The living record of
peptide science.

In-Cell FRET Indicates Magainin Peptide Induced Permeabilization of Bacterial Cell Membranes at Lower Peptide-to-Lipid Ratios Relevant to Liposomal Studies.

ACS Infect Dis

Takumi Kaji, Yoshiaki Yano, Katsumi Matsuzaki

Antimicrobial peptides (AMPs) are promising candidates for anti-infective drugs. The majority of AMPs are considered to disrupt the lipid matrix of bacterial membranes, exerting bactericidal activity. A number of biophysical studies have been carried out to elucidate the underlying molecular mechanisms. However, the fact that the number of peptide molecules bound to a bacterial cell under bactericidal conditions is much larger than that expected from liposomal studies raises the question of whether membrane permeabilization mechanisms proposed by liposomal studies are relevant to bacteria. In this study, the peptide-to-lipid molar ratio needed for an antimicrobial magainin peptide to permeabilize the cell membrane of the Gram-positive bacterium Bacillus megaterium was estimated by random fluorescence resonance energy transfer from a BODIPY FL-labeled lipid to a Texas Red-labeled peptide. The comparison of the observed energy transfer efficiency with the two-dimensional energy transfer theory estimated that the leakage of the calcein dye from bacterial cells occurred at a peptide-to-lipid molar ratio of 0.025. At this ratio, the peptide induced dye leakage from liposomes mimicking the bacterial membrane, indicating that the lipid matrix is a target of membrane-acting AMPs and that liposomes are a useful model system to investigate their mechanisms of action. Furthermore, a binding assay suggested that most peptide molecules were bound to cellular components other than cell membranes.

A new model of myofibroblast-cardiomyocyte interactions and their differences across species.

Biophys J

Fusheng Liu, Hou Wu, Xiaoyu Yang +5 more

Although coupling between cardiomyocytes and myofibroblasts is well known to affect the physiology and pathophysiology of cardiac tissues across species, relating these observations to humans is challenging because the effect of this coupling varies across species and because the sources of these effects are not known. To identify the sources of cross-species variation, we built upon previous mathematical models of myofibroblast electrophysiology and developed a mechanoelectrical model of cardiomyocyte-myofibroblast interactions as mediated by electrotonic coupling and transforming growth factor-β1. The model, as verified by experimental data from the literature, predicted that both electrotonic coupling and transforming growth factor-β1 interaction between myocytes and myofibroblast prolonged action potential in rat myocytes but shortened action potential in human myocytes. This variance could be explained by differences in the transient outward K+ current associated with differential Kv4.2 gene expression across species. Results are useful for efforts to extrapolate the results of animal models to the predicted effects in humans and point to potential therapeutic targets for fibrotic cardiomyopathy.

Idiopathic combined adrenocorticotropin and growth hormone deficiency mimicking chronic fatigue syndrome.

BMJ Case Rep

Kazuki Tokumasu, Kanako Ochi, Fumio Otsuka

A 42-year-old man who had suffered from severe fatigue for 5 years was diagnosed as having chronic fatigue syndrome (CFS) and fibromyalgia. Endocrinological workup using combined anterior pituitary function tests showed that the patient had adrenocorticotropin hormone (ACTH) deficiency, with a normal pituitary MRI. Treatment with a physiologic dose of oral hydrocortisone replacement physically ameliorated his general fatigue. A secondary workup using a growth hormone-releasing peptide-2 test revealed that he also had growth hormone (GH) deficiency, and GH replacement therapy was started. His muscle pain and depression were improved by the therapy. Here, we present a rare case of combined deficiency of ACTH and GH in a middle-aged man with severe general fatigue. This case report aims to raise awareness of combined deficiency of ACTH and GH as a differential diagnosis of CFS and its mimics.

The Role of Thyroid Hormone in Neuronal Protection.

Compr Physiol

Yan-Yun Liu, Gregory A Brent

Thyroid hormone is essential for brain development and brain function in the adult. During development, thyroid hormone acts in a spatial and temporal-specific manner to regulate the expression of genes essential for normal neural cell differentiation, migration, and myelination. In the adult brain, thyroid hormone is important for maintaining normal brain function. Thyroid hormone excess, hyperthyroidism, and thyroid hormone deficiency, hypothyroidism, are associated with disordered brain function, including depression, memory loss, impaired cognitive function, irritability, and anxiety. Adequate thyroid hormone levels are required for normal brain function. Thyroid hormone acts through a cascade of signaling components: activation and inactivation by deiodinase enzymes, thyroid hormone membrane transporters, and nuclear thyroid hormone receptors. Additionally, the hypothalamic-pituitary-thyroid axis, with negative feedback of thyroid hormone on thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) secretion, regulates serum thyroid hormone levels in a narrow range. Animal and human studies have shown both systemic and local reduction in thyroid hormone availability in neurologic disease and after brain trauma. Treatment with thyroid hormone and selective thyroid hormone analogs has resulted in a reduction in injury and improved recovery. This article will describe the thyroid hormone signal transduction pathway in the brain and the role of thyroid hormone in the aging brain, neurologic diseases, and the protective role when administered after traumatic brain injury. © 2021 American Physiological Society. Compr Physiol 11:1-21, 2021.

Self-Cross-Linked Hydrogel of Cysteamine-Grafted γ-Polyglutamic Acid Stabilized Tripeptide KPV for Alleviating TNBS-Induced Ulcerative Colitis in Rats.

ACS Biomater Sci Eng

Jie Sun, Pengpeng Xue, Jiayi Liu +7 more

KPV (Lys-Pro-Val), which is a tripeptide derived from α-MSH (α-melanocyte-stimulating hormone), has an anti-inflammatory effect on colitis. However, KPV solution is very unstable when rectally administered, compromising its therapeutic efficacy. Herein, cysteamine-grafted γ-polyglutamic acid (SH-PGA) was synthesized by conjugating cysteamine with the carboxyl groups of γ-PGA. The synthesized SH-PGA has the thiol grafting amount of 4.5 ± 0.3 mmol/g. Without the use of the cross-linker, the SH-PGA hydrogel with 4% of the polymer was formed by self-cross-linking of thiol groups. Moreover, the formation of the SH-PGA hydrogel was not affected by KPV. The KPV/SH-PGA hydrogel presented higher elastic modulus (G') than the corresponding viscous modulus (G″) at 0.01-10 Hz, exhibiting good mechanical stability. The KPV/SH-PGA hydrogel presented a shear-thinning behavior, which was helpful for rectal administration. Only 30% of KPV was released from the KPV/SH-PGA hydrogel within 20 min, followed by a sustained-release behavior. Importantly, the stability of KPV in the SH-PGA hydrogel was obviously enhanced, which was presented by detecting its anti-inflammatory activity and promoting cell migration potential after 2 h of exposure to 37 °C. The enhanced therapeutic effect of the KPV/SH-PGA hydrogel on colitis was confirmed on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced ulcerative colitis rats. The colitis symptoms including body weight loss and the disease activity index score were obviously attenuated by rectally administering the KPV/SH-PGA hydrogel. Besides, the KPV/SH-PGA hydrogel treatment prevented the colon shortening of TNBS-infused rats and decreased the colonic myeloperoxidase level. The morphology of the colon including the epithelial barrier, crypt, and intact goblet cells was recovered after KPV/SH-PGA hydrogel treatment. Besides, the KPV/SH-PGA hydrogel decreased the expression of proinflammatory cytokines such as tumor necrosis factor α and interleukin 6. Collectively, the KPV/SH-PGA hydrogel may provide a promising strategy for the treatment of ulcerative colitis.

Humanin Alleviates Insulin Resistance in Polycystic Ovary Syndrome: A Human and Rat Model-Based Study.

Endocrinology

Yingying Wang, Zhengyan Zeng, Shuhua Zhao +10 more

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenism and insulin resistance (IR); however, the pathogenesis of local ovarian IR in PCOS remains largely unclear. Humanin, a mitochondria-derived peptide, has been reported to be associated with IR. Our previous study confirmed that humanin is expressed in multiple cell types in the ovary and is present in follicular fluid. However, it remains unknown whether humanin participates in the pathogenesis of local ovarian IR or whether humanin supplementation can improve IR in PCOS patients. In this study, we compared humanin concentrations in follicular fluid from PCOS patients with and without IR. We further investigated the effect of humanin analogue (HNG) supplementation on IR in a rat model of dehydroepiandrosterone-induced PCOS. Humanin concentrations in the follicular fluid were found to be significantly lower in PCOS patients with IR than in those without IR. HNG supplementation attenuated both the increases in the levels of fasting plasma glucose and fasting insulin in rats with PCOS and the decreases in phosphorylation of IRS1, PI3K, AKT, and GLUT4 proteins in the granulosa cells of these rats. Combined supplementation with HNG and insulin significantly improved glucose consumption in normal and humanin-siRNA-transfected COV434 cells. In conclusion, downregulated humanin in the ovaries may be involved in the pathogenesis of IR in PCOS, and exogenous supplementation with HNG improved local ovarian IR through modulation of the IRS1/PI3K/Akt signaling pathway in a rat model. This finding supports the potential future use of HNG as a therapeutic drug for PCOS.

Purinergic Signaling Involvement in Thymosin β4-mediated Corneal Epithelial Cell Migration.

Curr Eye Res

Heung-Mo Yang, Shin Wook Kang, Jihye Sung +2 more

Purpose: This study aimed to determine the effect of thymosin beta 4 (Tβ4) on human corneal epithelial cell migration and the downstream signaling pathways. Tβ4 has a role in tissue development, cell migration, inflammation, and wound healing. A previous study showed that Tβ4 directly binds to F0-F1 ATP synthase. Other studies reported the role of extracellular ATP and purinergic receptors in cell migration with several cell types. Despite advancing to the clinical stage for treatment of eye disorders, the effect of Tβ4 on human corneal epithelial cell (HCEC) migration and proliferation and the precise downstream signaling pathway(s) have not been identified. Methods: Various concentrations of Tβ4 were tested in vitro on human corneal epithelial cell proliferation using the CCK-8 Kit and on cell migration using the gap closure migration assay. Additionally, ATP levels at various time points were determined using the ATP Lite One-Step Kit. The Fluo 8 NO Wash Calcium Assay Kit was used to measure the intracellular Ca2+ concentration after treatment with various concentrations of Tβ4. P2X7 inhibitors were tested on ATP signaling and migration. Total- and phospho-ERK1/2 levels were determined in western blot. Results: Tβ4 enhanced HCEC proliferation and migration in a dose- and time-dependent manner. Moreover, these functions were related to increased extracellular ATP levels, intracellular Ca2+ influx, and ERK1/2 phosphorylation. Tβ4-mediated HCEC migration was inhibited by specific P2X7 purinergic receptor antagonists suggesting the role of this receptor in Tβ4-mediated human corneal epithelial cell migration. Conclusions: These results suggest that Tβ4-mediated HCEC proliferation and migration are associated with increased ATP levels, P2X7 R-mediated Ca2+ influx, and the ERK1/2 signaling pathway. This study begins to describe the mechanisms for Tβ4-mediated corneal healing and regeneration.

Humanin: A Potential Treatment for PCOS?

Endocrinology

Valentina Rodriguez Paris, Kirsty A Walters

Psychometric validation of the Female Sexual Distress Scale-Desire/Arousal/Orgasm.

J Patient Rep Outcomes

Leonard R Derogatis, Dennis A Revicki, Raymond C Rosen +3 more

For the treatment of female sexual dysfunction, the most relevant outcome measures are patient-reported treatment effects and changes in symptoms, underscoring the need for reliable, validated patient-reported outcome (PRO) instruments. The aim of this study was to evaluate the psychometric characteristics (validity and reliability) of the Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) PRO measure, which was adapted from the validated FSDS-Revised (FSDS-R) questionnaire and added 2 questions involving arousal and orgasm.

Myokines and Heart Failure: Challenging Role in Adverse Cardiac Remodeling, Myopathy, and Clinical Outcomes.

Dis Markers

Alexander E Berezin, Alexander A Berezin, Michael Lichtenauer

Heart failure (HF) is a global medical problem that characterizes poor prognosis and high economic burden for the health system and family of the HF patients. Although modern treatment approaches have significantly decreased a risk of the occurrence of HF among patients having predominant coronary artery disease, hypertension, and myocarditis, the mortality of known HF continues to be unacceptably high. One of the most important symptoms of HF that negatively influences tolerance to physical exercise, well-being, social adaptation, and quality of life is deep fatigue due to HF-related myopathy. Myopathy in HF is associated with weakness of the skeletal muscles, loss of myofibers, and the development of fibrosis due to microvascular inflammation, metabolic disorders, and mitochondrial dysfunction. The pivotal role in the regulation of myocardial and skeletal muscle rejuvenation, attenuation of muscle metabolic homeostasis, and protection against ischemia injury and apoptosis belongs to myokines. Myokines are defined as a wide spectrum of active molecules that are directly synthesized and released by both cardiac and skeletal muscle myocytes and regulate energy homeostasis in autocrine/paracrine manner. In addition, myokines have a large spectrum of pleiotropic capabilities that are involved in the pathogenesis of HF including cardiac remodeling, muscle atrophy, and cardiac cachexia. The aim of the narrative review is to summarize the knowledge with respect to the role of myokines in adverse cardiac remodeling, myopathy, and clinical outcomes among HF patients. Some myokines, such as myostatin, irisin, brain-derived neurotrophic factor, interleukin-15, fibroblast growth factor-21, and growth differential factor-11, being engaged in the regulation of the pathogenesis of HF-related myopathy, can be detected in peripheral blood, and the evaluation of their circulating levels can provide new insights to the course of HF and stratify patients at higher risk of poor outcomes prior to sarcopenic stage.

Continuous infusion of substance P into rat striatum relieves mechanical hypersensitivity caused by a partial sciatic nerve ligation via activation of striatal muscarinic receptors.

Behav Brain Res

Yoki Nakamura, Ryo Fukushige, Kohei Watanabe +4 more

Previous studies have demonstrated that continuous substance P (SP) infusion into the rat striatum attenuated hind paw formalin-induced nociceptive behaviors and mechanical hypersensitivity via a neurokinin-1 (NK1) receptor dependent mechanism. However, whether there is a role of striatal infusion of SP on chronic, neuropathic pain has yet to be demonstrated. The present study investigated the effect of continuous SP infusion into the rat striatum using a reverse microdialysis method is antinociceptive in a rat model of chronic, mononeuropathic pain. Two weeks after partial sciatic nerve injury, the ipsilateral hind paw demonstrated mechanical hypersensitivity. Infusion of SP (0.2, 0.4, or 0.8 μg/mL, 1 μL/min) for 120 min into the contralateral striatum dose-dependently relieved mechanical hypersensitivity. The antinociceptive effect of SP infusion was inhibited by co-infusion with the NK1 receptor antagonist CP96345 (10 μM). Neither ipsilateral continuous infusion nor acute microinjection of SP (10 ng) into the contralateral striatum was antinociceptive. A role of striatal muscarinic cholinergic neurons is suggested since co-infusion of SP with atropine (10 μM), but not the nicotinic receptor mecamylamine (10 μM), blocked antinociception. The current study suggests that activation of striatal muscarinic receptors through NK1 receptors could be a novel approach to managing chronic pain.

Therapeutic approaches of trophic factors in animal models and in patients with spinal cord injury.

Growth Factors

María Del Carmen Díaz-Galindo, Denisse Calderón-Vallejo, Carlos Olvera-Sandoval +1 more

Trophic factors are naturally produced by different tissues that participate in several functions such as the intercellular communication, in the development, stability, differentiation and regeneration at the cellular level. Specifically, in the case of spinal injuries, these factors can stimulate neuronal recovery. They are applied both in experimental models and in clinical trials in patients. The trophic factors analysed in this review include gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), growth hormone (GH), melatonin, oestrogens, the family of fibroblast growth factors (FGFs), the family of neurotrophins and the glial cell-derived neurotrophic factor (GDNF). There are some trophic (neurotrophic) factors that already been tested in patients with spinal cord injury (SCI), but only shown partial recovery effect. It is possible that, the administration of these trophic factors together with physical rehabilitation, act synergistically and, therefore, significantly improve the quality of life of patients with SCI.

Molecular basis for kinin selectivity and activation of the human bradykinin receptors.

Nat Struct Mol Biol

Yu-Ling Yin, Chenyu Ye, Fulai Zhou +6 more

Bradykinin and kallidin are endogenous kinin peptide hormones that belong to the kallikrein-kinin system and are essential to the regulation of blood pressure, inflammation, coagulation and pain control. Des-Arg10-kallidin, the carboxy-terminal des-Arg metabolite of kallidin, and bradykinin selectively activate two G protein-coupled receptors, type 1 and type 2 bradykinin receptors (B1R and B2R), respectively. The hyperactivation of bradykinin receptors, termed 'bradykinin storm', is associated with pulmonary edema in COVID-19 patients, suggesting that bradykinin receptors are important targets for COVID-19 intervention. Here we report two G protein-coupled complex structures of human B1R and B2R bound to des-Arg10-kallidin and bradykinin, respectively. Combined with functional analysis, our structures reveal the mechanism of ligand selectivity and specific activation of the bradykinin receptor. These findings also provide a framework for guiding drug design targeting bradykinin receptors for the treatment of inflammation, cardiovascular disorders and COVID-19.

Delta Sleep-Inducing Peptide Recovers Motor Function in SD Rats after Focal Stroke.

Molecules

Elena A Tukhovskaya, Alina M Ismailova, Elvira R Shaykhutdinova +6 more

Background and Objectives: Mutual effect of the preliminary and therapeutic intranasal treatment of SD rats with DSIP (8 days) on the outcome of focal stroke, induced with intraluminal middle cerebral occlusion (MCAO), was investigated. Materials and Methods: The groups were the following: MCAO + vehicle, MCAO + DSIP, and SHAM-operated. DSIP or vehicle was applied nasally 60 (±15) minutes prior to the occlusion and for 7 days after reperfusion at dose 120 µg/kg. The battery of behavioral tests was performed on 1, 3, 7, 14, and 21 days after MCAO. Motor coordination and balance and bilateral asymmetry were tested. At the end of the study, animals were euthanized, and their brains were perfused, serial cryoslices were made, and infarction volume in them was calculated. Results: Although brain infarction in DSIP-treated animals was smaller than in vehicle-treated animals, the difference was not significant. However, motor performance in the rotarod test significantly recovered in DSIP-treated animals. Conclusions: Intranasal administration of DSIP in the course of 8 days leads to accelerated recovery of motor functions.

Growth Hormone Releasing Hormone Reduces Circulating Markers of Immune Activation in Parallel with Effects on Hepatic Immune Pathways in Individuals with HIV-infection and Nonalcoholic Fatty Liver Disease.

Clin Infect Dis

Takara L Stanley, Lindsay T Fourman, Lai Ping Wong +13 more

The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis modulates critical metabolic pathways; however, little is known regarding effects of augmenting pulsatile GH secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and liver tissue in people with human immunodeficiency virus (HIV) (PWH) and nonalcoholic fatty liver disease (NAFLD).

Ion-poor water and dietary salt deprivation upregulate the ghrelinergic system in the goldfish (Carassius auratus).

J Fish Biol

YouRee Lim, Vivienne Lee, Ayelen Blanco +2 more

Because the ghrelinergic system in teleost fishes is broadly expressed in organs that regulate appetite as well as those that contribute to the regulation of salt and water balance, we hypothesized that manipulating salt and water balance in goldfish (Carassius auratus) would modulate the ghrelinergic system. Goldfish were acclimated to either freshwater (FW) or ion-poor FW (IPW) and were fed either a control diet containing 1% NaCl or low-salt diet containing 0.1% NaCl. Endpoints of salt and water balance, i.e., serum Na+ and Cl- levels, muscle moisture content and organ-specific Na+ -K+ -ATPase (NKA) activity, were examined in conjunction with brain, gill and gut mRNA abundance of preproghrelin and its receptor, growth hormone secretagogue receptor (ghs-r). Acclimation of fish to IPW reduced serum osmolality and Cl- levels and elevated kidney NKA activity, while FW fish fed a low NaCl diet exhibited a modest reduction in muscle moisture content but otherwise no apparent osmoregulatory disturbance. In contrast, a combined treatment of IPW acclimation and low dietary NaCl content reduced serum osmolality and Cl- levels, elevated muscle moisture content and increased gill, kidney and intestinal NKA activity. This intensified response to the combined effects of water and dietary ion deprivation is consistent with an increased effort to enhance ion acquisition. In association with these latter observations, a significant upregulation of preproghrelin mRNA expression in brain and gut was observed. A significant increase in ghs-r mRNAs was also observed in the gill of goldfish acclimated to IPW alone but a reduction in dietary NaCl content did not impact the ghrelinergic system of goldfish in FW. The results support the hypothesis that the ghrelinergic system is modulated in response to manipulated salt and water balance. Whether the central and peripheral ghrelinergic system contributes to ionic homeostasis in goldfish currently remains unclear and warrants further research.

Deficiency of arcuate nucleus kisspeptin results in postpubertal central hypogonadism.

Am J Physiol Endocrinol Metab

Nimisha Nandankar, Ariel L Negrón, Andrew Wolfe +2 more

Kisspeptin (encoded by Kiss1), a neuropeptide critically involved in neuroendocrine regulation of reproduction, is primarily synthesized in two hypothalamic nuclei: the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC). AVPV kisspeptin is thought to regulate the estrogen-induced positive feedback control of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH), and the preovulatory LH surge in females. In contrast, ARC kisspeptin neurons, which largely coexpress neurokinin B and dynorphin A (collectively named KNDy neurons), are thought to mediate estrogen-induced negative feedback control of GnRH/LH and be the major regulators of pulsatile GnRH/LH release. However, definitive data to delineate the specific roles of AVPV versus ARC kisspeptin neurons in the control of GnRH/LH release is lacking. Therefore, we generated a novel mouse model targeting deletion of Kiss1 to the ARC nucleus (Pdyn-Cre/Kiss1fl/fl KO) to determine the functional differences between ARC and AVPV kisspeptin neurons on the reproductive axis. The efficacy of the knockout was confirmed at both the mRNA and protein levels. Adult female Pdyn-Cre/Kiss1fl/fl KO mice exhibited persistent diestrus and significantly fewer LH pulses when compared with controls, resulting in arrested folliculogenesis, hypogonadism, and infertility. Pdyn-Cre/Kiss1fl/fl KO males also exhibited disrupted LH pulsatility, hypogonadism, and variable, defective spermatogenesis, and subfertility. The timing of pubertal onset in males and females was equivalent to controls. These findings add to the current body of evidence for the critical role of kisspeptin in ARC KNDy neurons in GnRH/LH pulsatility in both sexes, while directly establishing ARC kisspeptin's role in regulating estrous cyclicity in female mice, and gametogenesis in both sexes, and culminating in disrupted fertility. The Pdyn-Cre/Kiss1fl/fl KO mice present a novel mammalian model of postpubertal central hypogonadism.NEW & NOTEWORTHY We demonstrate through a novel, conditional knockout mouse model of arcuate nucleus (ARC)-specific kisspeptin in the KNDy neuron that ARC kisspeptin is critical for estrous cyclicity in female mice and GnRH/LH pulsatility in both sexes. Our study reveals that ARC kisspeptin is essential for normal gametogenesis, and the loss of ARC kisspeptin results in significant hypogonadism, impacting fertility status. Our findings further confirm that normal puberty occurs despite a loss of ARC kisspeptin.

ActRIIB:ALK4-Fc alleviates muscle dysfunction and comorbidities in murine models of neuromuscular disorders.

J Clin Invest

Jia Li, Maureen Fredericks, Marishka Cannell +18 more

Patients with neuromuscular disorders suffer from a lack of treatment options for skeletal muscle weakness and disease comorbidities. Here, we introduce as a potential therapeutic agent a heterodimeric ligand-trapping fusion protein, ActRIIB:ALK4-Fc, which comprises extracellular domains of activin-like kinase 4 (ALK4) and activin receptor type IIB (ActRIIB), a naturally occurring pair of type I and II receptors belonging to the TGF-β superfamily. By surface plasmon resonance (SPR), ActRIIB:ALK4-Fc exhibited a ligand binding profile distinctly different from that of its homodimeric variant ActRIIB-Fc, sequestering ActRIIB ligands known to inhibit muscle growth but not trapping the vascular regulatory ligand bone morphogenetic protein 9 (BMP9). ActRIIB:ALK4-Fc and ActRIIB-Fc administered to mice exerted differential effects - concordant with SPR results - on vessel outgrowth in a retinal explant assay. ActRIIB:ALK4-Fc induced a systemic increase in muscle mass and function in wild-type mice and in murine models of Duchenne muscular dystrophy (DMD), amyotrophic lateral sclerosis (ALS), and disuse atrophy. Importantly, ActRIIB:ALK4-Fc improved neuromuscular junction abnormalities in murine models of DMD and presymptomatic ALS and alleviated acute muscle fibrosis in a DMD model. Furthermore, in combination therapy ActRIIB:ALK4-Fc increased the efficacy of antisense oligonucleotide M12-PMO on dystrophin expression and skeletal muscle endurance in an aged DMD model. ActRIIB:ALK4-Fc shows promise as a therapeutic agent, alone or in combination with dystrophin rescue therapy, to alleviate muscle weakness and comorbidities of neuromuscular disorders.

Growth differentiation factor 11 attenuates cardiac ischemia reperfusion injury via enhancing mitochondrial biogenesis and telomerase activity.

Cell Death Dis

Lin Chen, Guangjin Luo, Yameng Liu +13 more

It has been reported that growth differentiation factor 11 (GDF11) protects against myocardial ischemia/reperfusion (IR) injury, but the underlying mechanisms have not been fully clarified. Considering that GDF11 plays a role in the aging/rejuvenation process and that aging is associated with telomere shortening and cardiac dysfunction, we hypothesized that GDF11 might protect against IR injury by activating telomerase. Human plasma GDF11 levels were significantly lower in acute coronary syndrome patients than in chronic coronary syndrome patients. IR mice with myocardial overexpression GDF11 (oe-GDF11) exhibited a significantly smaller myocardial infarct size, less cardiac remodeling and dysfunction, fewer apoptotic cardiomyocytes, higher telomerase activity, longer telomeres, and higher ATP generation than IR mice treated with an adenovirus carrying a negative control plasmid. Furthermore, mitochondrial biogenesis-related proteins and some antiapoptotic proteins were significantly upregulated by oe-GDF11. These cardioprotective effects of oe-GDF11 were significantly antagonized by BIBR1532, a specific telomerase inhibitor. Similar effects of oe-GDF11 on apoptosis and mitochondrial energy biogenesis were observed in cultured neonatal rat cardiomyocytes, whereas GDF11 silencing elicited the opposite effects to oe-GDF11 in mice. We concluded that telomerase activation by GDF11 contributes to the alleviation of myocardial IR injury through enhancing mitochondrial biogenesis and suppressing cardiomyocyte apoptosis.

Upregulation of elafin expression in the fallopian tube of ectopic tubal pregnancies compared to the normal tubes.

J Reprod Immunol

Fatemeh Zakizadeh, Hamidreza Mahmoudzadeh-Sagheb, Azam Asemi-Rad +5 more

Ectopic pregnancy is one of the most important causes of maternal deaths and fallopian tubes are the location of 95% of ectopic pregnancies. Elafin is a natural antimicrobial molecule that plays an important role as an anti-inflammatory agent in mucosal surfaces and has been found in the female reproductive tract.