were randomized to receive either serelaxin (0.5 mg/kg per day; n=11) or vehicle (n=13) for 4 weeks. Cardiac magnetic resonance imaging was performed at baseline and repeated at the end of the study (week 14). Cine images were used to calculate left ventricular (LV) global longitudinal, circumferential, and radial strain. Hearts were examined for histology and gene expression. Compared with SHAM, mice 10 weeks after TAC showed increased LV mass with significant decreases in LV deformation parameters, indicating subclinical deterioration of myocardial function. At week 14, TAC mice given serelaxin demonstrated significant improvements in all LV strain parameters and no decrease in LV stroke volume and ejection fraction compared with TAC mice given vehicle. A significant positive correlation between global circumferential strain and the extent of myocardial fibrosis was found, and global circumferential strain correlated significantly with the expression of heart failure genes in serelaxin-treated mice. Conclusions Serelaxin improved cardiac magnetic resonance-derived myocardial deformation parameters as well as histomorphometric and gene expression findings in mice with heart failure. Cardiac magnetic resonance-derived myocardial mechanics correlate with histology and gene expression, stressing its utilization in myocardial remodeling.
Preoperative growth hormone (GH) peak values during a GH releasing peptide-2 test reflect the severity of hypopituitarism and the postoperative recovery of GH secretion in patients with non-functioning pituitary adenomas.
Endocr J
Akimi Soga, Izumi Fukuda, Shunsuke Kobayashi +3 more
Non-functioning pituitary adenoma (NFPA) is one common cause of adult growth hormone deficiency (AGHD). In Japan, a GH-releasing peptide (GHRP)-2 test is used to evaluate GH secretion. Although the cut-off for peak GH during a GHRP-2 test for severe AGHD is ≤9 ng/mL, severe AGHD may further diminish responses (range, nearly no-response to ≤9 ng/mL). We studied whether the peak GH responses during a GHRP-2 test could be predicted based on clinical characteristics of patients with NFPA. We compared patients with almost no-response during a GHRP-2 test with other patients considered as severe AGHD. Among the 76 patients with NFPA who were admitted to our institution, 36 patients (mean age, 61 years; male/female, n = 23/n = 13) were diagnosed with severe AGHD based on a preoperative GHRP-2 test. Based on the preoperative median peak GH concentration (2.83 ng/mL), patients were divided into two groups (<median = low or group L, n = 18; ≥median = moderate or group M, n = 18). Clinical manifestations, body mass index, severity of hypopituitarism and tumor size, volume, and extension were analyzed retrospectively. Compared with group M, group L patients were significantly older and more gonadotropin and ACTH deficient. A lower peak GH release during a GHRP-2 test was associated with a higher number of anterior pituitary hormone deficiencies across all 76 patients. Postoperatively, seven in group M and no patient in group L were assessed as having no longer severe AGHD, respectively. Preoperative peak GH concentrations assessed during a GHRP-2 test reflected the severity of hypopituitarism and the recovery of postoperative GH secretion.
TMEPAI/PMEPA1 Is a Positive Regulator of Skeletal Muscle Mass.
Front Physiol
Adam Hagg, Swati Kharoud, Georgia Goodchild +7 more
Inhibition of myostatin- and activin-mediated SMAD2/3 signaling using ligand traps, such as soluble receptors, ligand-targeting propeptides and antibodies, or follistatin can increase skeletal muscle mass in healthy mice and ameliorate wasting in models of cancer cachexia and muscular dystrophy. However, clinical translation of these extracellular approaches targeting myostatin and activin has been hindered by the challenges of achieving efficacy without potential effects in other tissues. Toward the goal of developing tissue-specific myostatin/activin interventions, we explored the ability of transmembrane prostate androgen-induced (TMEPAI), an inhibitor of transforming growth factor-β (TGF-β1)-mediated SMAD2/3 signaling, to promote growth, and counter atrophy, in skeletal muscle. In this study, we show that TMEPAI can block activin A, activin B, myostatin and GDF-11 activity in vitro. To determine the physiological significance of TMEPAI, we employed Adeno-associated viral vector (AAV) delivery of a TMEPAI expression cassette to the muscles of healthy mice, which increased mass by as much as 30%, due to hypertrophy of muscle fibers. To demonstrate that TMEPAI mediates its effects via inhibition of the SMAD2/3 pathway, tibialis anterior (TA) muscles of mice were co-injected with AAV vectors expressing activin A and TMEPAI. In this setting, TMEPAI blocked skeletal muscle wasting driven by activin-induced phosphorylation of SMAD3. In a model of cancer cachexia associated with elevated circulating activin A, delivery of AAV:TMEPAI into TA muscles of mice bearing C26 colon tumors ameliorated the muscle atrophy normally associated with cancer progression. Collectively, the findings indicate that muscle-directed TMEPAI gene delivery can inactivate the activin/myostatin-SMAD3 pathway to positively regulate muscle mass in healthy settings and models of disease.
Novel anti-inflammatory and chondroprotective effects of the human melanocortin MC1 receptor agonist BMS-470539 dihydrochloride and human melanocortin MC3 receptor agonist PG-990 on lipopolysaccharide activated chondrocytes.
Eur J Pharmacol
Vedia C Can, Ian C Locke, Magdalena K Kaneva +5 more
Human melanocortin MC1 and MC3 receptors expressed on C-20/A4 chondrocytes exhibit chondroprotective and anti-inflammatory effects when activated by melanocortin peptides. Nearly 9 million people in the UK suffer from osteoarthritis, and bacterial infections play a role in its development. Here, we evaluate the effect of a panel of melanocortin peptides with different selectivity for human melanocortin MC1 (α-MSH, BMS-470539 dihydrochloride) and MC3 ([DTrp8]-γ-MSH, PG-990) receptors and C-terminal peptide α-MSH11-13(KPV), on inhibiting LPS-induced chondrocyte death, pro-inflammatory mediators and induction of anti-inflammatory proteins. C-20/A4 chondrocytes were treated with a panel of melanocortin peptides prophylactically and therapeutically in presence of LPS (0.1 μg/ml). The chondroprotective properties of these peptides determined by cell viability assay, RT-PCR, ELISA for detection of changes in inflammatory markers (IL-6, IL-8 and MMP-1, -3 and -13) and western blotting for expression of the anti-inflammatory protein heme-oxygenase-1. C-20/A4 expressed human melanocortin MC1 and MC3 receptors and melanocortin peptides elevated cAMP. LPS stimulation caused a reduction in C-20/A4 viability, attenuated by the human melanocortin MC1 receptor agonist BMS-470539 dihydrochloride, and MC3 receptor agonists PG-990 and [DTrp8]-γ-MSH. Prophylactic and therapeutic regimes of [DTrp8]-γ-MSH significantly inhibited LPS-induced modulation of cartilage-damaging IL-6, IL-8, MMPs -1,-3 and -13 mediators both prophylactically and therapeutically, whilst human melanocortin MC1 and MC3 receptor agonists promoted an increase in HO-1 production. In the presence of LPS, activation of human melanocortin MC1 and MC3 receptors provided potent chondroprotection, upregulation of anti-inflammatory proteins and downregulation of inflammatory and proteolytic mediators involved in cartilage degradation, suggesting a new avenue for osteoarthritis treatment.
AEDG Peptide (Epitalon) Stimulates Gene Expression and Protein Synthesis during Neurogenesis: Possible Epigenetic Mechanism.
Molecules
Vladimir Khavinson, Francesca Diomede, Ekaterina Mironova +5 more
It was shown that AEDG peptide (Ala-Glu-Asp-Gly, Epitalon) regulates the function of the pineal gland, the retina, and the brain. AEDG peptide increases longevity in animals and decreases experimental cancerogenesis. AEDG peptide induces neuronal cell differentiation in retinal and human periodontal ligament stem cells. The aim of the study was to investigate the influence of AEDG peptide on neurogenic differentiation gene expression and protein synthesis in human gingival mesenchymal stem cells, and to suggest the basis for the epigenetic mechanism of this process. AEDG peptide increased the synthesis of neurogenic differentiation markers: Nestin, GAP43, β Tubulin III, Doublecortin in hGMSCs. AEDG peptide increased Nestin, GAP43, β Tubulin III and Doublecortin mRNA expression by 1.6-1.8 times in hGMSCs. Molecular modelling method showed, that AEDG peptide preferably binds with H1/6 and H1/3 histones in His-Pro-Ser-Tyr-Met-Ala-His-Pro-Ala-Arg-Lys and Tyr-Arg-Lys-Thr-Gln sites, which interact with DNA. These results correspond to previous experimental data. AEDG peptide and histones H1/3, H1/6 binding may be one of the mechanisms which provides an increase of Nestin, GAP43, β Tubulin III, and Doublecortin neuronal differentiation gene transcription. AEDG peptide can epigenetically regulate neuronal differentiation gene expression and protein synthesis in human stem cells.
The Challenge of Basic Itch Research.
Acta Derm Venereol
Earl Carstens, Taylor Follansbee, Mirela Iodi Carstens
Basic mechanisms and pathways of itch signaling are reviewed, with an emphasis on the progress to date as well as remaining challenges in translating current knowledge to the clinical treatment of chronic itch. Recent studies reveal 3 subsets of pruriceptive sensory neurons highly expressing itch-related genes. Their fibers project into the spinal cord to activate neurons expressing gastrin releasing peptide (GRP) and its receptor (GRPR), which connect to neurons that express the substance P (NK-1) receptor and project to the parabrachial nucleus and thalamus. Spinal inhibitory interneurons release GABA, glycine and dynorphin to modulate segmental itch transmission. However, near-ly all pruriceptive neurons also respond to algogens such as capsaicin. Alternative theories of itch-pain discrimination, such as intensity or spatial contrast, are based on the observation that focal stimulation of nociceptive nerve endings elicits itch while more wide-spread stimulation elicits pain. These findings cloud the issue of a labeled line for itch- a long-debated but currently unresolved challenge. In higher primates there is a dichotomy of histaminergic and non-histaminergic itch-signaling pathways which is less demarcated in rodents, suggesting species differences. A cardinal symptom of chronic itch is alloknesis, i.e., mechanical or touch-evoked itch. Recent evidence indicates that low-threshold mechanosensory afferents can access the spinal itch pathway, but are normally kept in check by inhibitory interneurons expressing neuropeptide Y (NPY). In chronic itch, NPY-mediated inhibition is reduced, allowing touch to excite itch-signaling pathways. These recent advances provide novel targets for development of therapeutic strategies to relieve chronic itch.
The occurrence of putative cognitive enhancing research peptides in seized pharmaceutical preparations: An incentive for controlling agencies to prepare for future encounters of the kind.
Drug Test Anal
Celine Vanhee, Antoine Francotte, Steven Janvier +1 more
At the end of 2017 and 2018 two different unknown suspicious preparations were encountered and were subjected to a plethora of different analyses in order to identify, if present, any bioactive compound. It turned out that these samples contained the assumedly cognitive enhancing research peptides Selank and Semax, which, to our knowledge, have not completed any clinical trials. Moreover, an online search, excluding the dark web, demonstrated that these kinds of nootropic research peptides are freely available either as lyophilized powder for injection purposes or are present in nasal sprays. It stands to reason that controlling laboratories need to anticipate the uprising of these types of potentially dangerous molecules and must therefore be able to correctly identify these compounds. Therefore, these findings served as an incentive to develop a novel combined liquid chromatography tandem mass spectroscopy (LC-MS/MS) methodology, applicable to both hydrophilic or more hydrophobic peptides, which was utilized to analyze a total of 10 putative cognitive enhancing polypeptides, with variable biochemical characteristics, that are currently being sold online. The screening rationale, complying to the recommendation paper of the General European Official Medicines Control Laboratory (OMCL) network on the interpretation of screening results for unknown peptides by mass spectrometry, was also validated in different matrices as required by ISO 17025.
Insulin-Like Growth Factor 2 (IGF-2) Regulates Neuronal Density and IGF-2 Distribution Following Hippocampal Intracerebral Hemorrhage.
J Stroke Cerebrovasc Dis
Farzaneh Vafaee, Asadollah Zarifkar, Masoumeh Emamghoreishi +4 more
The insulin-like growth factor 2 (IGF-2) is a growth factor and anti-inflammatory cytokine that plays a crucial role in memory consolidation. However, the precise role of this factor in acute brain damage is still unclear. The present study aimed to evaluate the variations in hippocampal IGF-2 distribution on different days and investigate the effect of recombinant IGF-2 on memory cell density, and IGF-2 distribution following acute hippocampal damage resulting from intracerebral hemorrhage (ICH).
Does hereditary angioedema make COVID-19 worse?
World Allergy Organ J
Yingyang Xu, Shuang Liu, Yan Zhang +1 more
The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, enters host cells via angiotensin-converting enzyme 2 (ACE2) and depletes ACE2, which is necessary for bradykinin metabolism. The depletion of ACE2 results in the accumulation of des-Arg (9)-bradykinin and possible bradykinin, both of which bind to bradykinin receptors and induce vasodilation, lung injury, and inflammation. It is well known that an overactivated contact system and excessive production of bradykinin comprise the key mechanisms that drive the pathogenesis of hereditary angioedema (HAE). It is reasonable to speculate that COVID-19 may increase disease activity in patients with HAE and vice versa. In this review, we explore the potential interactions between COVID-19 and HAE in terms of the contact system, the complement system, cytokine release, increased T helper 17 cells, and hematologic abnormalities. We conclude with the hypothesis that comorbidity with HAE might favor COVID-19 progression and may worsen its outcomes, while COVID-19 might in turn aggravate pre-existing HAE and prompt the onset of HAE in asymptomatic carriers of HAE-related mutations. Based on the pathophysiologic links, we suggest that long-term prophylaxis should be considered in patients with HAE at risk of SARS-CoV-2 infection, especially the prophylactic use of C1 inhibitor and lanadelumab and that HAE patients must have medications for acute attacks of angioedema. Additionally, therapeutic strategies employed in HAE should be considered for the treatment of COVID-19, and clinical trials should be performed.
Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition.
Int J Mol Sci
Jian-Ching Wu, Han-En Tsai, Yi-Hsiang Hsiao +3 more
Melanotan II (MTII), a synthetic analogue of the alpha-melanocyte stimulating hormone (α-MSH), has been applied for skin tanning in humans. However, the carcinogenic consequence of topical MTII has been equivocal. This study aims to delineate the anti-neoplastic efficacy and mechanism of MTII using the B16-F10 melanoma model in vitro and in vivo. It was found that, despite a lack of influence on proliferation, MTII potently inhibited the migration, invasion, and colony-forming capability of melanoma cells. Moreover, topical MTII application significantly attenuated the tumor progression in mice bearing established melanoma. Histological analysis revealed that MTII therapy induced apoptosis while inhibiting the proliferation and neovaluarization in melanoma tissues. By immunoblot and immunohistochemical analysis, it was found that MTII dose-dependently increased the phosphatase and tensin homolog (PTEN) protein level while reducing PTEN phosphorylation, which resulted in the inhibition of AKT/nuclear factor kappa B (NFκB) signaling. Consistently, MTII treatment inhibited cyclooxygenase II (COX-2) expression and prostaglandin E2 (PGE2) production in melanoma cells. Finally, studies of antibody neutralization suggest that the melanocortin 1 receptor (MC1R) plays a critical role in MTII-induced PTEN upregulation and melanoma suppression. Together, these results indicate that MTII elicits PTEN upregulation via MC1R, thereby suppressing melanoma progression through downregulating COX-2/PGE2 signaling. Hence, topical MTII therapy may facilitate a novel therapeutic strategy against melanoma.
In Vitro Modeling of Bradykinin-Mediated Angioedema States.
Pharmaceuticals (Basel)
François Marceau, Hélène Bachelard, Xavier Charest-Morin +2 more
Kinins (peptides related to bradykinin, BK) are formed from circulating substrates, the kininogens, by the action of two proteases, the kallikreins. The only clinical application of a BK receptor ligand, the B2 receptor antagonist icatibant, is the treatment of the rare hereditary angioedema (HAE) caused by the deficiency of C1-esterase inhibitor (C1-INH). Less common forms of HAE (genetic variants of factor XII, plasminogen, kininogen) are presumably mediated by increased BK formation. Acquired forms of BK-mediated angioedema, such as that associated with angiotensin-I converting enzyme (ACE) inhibition, are also known. Antibody-based analytical techniques are briefly reviewed, and support that kinins are extremely short-lived, prominently cleared by ACE. Despite evidence of continuous activation of the kallikrein-kinin system in HAE, patients are not symptomatic most of the time and their blood or plasma obtained during remission does not generate excessive immunoreactive BK (iBK), suggesting effective homeostatic mechanisms. HAE-C1-INH and HAE-FXII plasmas are both hyperresponsive to fibrinolysis activation. On another hand, we suggested a role for the alternate tissue kallikrein-kinin system in patients with a plasminogen mutation. The role of the BK B1 receptor is still uncertain in angioedema states. iBK profiles under in vitro stimulation provide fresh insight into the physiopathology of angioedema.
Luteal Presence and Ovarian Response at the Beginning of a Timed Artificial Insemination Protocol for Lactating Dairy Cows Affect Fertility: A Meta-Analysis.
Animals (Basel)
Stefan Borchardt, Alina Pohl, Wolfgang Heuwieser
Progesterone (P4) concentration during follicular growth has a major impact on fertility response in timed artificial insemination (TAI) protocols. Luteal presence at the beginning of a TAI protocol and ovarian response after the first gonadotropin-releasing hormone (GnRH) injection (G1) affect P4 concentration and subsequently pregnancy per artificial insemination (P/AI). A systematic review of the literature and meta-analytical assessment was performed with the objective of evaluating the magnitude of the effect of luteal presence and ovarian response at the beginning of a TAI protocol on P/AI in lactating dairy cows. We considered only studies using synchronisation protocols consisting of GnRH and prostaglandin F 2α. The time interval between G1 and prostaglandin F 2α (PGF 2α) had to range from 5 to 7 d. The time interval between the PGF 2α injection and G2 had to range from 48 to 72 h. We used 28 controlled experiments from 27 published manuscripts including 16,489 cows with the objective of evaluating the effect size of having a functional corpus luteum (CL) at G1 on P/AI. Information regarding ovulatory response after G1 was available for 5676 cows. In a subset of cows (n = 4291), information was available for luteal presence and ovulatory response at the initiation of the TAI protocol. A functional CL at G1 increased (p < 0.001) the relative risk of conceiving (RR (relative risk) = 1.32; 95% CI = 1.21-1.45) in lactating dairy cows. Ovulation after G1 increased (p < 0.001) the relative risk of conceiving (RR = 1.29; 95% CI = 1.20-1.38) in lactating dairy cows. The effect of ovulatory response on P/AI after G1 was affected by luteal presence at G1. In summary, there was a clear benefit on P/AI for cows starting a TAI protocol with a functional CL (+10.5 percentage units) and cows ovulating at the beginning of a TAI protocol (+11.0 percentage units).
Reliability and validity of the elements of desire questionnaire in premenopausal women with hypoactive sexual desire disorder.
J Patient Rep Outcomes
Dennis A Revicki, Stanley E Althof, Leonard R Derogatis +6 more
The Elements of Desire Questionnaire (EDQ) is a patient-reported outcome (PRO) measure developed to evaluate sexual desire and was included in two identically designed phase 3 clinical trials (RECONNECT) as an exploratory endpoint. The EDQ was developed based on a literature review, qualitative research with patients with hypoactive sexual desire disorder (HSDD), and input from clinical experts. This instrument is intended to be used to collect efficacy data in clinical trials evaluating potential treatments for HSDD. The objective of this study was to evaluate the measurement properties of both the monthly and daily recall versions of the EDQ during the RECONNECT trials.
Short-Term Administration of Serelaxin Produces Predominantly Vascular Benefits in the Angiotensin II/L-NAME Chronic Heart Failure Model.
JACC Basic Transl Sci
Joseph C McCarthy, Mark Aronovitz, Jennifer J DuPont +3 more
In patients hospitalized with acute heart failure, temporary serelaxin infusion reduced 6-month mortality through unknown mechanisms. This study therefore explored the cardiovascular effects of temporary serelaxin administration in mice subjected to the angiotensin II (AngII)/L-NG-nitroarginine methyl ester (L-NAME) heart failure model, both during serelaxin infusion and 19 days post-serelaxin infusion. Serelaxin administration did not alter AngII/L-NAME-induced cardiac hypertrophy, geometry, or dysfunction. However, serelaxin-treated mice had reduced perivascular left ventricular fibrosis and preserved left ventricular capillary density at both time points. Furthermore, resistance vessels from serelaxin-treated mice displayed decreased potassium chloride-induced constriction and reduced aortic fibrosis. These findings suggest that serelaxin improves outcomes in patients through vascular-protective effects.
Local Vibration Stimuli Induce Mechanical Stress-Induced Factors and Facilitate Recovery From Immobilization-Induced Oxidative Myofiber Atrophy in Rats.
Front Physiol
Fusako Usuki, Masatake Fujimura, Atsushi Nakamura +3 more
Muscle atrophy can be caused by unloading stress such as microgravity environments or cast immobilization. Therapies for such disuse muscle atrophy and their underlying mechanisms are incompletely understood. Here, we investigated the therapeutic effects of local vibration stimulation on immobilization-induced skeletal muscle atrophy. A rat model was made by placing the left hindlimb in a cast for 1 week, leading to oxidative myofiber atrophy without myopathic changes in soleus skeletal muscle. Vibration stimulus (90 Hz, 15 min) to the plantar fascia of the atrophic hindlimb was performed once a day using a hand-held vibration massager after removal of a cast at the end of the immobilization period. After 2 weeks, rats were dissected, and quantitative analysis of the cross-sectional areas of soleus myofibers was performed. The results revealed that vibration induced significant recovery from disuse muscle atrophy, compared with untreated immobilized samples. Furthermore, vibration treatment suppressed the fiber transition from slow to fast fiber types compared with vibration-untreated immobilized samples. Western blotting analyses of mechanical stress-induced factors revealed that the expression of mechano-growth factor (MGF), systemic insulin-like growth factor I, and the mechanotransduction protein, Yes-associated protein 1 (YAP1), was decreased in untreated immobilized soleus muscle, whereas vibration stimulation restored their expression. No change in the level of phosphorylation of YAP1Ser127 was observed, leading to no change in p-YAP1/YAP1 ratio in vibration-treated immobilized soleus muscle. The results indicate that vibration stimulus is effective to restore immobilization-induced inactivation of YAP1 pathway. Phosphorylation of ERK 1/2, but not AKT, was enhanced in vibration-treated immobilized soleus muscle. Furthermore, vibration stimuli restored immobilization-induced downregulation of the paired box transcription factor, PAX7, a critical factor for regenerative myogenesis in muscle satellite cells. Our results indicate that cyclic vibration stimuli are effective in activating satellite cells and facilitate recovery from immobilization-induced oxidative myofiber atrophy through upregulation of MGF and YAP1.
Social Context, Stress, Neuropsychiatric Disorders, and the Vasopressin 1b Receptor.
Front Neurosci
Heather K Caldwell, Elizabeth A Aulino, Karla M Rodriguez +2 more
The arginine vasopressin 1b receptor (Avpr1b) is involved in the modulation of a variety of behaviors and is an important part of the mammalian hormonal stress axis. The Avpr1b is prominent in hippocampal CA2 pyramidal cells and in the anterior pituitary corticotrophs. Decades of research on this receptor has demonstrated its importance to the modulation of social recognition memory, social forms of aggression, and modulation of the hypothalamic-pituitary-adrenal axis, particularly under conditions of acute stress. Further, work in humans suggests that the Avpr1b may play a role in human neuropsychiatric disorders and its modulation may have therapeutic potential. This paper reviews what is known about the role of the Avpr1b in the context of social behaviors, the stress axis, and human neuropsychiatric disorders. Further, possible mechanisms for how Avpr1b activation within the hippocampus vs. Avpr1b activation within anterior pituitary may interact with one another to affect behavioral output are proposed.
Altered Behaviors and Impaired Synaptic Function in a Novel Rat Model With a Complete Shank3 Deletion.
Front Cell Neurosci
Tian-Jia Song, Xing-Yu Lan, Meng-Ping Wei +15 more
Mutations within the Shank3 gene, which encodes a key postsynaptic density (PSD) protein at glutamatergic synapses, contribute to the genetic etiology of defined autism spectrum disorders (ASDs), including Phelan-McDermid syndrome (PMS) and intellectual disabilities (ID). Although there are a series of genetic mouse models to study Shank3 gene in ASDs, there are few rat models with species-specific advantages. In this study, we established and characterized a novel rat model with a deletion spanning exons 11-21 of Shank3, leading to a complete loss of the major SHANK3 isoforms. Synaptic function and plasticity of Shank3-deficient rats were impaired detected by biochemical and electrophysiological analyses. Shank3-depleted rats showed impaired social memory but not impaired social interaction behaviors. In addition, impaired learning and memory, increased anxiety-like behavior, increased mechanical pain threshold and decreased thermal sensation were observed in Shank3-deficient rats. It is worth to note that Shank3-deficient rats had nearly normal levels of the endogenous social neurohormones oxytocin (OXT) and arginine-vasopressin (AVP). This new rat model will help to further investigate the etiology and assess potential therapeutic target and strategy for Shank3-related neurodevelopmental disorders.