Administration Of Peptide Research Articles

Selective removal of misfolded SOD1 delays disease onset in a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. There is no cure currently. The discovery that mutations in the gene SOD1 are a cause of ALS marks a breakthrough in the search for effective treatments for ALS. SOD1 is an antioxidant that is highly expressed in motor neurons. Human SOD1 is prone to aberrant modifications. Familial ALS-linked SOD1 variants are particularly susceptible to aberrant modifications. Once modified, SOD1 undergoes conformational changes and becomes misfolded. This study aims to determine the effect of selective removal of misfolded SOD1 on the pathogenesis of ALS. Based on the chaperone-mediated protein degradation pathway, we designed a fusion peptide named CT4 and tested its efficiency in knocking down intracellularly misfolded SOD1 and its efficacy in modifying the pathogenesis of ALS. Expression of the plasmid carrying the CT4 sequence in human HEK cells resulted in robust removal of misfolded SOD1 induced by serum deprivation. Co-transfection of the CT4 and the G93A-hSOD1 plasmids at various ratios demonstrated a dose-dependent knockdown efficiency on G93A-hSOD1, which could be further increased when misfolding of SOD1 was enhanced by serum deprivation. Application of the full-length CT4 peptide to primary cultures of neurons expressing the G93A variant of human SOD1 revealed a time course of the degradation of misfolded SOD1; misfolded SOD1 started to decrease by 2 h after the application of CT4 and disappeared by 7 h. Intravenous administration of the CT4 peptide at 10mg/kg to the G93A-hSOD1 reduced human SOD1 in spinal cord tissue by 68% in 24 h and 54% in 48 h in presymptomatic ALS mice. Intraperitoneal administration of the CT4 peptide starting from 60days of age significantly delayed the onset of ALS and prolonged the lifespan of the G93A-hSOD1 mice. The CT4 peptide directs the degradation of misfolded SOD1 in high efficiency and specificity. Selective removal of misfolded SOD1 significantly delays the onset of ALS, demonstrating that misfolded SOD1 is the toxic form of SOD1 that causes motor neuron death. The study proves that selective removal of misfolded SOD1 is a promising treatment for ALS.

Caveolin-1 scaffolding domain peptide prevents corpus cavernosum fibrosis and erectile dysfunction in bilateral cavernous nerve injury-induced rats.

Corpus cavernosum (CC) fibrosis significantly contributes to post-radical prostatectomy erectile dysfunction (pRP-ED). Caveolin-1 scaffolding domain (CSD)-derived peptide has gained significant concern as a potent antagonist of tissue fibrosis. However, applying CSD peptide on bilateral cavernous nerve injury (BCNI)-induced rats remains uninvestigated. The aim was to explore the therapeutic outcome and underlying mechanism of CSD peptide for preventing ED in BCNI rats according to the hypothesis that CSD peptide may exert beneficial effects on erectile tissue and function following BCNI through limiting collagen synthesis in CC smooth muscle cells (CCSMCs) and CC fibrosis. After completing a random assignment of male Sprague Dawley rats (10 weeks of age), BCNI rats received either saline or CSD peptide treatment, as opposed to sham-operated rats. The evaluations of erectile function (EF) and succedent collection and histological and molecular biological examinations of penile tissue were accomplished 3weeks postoperatively. In addition, the fibrotic model of CCSMCs was used to further explore the mechanism of CSD peptide action in vitro. The assessments of EF, SMC/collagen ratio, α-smooth muscle actin, caveolin-1 (CAV1), and profibrotic indicators expressions were conducted. BCNI rats exhibited significant decreases in EF, SMC/collagen ratio, α-SMA, and CAV1 levels, and increases in collagen content together with transforming growth factor (TGF)-β1/Smad2 activity. However, impaired EF, activated CC fibrosis, and Smad2 signaling were attenuated after 3weeks of CSD peptide treatment in BCNI rats. In vitro, TGF-β1-induced CCSMCs underwent fibrogenetic transformation characterized by lower expression of CAV1, higher collagen composition, and phosphorylation of Smad2; then, the delivery of CSD peptide could significantly block CCSMC fibrosis by inactivating Smad2 signaling. Based on available evidence of CSD peptide in the prevention of ED in BCNI rats, this study can aid in the development and clinical application of CSD peptide targeting pRP-ED. This study provides data to suggest that CSD peptide protects against BCNI-induced deleterious alterations in EF and CC tissues. However, the available evidence still does not fully clarify the detailed mechanism of action of CSD peptide. Administration of CSD peptide significantly retarded collagen synthesis in CCSMCs, limited CC fibrosis, and prevented ED via confrontation of TGF-β1/Smad signaling in BCNI rats.

Nanotechnology and Nanocapsule-Based Approaches for the Diagnosis and Therapeutics of Diabetes Mellitus: A Concise Survey

A serious health concern of frightening proportions is diabetes mellitus, a common metabolic illness marked by increased blood sugar levels as a result of insufficient insulin production or response. Nanosensors and nanomaterials have recently shown tremendous promise for enhancing glucose detection for the treatment of diabetes. Significant improvements in glucose sensor sensitivity, specificity, and reversibility have been achieved through the incorporation of nanoscale carbon structures, nanocomposites, and other nanomaterials. The use of these tailored nanocarriers offers a viable technique to enhance patient compliance and diabetes management by addressing the difficulties associated with oral peptide medication delivery for the treatment of diabetes caused by adverse circumstances in the gastrointestinal system. Nanocapsules are a promising approach for effective medication transportation via biological barriers by protecting drug molecules from the biological environment. A workable solution to problems with oral peptide medicine distribution for treating diabetes, particularly when it comes to unfavorable gastrointestinal conditions, is the use of customized nanocarriers. These nanocarriers have a flexible design and special in vivo characteristics that make it possible to go beyond cellular and tissue absorption barriers while improving the stability and effectiveness of therapeutic peptides. The management of diabetes mellitus has a great deal of potential for targeted lipid-based nanoparticles, which operate as an efficient drug delivery technique for oral administration of therapeutic peptides. With these developments in nanotechnology and nanocapsule-based techniques, diabetes treatment might be improved, patient compliance could be increased, and drug administration frequency could be decreased, potentially changing the field. This article presents a comprehensive review of recent advances in nanotechnology for diabetes mellitus diagnosis and the utilization of nanocapsules in diabetes treatment
 Keywords: Nanotechnology, Nanocapsules, Diabetes Mellitus, Nanocarriers, Nanomaterial, Nanotube

Associations between feeding and glucagon-like peptide-2 in healthy ponies.

Gastrointestinal peptides, such as glucagon-like peptide-2 (GLP-2), could play a direct role in the development of equine hyperinsulinaemia. To describe the secretory pattern of endogenous GLP-2 over 24 h in healthy ponies and determine whether oral administration of a synthetic GLP-2 peptide increases blood glucose or insulin responses to feeding. A cohort study followed by a randomised, controlled, cross-over study. In the cohort study, blood samples were collected every 2 h for 24 h in seven healthy ponies and plasma [GLP-2] was measured. In the cross-over study, 75 μg/kg bodyweight of synthetic GLP-2, or carrier only, was orally administered to 10 ponies twice daily for 10 days. The area under the curve (AUC0-3h ) of post-prandial blood glucose and insulin were determined before and after each treatment. Endogenous [GLP-2] ranged from <0.55 to 1.95 ± 0.29 [CI 0.27] ng/mL with similar peak concentrations in response to meals containing 88-180 g of non-structural carbohydrate, that were ~4-fold higher (P < 0.001) than the overnight nadir. After GLP-2 treatment peak plasma [GLP-2] increased from 1.1 [0.63-1.37] ng/mL to 1.54 [1.1-2.31] ng/mL (28.6%; P = 0.002), and AUC0-3h was larger (P = 0.01) than before treatment. The peptide decreased (7%; P = 0.003) peak blood glucose responses to feeding from 5.33 ± 0.45 mmol/L to 5.0 ± 0.21 mmol/L, but not AUC0-3h (P = 0.07). There was no effect on insulin secretion. The study only included healthy ponies and administration of a single dose of GLP-2. The diurnal pattern of GLP-2 secretion in ponies was similar to other species with no apparent effect of daylight. Although GLP-2 treatment did not increase post-prandial glucose or insulin responses to eating, studies using alternative dosing strategies for GLP-2 are required.

Effect of Short PSG Peptides on Inflammatory Markers in Allogeneic Bone Marrow Cell Transplantation in Wistar Rats.

Short linear peptide fragments of placental trophoblastic β1-glycoprotein (PSG) (YECE, YQCE, YVCS, and YACS) were studied in the context of their immunomodulatory effects at the level of inflammatory markers. The original host-versus-graft model was used in male Wistar rats without prior conditioning of recipient bone marrow. A composition of PSG peptide fragments was injected to animals after allogeneic transplantation of bone marrow cells in a dynamic experiment, inflammatory markers α1-acid glycoprotein (AGP, orosomucoid), α2-macroglobulin (α2M) were assayed by ELISA, and biochemical parameters (total protein, glucose, creatinine, and urea) were measured. The levels of α2M and AGP increased in response to allotransplantation, whereas administration of PSG peptides normalized serum α2M levels by the end of the experiment. The decrease in α2M level coincided with the independent effect of PSG peptide administration. The levels of total protein, glucose, creatinine, and urea in rat serum after allotransplantation were reduced throughout the experiment. Administration of PSG peptides contributed to normalization of serum total protein, creatinine, and urea levels by the end of the experiment. Administration of PSG peptides after allogeneic transplantation of bone marrow suspension contributed to normalization of the levels of α2M, total protein, creatinine, and urea, which can be interpreted as an anti-inflammatory effect of these peptides.

Reparative and Antioxidant Effects of New Analogues of Immunomodulator Thymogen in Experimental Model of Liver Damage.

We studied the reparative and antioxidant effects of Thymogen and its new structural analogues obtained by binding amino acid D-Ala to the N- or C-end of the peptide molecule in acute toxic hepatopathy. Intragastric administration of carbon tetrachloride for 5 days caused the development of fat degeneration of hepatocytes, a decrease in catalase activity, and an increase in malondialdehyde concentration. Administration of peptides suppressed oxidative peroxidation and stimulated reparative regeneration of hepatocytes; Thymogen analogues produced more pronounced hepatotropic and antioxidant effects than Thymogen. Inclusion of D-Ala enhanced the effect of Thymogen on the processes of regeneration in hepatocytes and the antioxidant effect under conditions of acute carbon tetrachloride hepatopathy. The highest efficiency was achieved when the amino acid was added to the C-end of the molecule.

Vazointestinal Peptid ve Naringeninin Rotenon Kaynaklı Deneysel Parkinson Hastalığı Modeli Üzerine Etkileri

Aim: The aim of this study was to evaluate the intraperitoneal administration of naringenin and vasointestinal peptide (VIP), which are shown effective in various scientific studies, in terms of anti-Parkinsonian activity in rats. Material and Methods: Forty-eight Wistar albino female rats were divided into 4 groups. No intervention was made in the control group, rotenone was given to the RT group, rotenone and VIP (25 ng/kg) to the RT+VIP group, and rotenone and naringenin (10 mg/kg) to the RT+NG group. All treatments were administered intraperitoneally for 14 days. The hole and board method was used to show the effects of the Parkinson's model on behavior. On the last day of the experiment, motor tests were carried out with the hole and board apparatus. After the study was completed, biochemical analyzes were performed from brain tissue samples. Results: In comparison to the RT group, while the alpha-sync level in the RT+NG (p=0.023), malondialdehyde (MDA) levels both in the RT+VIP (p=0.039) and RT+NG (p=0.032), and superoxide dismutase (SOD) inhibition in the RT+VIP (p=0.042) groups decreased significantly, the 8-OHdG levels in the RT+VIP (p=0.042) and RT+NG (p=0.034) groups increased significantly. Statistically significant improvement was found both in biochemical and motor activities with the VIP and naringenin treatments applied. Conclusion: According to the results obtained, the symptoms of Parkinson's disease were formed biochemically by rotenone application. The administration of VIP and naringenin treatments has shown positive effects experimentally and has been promising as an adjunct treatment element in the fight against Parkinson's disease.

C5aR+ dendritic cells fine-tune the Peyer’s patch microenvironment to induce antigen-specific CD8+ T cells

The mucosal delivery route is considered ideal for immunization. However, induction of antigen-specific mucosal immunity is difficult due to the tolerogenic environment. Therefore, developing an immunogenic mucosal dendritic cell (DC)-targeting strategy is required. Herein, we investigated the characteristics and immunogenic potential of Peyer’s patch (PP) DCs as an oral vaccination-targeting strategy. Single-cell RNA sequencing analysis of the PP DCs showed that complement C5a receptor- and lysozyme-expressing DCs exhibit increased expression of genes related to chemotaxis. Administration of the Co1 peptide, a C5aR ligand, increased CD8+ T cell infiltration and response to the co-delivered model antigen in mice. Furthermore, in the SARS-CoV-2 vaccine model, vaccination with Co1 elicited both systemic and mucosal immunity. Collectively, these findings demonstrate that C5aR signaling in mucosal DCs plays a role in regulating adjuvant activity by modulating the tissue microenvironment.

The kiss2/kiss2r system directly modulates the activity of the pituitary gland in largemouth bass (Micropterus salmoides)

The kisspeptin system, which involves hypothalamic neuropeptides, plays pivotal roles in the regulation of teleost reproduction. A previous study suggested that the kiss2/kissr2 system in largemouth bass (Micropterus salmoides) was involved in regulating gonadal development through the hypothalamus-pituitary-gonad (HPG) axis. However, whether the kiss2/kiss2r system directly regulates the activity of pituitary gland were not studied. This study aimed to elucidate the detailed mechanism of kisspeptin-induced effects on gonadotropin hormone-producing cells in vivo and in vitro. In situ hybridization analysis revealed very widespread expression of kiss2r mRNA in the optic tectum, hypothalamus and pituitary. In the pituitary, kiss2r-expressing cells were mainly located in the proximal pars distalis and pars intermedia, among which the fshβ- and lhβ-positive cells exhibited expression of kiss2r messengers. Furthermore, primary culture of pituitary cells and peptide administration experiments revealed that the Kiss2-10 peptide stimulates the expression of fshβ and lhβ and the secretion of FSH and LH in 24 h. In addition, histology analysis revealed that three injections of the Kiss2-10 peptide promoted ovary development and increased oocyte size but had little effect on testis development. These results suggested that the intrapituitary kisspeptinergic system, as a hypophysiotropic neuropeptide factor, directly modulates of gonadotroph function. This study will help uncover the reproductive endocrinology network and improve artificial breeding technology for largemouth bass.

Amyloid Precursor Protein and Tau Peptides Linked Together Ameliorate Loss of Cognition in an Alzheimer's Disease Animal Model.

The major proteins involved in Alzheimer's disease (AD) are amyloid precursor protein (APP) and Tau. We demonstrate that APP1 (390-412) and Tau1 (19-34), linked together with either a flexible or a rigid peptide bridge, are able to inhibit, in vitro, the interaction between APP and Tau proteins. Furthermore, nasal administration of biotin-labelled Flex peptide for two weeks indicated the localization of the peptide around and close to plaques in the hippocampus area. In vivo studies in 5xFAD transgenic (Tg) mice, which exhibit plaque load and mild cognitive decline at four months of age, show that nasal administration of the flexible linked peptide reduced amyloid plaque burden. Additionally, nasal treatment with either flexible or rigid linked peptides prevented cognitive function deterioration. A significant treatment effect was achieved when either treatment was initiated at the age of three months, before severe cognitive deficiency is evident, or at five months, when such deficiency is already observed. The nasally treated mice demonstrated a cognitive ability not significantly different from the non-Tg littermate controls. Testing the effect of the flexible peptide by gavage feeding on the cognitive function of 5xFAD Tg mice demonstrated that feeding as well as nasal treatment significantly improves the cognitive ability of Tg mice compared to control PBS-treated mice.

Administration of Collagen Peptide Prevents the Progression of Pulmonary Fibrosis in Bleomycin-Treated Mice

Collagen peptides (CPs) are food-derived peptides that possess a variety of bioactive properties. Our study investigates the effects of CP on pulmonary fibrosis in bleomycin (BLM)-treated mice. C57BL/6J mice were subcutaneously injected with BLM for two weeks followed by a three-week experimental diet containing 25 mg/g of CP derived from chicken feet. Supplementation with CP suppressed the increase in lung weight and disruption of lung architecture observed in mice treated with BLM. BLM-treated mice also exhibited higher hydroxyproline content and increased expression levels of type I and III collagen subunit genes in the lungs. CP supplementation exerted no effect on these collagen-related factors; however, it significantly suppressed the gene expression of fibronectin and inflammation-related molecules in the lungs of BLM-treated mice. These findings suggest that CP administration prevents the development of pulmonary fibrosis by acting as an anti-inflammatory agent.

Extension Region Domain of Soybean 7S Globulin Contributes to Serum Triglyceride-Lowering Effect via Modulation of Bile Acids Homeostasis.

Soybean 7S globulin (β-conglycinin), a major soybean storage protein, has been demonstrated to exert remarkable triglyceride (TG) and cholesterol-lowering effects, yet the underlying mechanism remains controversial. A comparative investigation is performed to assess the contribution of different structural domains of soybean 7S globulin, including core region (CR) and extension region (ER) domains, to biological effects of soybean 7S globulin using a high-fat diet rat model. The results show that ER domain mainly contributes to the serum TG-lowering effect of soybean 7S globulin, but not for CR domain. Metabolomics analysis reveals that oral administration of ER peptides obviously influences the metabolic profiling of serum bile acids (BAs), as well as significantly increased the fecal excretion of total BAs. Meanwhile, ER peptides supplementation reshapes the composition of gut microbiota and impacts the gut microbiota-dependent biotransformation of BAs which indicate by a significantly increased secondary BAs concentration in fecal samples. These results highlight that TG-lowering effects of ER peptides mainly stem from their modulation of BAs homeostasis. Oral administration of ER peptides can effectively lower serum TG level by regulating BAs metabolism. ER peptides have potential to be used as a candidate pharmaceutical for the intervention of dyslipidemia.

The Nuclear Localization Signal of NF-κB p50 Enters the Cells via Syndecan-Mediated Endocytosis and Inhibits NF-κB Activity

It is well established that cationic peptides can enter cells following attachment to polyanionic membrane components. We report that the basic nuclear localization signal (NLS) of the NF-κB p50 subunit is internalized via lipid raft-dependent endocytosis mediated by heparan sulfate proteoglycans and exerts significant NF-κB inhibitory activities both in vitro and in vivo. In vitro uptake experiments revealed that the p50 NLS peptide (CYVQRKRQKLMP) enters the cytoplasm and accumulates in the nucleus at 37 °C. Depleting cellular ATP pools or decreasing temperature to 4 °C abolished peptide internalization, confirming the active, energy-dependent endocytic uptake. Co-incubation with heparan sulfate or replacing the peptide’s basic residues with glycines markedly reduced the intracellular entry of the p50 NLS, referring to the role of polyanionic cell-surface proteoglycans in internalization. Furthermore, treatment with methyl-β-cyclodextrin greatly inhibited the peptide’s membrane translocation. Overexpression of the isoforms of the syndecan family of transmembrane proteoglycans, especially syndecan-4, increased the cellular internalization of the NLS, suggesting syndecans’ involvement in the peptide’s cellular uptake. In vitro, p50 NLS reduced NF-κB activity in TNF-α-induced L929 fibroblasts and LPS-stimulated RAW 264.7 macrophages. TNF-α-induced ICAM-1 expression of HMEC-1 human endothelial cells could also be inhibited by the peptide. Fifteen minutes after its intraperitoneal injection, the peptide rapidly entered the cells of the pancreas, an organ with marked syndecan-4 expression. In an acute pancreatitis model, an inflammatory disorder triggered by the activation of stress-responsive transcription factors like NF-κB, administration of the p50 NLS peptide reduced the severity of pancreatic inflammation by blocking NF-κB transcription activity and ameliorating the examined laboratory and histological markers of pancreatitis.

Neuroprotective Effects of a Serotonin Receptor Peptide Following Sham vs. Mild Traumatic Brain Injury in the Zucker Rat.

Accelerated cognitive decline frequently complicates traumatic brain injury. Obesity and type 2 diabetes mellitus drive peripheral inflammation which may accelerate traumatic brain injury-associated neurodegeneration. The Zucker rat harbors G-protein coupled receptor agonist IgG autoantibodies and in vitro neurotoxicity caused by these autoantibodies was prevented by a novel synthetic fragment of the serotonin 2A receptor. The aim of the present study was to test whether genetic obesity manifested in Zucker diabetic fatty rat is associated with greater spatial memory impairment before and after mild traumatic brain injury compared to Zucker lean rats. Furthermore, we investigated whether these neurodegenerative complications can be lessened by administration of a novel putative neuroprotective peptide comprised of a fragment of the second extracellular loop of the serotonin 2A receptor. Age-matched lean and fatty diabetic Zucker rats were tested in the Morris water maze (spatial memory) prior to receiving a sham-injury or lateral fluid percussion (LFP) mild traumatic brain injury. Behavioral testing was repeated at 1-week, 1-month, and 3-month intervals following injury. A synthetic peptide consisting of a portion of the 5-hydroxytryptamine (serotonin) 2A receptor (2 mg/kg) (vehicle, or an inactive scrambled version of the peptide (2 mg/kg)) was administered via intraperitoneal route every other day for 7 days after sham or LFP injury to lean rats or 7 days before and after sham or LFP injury to fatty rats. Mild traumatic brain injury impaired recall of spatial memory in fatty and lean rats. Zucker fatty rats subjected to sham-injury or mild TBI experienced a significantly greater longitudinal decline in recall of spatial memory compared to lean Zucker rats. A synthetic peptide fragment of the 5-hydroxytryptamine 2A receptor significantly enhanced acquisition of spatial learning and it appeared to strengthen recall of spatial learning (one-week) after sham injury in Zucker rats. These data suggest that the Zucker diabetic fatty rat is a suitable animal model to investigate the role of metabolic factor(s) in accelerated cognitive decline. A novel synthetic peptide comprised of a fragment of the second extracellular loop of the human serotonin 2A receptor appeared to have neuroprotective effects on both acquisition and recall of spatial memory in subsets of Zucker rats, with relatively greater benefit in sham-injured, lean Zucker rats.

Caudal DMN neurons innervate the spleen and release CART peptide to regulate neuroimmune function

BackgroundInflammation is a fundamental biological response to injury and infection, which if unregulated can contribute to the pathophysiology of many diseases. The vagus nerve, which primarily originates from the dorsal motor nucleus (DMN), plays an important role in rapidly dampening inflammation by regulating splenic function. However, direct vagal innervation of the spleen, which houses the majority of immune and inflammatory cells, has not been established. As an alternative to direct innervation, an anti-inflammatory reflex pathway has been proposed which involves the vagus nerve, the sympathetic celiac ganglion, and the neurotransmitter norepinephrine. Although sympathetic regulation of inflammation has been shown, the interaction of the vagus nerve and the celiac ganglia requires a unique interaction of parasympathetic and sympathetic inputs, making this putative mechanism of brain–spleen interaction controversial.BodyAs neuropeptides can be expressed at relatively high levels in neurons, we reasoned that DMN neuropeptide immunoreactivity could be used to determine their target innervation. Employing immunohistochemistry, subdiaphragmatic vagotomy, viral tract tracing, CRISPR-mediated knock-down, and functional assays, we show that cocaine and amphetamine-regulated transcript (CART) peptide-expressing projection neurons in the caudal DMN directly innervate the spleen. In response to lipopolysaccharide (LPS) stimulation, CART acts to reduce inflammation, an effect that can be augmented by intrasplenic administration of a synthetic CART peptide. These in vivo effects could be recapitulated in cultured splenocytes, suggesting that these cells express the as yet unidentified CART receptor(s).ConclusionOur results provide evidence for direct connections between the caudal DMN and spleen. In addition to acetylcholine, these neurons express the neuropeptide CART that, once released, acts to suppress inflammation by acting directly upon splenocytes.

Oral administration of collagen peptide in SKH-1 mice suppress UVB-induced wrinkle and dehydration through MAPK and MAPKK signaling pathways, in vitro and in vivo evidence.

The online version contains supplementary material available at 10.1007/s10068-023-01362-6.

P-668 Effects of the active site domain of visfatin on the improvement of ovarian function in 4-vinylcyclohexene diepoxide-induced ovarian failure mice

Abstract Study question Can only the active site of domain of visfatin improve ovarian function in mice with 4-vinylcyclohexene diepoxide (VCD)-induced ovarian failure? Summary answer The active site domain of visfatin improves ovarian function and fertility potential in VCD-induced mice by stimulating the ovarian angiogenesis and early follicular development. What is known already Ovarian aging is a representative unmet need in infertility treatment and many studies have attempted to improve oocytes quality by activating ovarian angiogenesis. Visfatin has been reported to have angiogenic activity. Our previous study reported that visfatin improved ovarian function and fertility potential in aged female mice. However, visfatin has many limitations in developing as a drug due to large molecular weight. Visfatin is composed of two structural domains, and the active site is located in the second structural domain (amino acid residues 181 to 390), which were defined as the active site domain (hereafter A-domain peptide) in this study. Study design, size, duration This is a controlled experimental study using a total of mice with 60 VCD-induced ovarian failure. The duration of this study was from January to November 2022. Participants/materials, setting, methods C57BL/6 female mice were randomly divided into six groups: Five groups received 160mg/kg VCD and one group received an equal volume of vehicle. Four VCD groups were intraperitoneally injected three times at intervals of 2 days with 500 and 1000 ng/ml of full-size visfatin and A-domain peptide, respectively. The remaining one group served as a negative control. After final treatment, follicular development, gene expression, AMH level, and fertility potential were examined. Main results and the role of chance In hematoxylin and eosin (H&amp;E) staining, numbers of functional follicles including primordial, primary, secondary, and antral follicles were significantly decreased in the VCD-vehicle group compared to the control. However, treatment of full-size visfatin and A-domain peptide increased the number of primordial and primary follicle. On immnohistochemistry (IHC), expression of BMP15, C-KIT, VEGF, and visfatin in ovarian tissues were significantly reduced in the VCD-vehicle group, but immunoreactivity of these factors strongly stained in the treatment of full-size visfatin and A-domain peptide. This effect was more remarkable in 500 ng/ml of A-domain peptide compared to other treatments. The serum AMH level was significantly lower in the VCD-vehicle group compared to the control group, but it was increased after the treatment with A-domain peptide and full-size visfatin. Limitations, reasons for caution This study does not elucidate a clear mechanism how A-domain peptide increases the ovarian function and fertility of VCD-induced ovarian failure mice although it stimulated the expression of genes associated with early follicular development and angiogenesis. Also, generalizability to humans may be limited because the study was conducted in mice. Wider implications of the findings This study suggests that administration of A-domain peptide could be applied as a new treatment strategy for ovarian aging, presumably by activating ovarian angiogenesis and dormant primordial follicles. Trial registration number Not applicable

Bioactive Protein and Peptide Release from a Mucoadhesive Electrospun Membrane

Protein-based biologics constitute a rapidly expanding category of therapeutic agents with high target specificity. Their clinical use has dramatically increased in recent years, but administration is largely via injection. Drug delivery across the oral mucosa is a promising alternative to injections, in order to avoid the gastrointestinal tract and first-pass metabolism. Current drug delivery formulations include liquid sprays, mucoadhesive tablets and films, which lack dose control in the presence of salivary flow. To address this, electrospun membranes that adhere tightly to the oral mucosa and release drugs locally have been developed. Here, we investigated the suitability of these mucoadhesive membranes for peptide or protein release. Bradykinin (0.1%) or insulin (1, 3, and 5%) were incorporated by electrospinning from ethanol/water mixtures. Immersion of membranes in buffer resulted in the rapid release of bradykinin, with a maximal release of 70 ± 12% reached after 1 h. In contrast, insulin was liberated more slowly, with 88 ± 11, 69.0 ± 5.4, and 63.9 ± 9.0% cumulative release of the total encapsulated dose after 8 h for membranes containing 1, 3, and 5% w/w insulin, respectively. Membrane–eluted bradykinin retained pharmacological activity by inducing rapid intracellular calcium release upon binding to its cell surface receptor on oral fibroblasts, when examined by flow cytometry. To quantify further, time-lapse confocal microscopy revealed that membrane–eluted bradykinin caused a 1.58 ± 0.16 fold-change in intracellular calcium fluorescence after 10 s compared to bradykinin solution (2.13 ± 0.21), relative to placebo. In conclusion, these data show that electrospun membranes may be highly effective vehicles for site-specific administration of biotherapeutic proteins or peptides directly to the oral mucosa for either local or systemic drug delivery applications.

High-mobility group box-1 peptide ameliorates bronchopulmonary dysplasia by suppressing inflammation and fibrosis in a mouse model

BackgroundThis study aimed to examine the effect of the HMGB1 peptide on Bronchopulmonary dysplasia (BPD)-related lung injury in a mouse model. ResultsHMGB1 peptide ameliorates lung injury by suppressing the release of inflammatory cytokines and decreasing soluble collagen levels in the lungs. Single-cell RNA sequencing showed that the peptide suppressed the hyperoxia-induced inflammatory signature in macrophages and the fibrotic signature in fibroblasts. These changes in the transcriptome were confirmed using protein assays. ConclusionSystemic administration of HMGB1 peptide exerts anti-inflammatory and anti-fibrotic effects in a mouse model of BPD. This study provides a foundation for the development of new and effective therapies for BPD.

Use of teduglutide in adults with short bowel syndrome-associated intestinal failure.

Short bowel syndrome (SBS) is a rare gastrointestinal disorder associated with intestinal failure (SBS-IF) and poor health-related outcomes. Patients with SBS-IF are unable to absorb sufficient nutrients or fluids to maintain significantly metabolic homeostasis via oral or enteral intake alone and require long-term intravenous supplementation (IVS), consisting of partial or total parenteral nutrition, fluids, electrolytes, or a combination of these. The goal of medical and surgical treatment for patients with SBS-IF is to maximize intestinal remnant absorptive capacity so that the need for IVS support may eventually be reduced or eliminated. Daily subcutaneous administration of the glucagon-like peptide 2 analog, teduglutide, has been shown to be clinically effective in reducing IVS dependence and potentially improving the health-related quality of life of patients with SBS-IF. The management of patients with SBS-IF is complex and requires close monitoring. This narrative review discusses the use of teduglutide for patients with SBS-IF in clinical practice. The screening of patient eligibility for teduglutide treatment, initiation, monitoring of efficacy and safety of treatment, adapting or weaning off IVS, and the healthcare setting needed for SBS-IF management are described, taking into consideration data from clinical trials, observational studies, and clinical experience.