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Anti-virulence and anti-efflux pump activity of synthetic defensins and histatin in Candida auris.
Microb Pathog
Siham Shaban, Mrudula Patel, Aijaz Ahmad
Novel antifungal therapies are needed to combat multidrug-resistant Candida auris, a pathogen with significant virulence and efflux pump activity. Building on our previous work demonstrating the fungicidal activity of selected antimicrobial peptides (AMPs) towards C. auris, this study investigates their effects against virulence factors and efflux pump. We evaluated the impact of human β-Defensin-3 (hBD-3), Human neutrophil peptide-1 (HNP-1) and human salivary histatin 5 (His 5) on C. auris virulence and resistance, using two clinical isolates. Their effect on adhesion and proteinase activity was studied using adherence assay and BSA plates, respectively. Their impact on biofilm formation and mature biofilm was studied using the MTT reduction test and further visualized using Confocal laser scanning microscope. Intracellular accumulation and external efflux of rhodamine-6-G was studied to establish their action on efflux pump activity. In addition, their effect on the expression of related genes was studied using RT-qPCR. At sub-minimum inhibitory concentrations (sub-MICs) and minimum inhibitory concentrations (MICs), all three test AMPs significantly reduced both adherence and proteinase activity. All the test peptides substantially inhibited the metabolic activity and decreased the density of growing and mature biofilms. Moreover, the tested peptides effectively obstructed efflux pumps and downregulated the genes linked to virulence and efflux pumps, including CDR1, CDR2, MDR1, SAP3, SNQ2, PGA26, PGA7 and PGA52. Finally, the safety of these peptides was verified by a haemolytic test. The finding of this study demonstrated the anti-virulence and anti-efflux pump properties of the tested AMPs. Therefore, these peptides can be a potentially effective alternative for managing infections caused by C. auris.
Targeted delivery of apelin using a novel extracellular vesicle platform for pulmonary arterial hypertension treatment.
Biomaterials
Jihong Kim, Yong-Soon Choi, Jaehyun Kim +15 more
Pulmonary arterial hypertension (PAH) is a severe disease characterized by endothelial dysfunction, vascular remodeling, and pulmonary artery occlusion, culminating in right ventricular hypertrophy and heart failure. While apelin peptides are promising therapeutic candidates due to their critical role in vascular homeostasis, their efficacy as agonists is limited by insufficient lesion-specific targeting and suboptimal in vivo stability. Here, we developed an engineered extracellular vesicle (EV) platform for precise apelin delivery to PAH lesions, maximizing therapeutic impact. Using interferon-induced transmembrane protein 3 (IFITM3), a type II transmembrane protein, we oriented the apelin peptide on the EV surface with its C-terminus fully exposed, preserving the critical binding interface for functional interaction with the apelin receptor. To further enhance targeting specificity, we integrated the PAH-targeting peptide CARSKNKDC (CAR), which selectively binds to heparan sulfate overexpressed on PAH endothelial cells, into the IFITM3-apelin scaffold, creating CAR-Apelin EVs. This dual-engineered EVs demonstrated exceptional targeting and therapeutic efficacy in PAH models. CAR-Apelin EVs significantly reversed pathological vascular remodeling and improved cardiac function, as evidenced by reduced right ventricular systolic pressure and hypertrophy. Our findings establish CAR-Apelin EVs as a transformative therapeutic strategy, providing a targeted and effective approach to meet critical unmet needs in PAH treatment.
Adjustment of the SMART risk score by bioactive adrenomedullin enables a more accurate prediction of mortality in patients with ASCVD.
Atherosclerosis
Berkan Kurt, Matthias Rau, Oliver Hartmann +18 more
Bioactive adrenomedullin 1-52 (bio-ADM) is a novel biomarker for the assessment of endothelial function and prediction of adverse outcomes in patients with acute heart failure and cardiogenic shock. The SMART (Second Manifestations of Arterial Disease) risk score is a validated tool for risk assessment in patients with established atherosclerotic cardiovascular disease (ASCVD). Here we assessed whether bio-ADM adds incremental prognostic value to the SMART risk score in stable patients with ASCVD.
Unraveling the pathophysiology of narcolepsy type 1 through hypothesis-driven and hypothesis-generating approaches.
Semin Immunol
Sean A Freeman, Ikram Ayoub, Yves Dauvilliers +1 more
Narcolepsy type 1 (NT1) is a chronic orphan neurological sleep disorder characterized by the loss of hypocretin-producing neurons in the lateral hypothalamus, which play a crucial role in wakefulness. Given the genetic association with the HLA-DQB1 * 06:02 allele and environmental links with the 2009 influenza pandemic, many lines of evidence point towards an immune mechanism, notably autoimmunity, underlying the disease pathophysiology. Autoreactive T cells are found in the blood of NT1 patients, and mouse models demonstrate their migratory capacity and contribution in the selective destruction of hypocretin-producing neurons. However, direct evidence for their role in human NT1 pathophysiology remains elusive. In complementing these findings, hypothesis-generating approaches-including multiparametric immune profiling, transcriptomic sequencing and large-scale proteomic of blood and cerebrospinal fluid-have uncovered promising new avenues into the immune system's involvement in NT1. In this review, we explore the mechanisms driving NT1 pathogenesis, emphasizing both hypothesis-driven and hypothesis-generating approaches, and discuss potential future directions that could pave the way for targeted immunotherapies.
Ero1a, the most strongly hypoxia-induced protein in PASMCs, promotes the development of hypoxia- and monocrotaline-induced pulmonary hypertension in rats.
Life Sci
Xiaojun Hao, Hao Li, Qingli Zeng +2 more
Pulmonary hypertension (PH) is a progressive and life-threatening condition characterized by elevated pressure in the pulmonary circulation, leading to right heart dysfunction and ultimately heart failure. Pulmonary artery smooth muscle cells (PASMCs) are key players in group 3 PH (due to lung diseases and/or hypoxia) progression, where their aberrant proliferation and migration drive vascular remodeling. Dysregulated proteins in PASMCs are critical in PH development. Our research was designed to investigate the most promising potential therapeutic targets for PH.
The role of vasopressin deficiency in the fluid intake suppression hyper-responsivity to central glucagon-like peptide-1 in the Brattleboro rat.
Physiol Behav
Sydney A David, Destiny J Brakey, Matthew J Paul +1 more
Food and fluid intakes are physiologically and behaviorally intertwined; one often affects the other. Likewise, pharmacological manipulations that influence eating often affect drinking. For example, glucagon-like peptide-1 (GLP-1) suppresses both eating and fluid intake, but the respective elements of the GLP-1 system remain unparsed. The Brattleboro rat has emerged as a model to test for separable elements in the control of fluid or food intake. Brattleboro rats have hereditary hypothalamic vasopressin deficiency. To compensate for the resultant polyuria, they drink copious amounts of water. Eating, however, is similar to that observed in wildtype littermates and other Long Evans rats. Interestingly, treatment with a GLP-1 receptor agonist exendin-4 (Ex4) causes an exaggerated suppression of drinking in Brattleboro rats, but suppression of eating is comparable to wildtype controls. To test if this hyper-responsivity depends on the polydipsia in these rats, we normalized their drinking using desmopressin (ddAVP), a V2R agonist, before treatment with Ex4. ddAVP attenuated, but did not completely prevent, the hyper-responsivity to Ex4. Conversely, we treated wildtype rats with acute or chronic tolvaptan, a V2R antagonist, which generated a Brattleboro-like polydipsia, but this did not recapitulate the hyper-responsivity to Ex4 observed in Brattleboro rats. Based on these results, we conclude that polydipsia alone is insufficient to generate a hyper-responsive fluid intake suppression by Ex4, and that Brattleboro rats have at least some persistent hyper-responsivity to Ex4, even after alleviation of their polydipsia. These results provide important context for future studies using Brattleboro rats to study the GLP-1 system.
FAM172A deletion aggravates high fat diet-induced MASLD via the eIF2α-ATF4-FGF21 loop.
Life Sci
Herui Wei, Meixin Gao, Shiwei Wang +5 more
Inhibition of endoplasmic reticulum stress (ERS) can effectively improve the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we attempted to further explore the mechanism of Fam172a in high fat diet (HFD) induced-MASLD.
Insights into the function and research status of membrane protein APJ.
Gene
Zhiying Ai, Bo Dong, Jing Chen
APJ, a membrane protein belonging to the G protein-coupled receptor (GPCR) family, was first discovered in 1993. It is activated by endogenous ligands such as Apelin and Elabela, coupling with various G proteins to trigger downstream signaling pathways. APJ is ubiquitously expressed in various organs and tissues, and plays pivotal roles in numerous physiological and pathological processes. This review provides a comprehensive overview of APJ's physiological functions, including its involvement in the cardiovascular system, metabolism, neuroendocrine stress responses, respiratory diseases, and appetite regulation. Furthermore, it discusses the potential of APJ as a biomarker for various tumors and its crucial role in tumor angiogenesis. Additionally, the review covers the development of small molecule antagonists targeting APJ and highlights the major challenges and future prospects in current APJ research. In conclusion, this review offers valuable insights into the multifaceted functions of APJ, its targeting antagonists, existing research challenges, and potential future directions, thereby contributing to further advancements in research and drug development in this field.
Acalabrutinib alleviates metabolic dysfunction-associated steatotic liver disease by regulating bile acid metabolism.
Int J Biochem Cell Biol
Yanbo Wang, Shiwei Chen, Bingjue Ye +5 more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic of chronic liver disease currently lacking effective treatment. Evaluating the therapeutic effects of existing drugs on MASLD is a time and cost-effective strategy. Bruton's tyrosine kinase (BTK) is an inflammatory signaling molecule playing an important role in the progression of MASLD. Aclabrutinib, a BTK inhibitor approved for treating mantle-cell lymphoma and chronic lymphocytic leukemia, has not been investigated for its potential to treat MASLD. This study examined the therapeutic effects and mechanisms of aclabrutinib on MASLD using a high-fat diet-induced mouse model. Results demonstrated significant alleviation of pathological parameters associated with MASLD upon administration of aclabrutinib. TSE PhenoMaster results revealed that aclabrutinib increased energy expenditure in mice. Furthermore, aclabrutinib upregulated the expression of genes associated with thermogenesis and lipolysis in adipose tissues. Additionally, it inhibited the transcription of genes related to lipid absorption in the small intestine and liver, while increasing the expression of hormone-sensitive lipase, hepatic nuclear factor 4 alpha and fibroblast growth factor 21 in the liver. Further analysis indicated that aclabrutinib promoted the alternative pathway of bile acid synthesis while restoring gut microbiota homeostasis. The altered bile acid profiles upregulated G protein-coupled bile acid receptor 1 expression in adipose tissues as well as vitamin D receptor expression in liver and small intestine. Our findings suggest that by regulating bile acid metabolism and gut microbiota, aclabrutinib may promote thermogenesis and lipolysis, thereby alleviating MASLD. This study provides novel insights into clinical applications targeting BTK for treating MASLD.
Metabolic dysfunction-associated steatotic liver disease in people with HIV.
Curr Opin HIV AIDS
Arijeet K Gattu, Lindsay T Fourman
Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent among people with HIV (PWH) and increasingly recognized as a major contributor to morbidity and mortality. The field of MASLD is rapidly evolving with adoption of a new nomenclature and approval of the first FDA-approved therapy within the past year. These developments underscore the need to consider the current state of the science specifically in the context of HIV.
Effect of thymosin α1 on Immune response and organ function in acute aortic dissection surgery: PANDA II trial protocol.
Future Cardiol
Hong Liu, Si-Chong Qian, Ying-Yuan Zhang +16 more
This multicenter randomized controlled trial evaluates the efficacy of thymosin alpha 1 (Tα1) supplementation in preventing organ dysfunction following acute type A aortic dissection (ATAAD) repair. Over 330 patients will be equally assigned to receive either Tα1 plus standard care or placebo with standard management. The primary endpoint involves calculating the difference in mean postoperative Sequential Organ Failure Assessment (SOFA) scores between groups, measured daily from postoperative days 7. By targeting post-operative immune system imbalance, this study aims to establish a novel therapeutic approach for reducing systemic inflammatory response syndrome (SIRS)-mediated organ injury and improving long-term outcomes in this high-risk population. Results will be disseminated through peer-reviewed publications and international conferences.Trial registration: ClinicalTrials.gov Registry (NCT05339529).
Comparative Analysis of CGRP, VIP and 
PACAP-38 Levels in Migraine with and 
Without Aura: A Case-control Study.
Ann Neurosci
N Sreevani, B Ramesh, K Maheshkumar +1 more
Migraine pathophysiology involves the release of vasoactive neuropeptides following trigeminovascular system activation. While calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) have been individually studied in migraine, their combined role in differentiating migraine subtypes remains unclear.
Isoenergetic reduction of dietary macronutrients affects body composition, physical activity, and post-prandial hormone responses in lean and obese cats fed to maintain body weight.
Front Vet Sci
Hannah Godfrey, Érico de Mello Ribeiro, Shoshana Verton-Shaw +5 more
High consumption of dietary carbohydrates (nitrogen-free extract, NFE) in extruded dry foods is postulated as a risk factor for feline obesity, though evidence is limited. This study utilized a three-test diet approach to isolate the effect of each macronutrient on body composition, voluntary physical activity, and serum satiety hormone response in lean and obese cats.
A novel approach for the treatment of AML, through GHRH antagonism: MIA-602.
Rev Endocr Metab Disord
Joel Costoya, Simonetta I Gaumond, Ravinder S Chale +2 more
Acute myeloid leukemia (AML) is the most aggressive and prevalent form of leukemia in adults. The gold-standard intervention revolves around the use of chemotherapy, and in some cases hematopoietic stem cell transplantation. Drug resistance is a frequent complication resulting from treatment, as it stands there are limited clinical measures available for refractory AML besides palliative care. The goal of this review is to renew interest in a novel targeted hormone therapy in the treatment of AML utilizing growth hormone-releasing hormone (GHRH) antagonism, given it may provide a potential solution for current barriers to achieving complete remission post-therapy. Recapitulating pre-clinical evidence, GHRH antagonists (GHRH-Ant) have significant anti-cancer activity across experimental human AML cell lines in vitro and in vivo and demonstrate significant inhibition of cancer in drug resistant analogs of leukemic cell lines as well. GHRH-Ant act in manners that are orthogonal to anthracyclines and when administered in combination synergize to produce a more potent anti-neoplastic effect. Considering the adversities associated with standard AML therapies and the developing issue of drug resistance, MIA-602 represents a novel approach worth further investigation.
Hydrogels with multiple RGD presentations increase cell adhesion and spreading.
Acta Biomater
Abolfazl Salehi Moghaddam, Katelyn Dunne, Wendy Breyer +2 more
A key challenge in designing hydrogels for cell culture is replicating the cell-matrix interactions found in tissues. Cells use integrins to bind their local matrix and form adhesions in which integrins dynamically move on the cell membrane while applying significant forces to the local matrix. Identifying the important biomaterial features for these interactions is challenging because it is difficult to independently adjust variables such as matrix stiffness, stress relaxation, the mobility of adhesion ligands, and the ability of these ligands to support cellular forces. In this work, we designed a hydrogel platform consisting of interpenetrating polymer networks of covalently crosslinked poly(ethylene glycol) (PEG) and self-assembled peptide amphiphiles (PA). We can tune the viscoelasticity of the hydrogel by modulating the composition of both networks. Ligand mobility can be adjusted independently of the matrix mechanical properties by attaching the arginine-glycine-aspartic acid (RGD) cell adhesion ligand to either the covalent PEG network, the dynamic PA network, or both networks at once. We find that endothelial cell adhesion formation and spreading is maximized in soft gels in which adhesion ligands are present on both the covalent and non-covalent networks. The dynamic nature of adhesion domains, coupled with their ability to exert substantial forces on the matrix, suggests that having different presentations of RGD ligands which are either mobile or capable of withstanding significant forces is needed to mimic different aspects of complex cell-matrix adhesions. These results will contribute to the design of hydrogels that better recapitulate physiological cell-matrix interactions. STATEMENT OF SIGNIFICANCE: Creating artificial environments that accurately mimic how cells interact with their surrounding matrix in natural tissues remains a fundamental challenge in biomaterials science. This study introduces a dual-network hydrogel platform that independently controls mechanical properties and adhesion ligand mobility by combining stable and dynamic polymer networks. A significant body of work has shown that matrix viscoelasticity and adhesion ligand mobility are important for cell adhesion and spreading. Our work builds on this by showing that endothelial cells function optimally when they can simultaneously engage with both mobile adhesion sites and force-resistant anchoring points, independent of matrix viscoelasticity. These insights will guide the design of more physiologically relevant hydrogels for tissue engineering applications and disease modeling.
Cell/Surface Interactions and Osseointegration of Ti-6AI-4V: Effects of Laser Microgrooves, Hydroxyapatite Nanorods, and Arginyl-Glycyl-Aspartic Acid (RGD) on Ti-6Al-4V.
J Biomed Mater Res A
Precious O Etinosa, Ali A Salifu, Sarah A Osafo +3 more
This work presents the results of an experimental study of surface-modified Ti-6Al-4V designed to enhance implant integration with human fetal osteoblast (hFOB) cells. Three surface profiles-laser-grooved (LG), Hydroxyapatite (HA)-coated laser-grooved (LGH), and arginyl glycyl aspartic acid (RGD)-functionalized HA-coated laser-grooved (LGHR)-were developed and evaluated for their effects on hFOB cell attachment, spreading, proliferation, and ECM formation over a 28-day period. Cell-laden surfaces were analyzed using scanning electron and fluorescence microscopies, and cell proliferation was quantified using the Alamar Blue assay to provide additional insights. The surface characterization revealed that the LG substrate facilitated contact guidance, promoting directional cell alignment and attachment. The LGH substrate additionally created a bioactive interface by mimicking natural bone tissue, releasing calcium and phosphate ions that enhanced cell attachment and spreading. The LGHR substrate provided specific biological cues, further improving early cell attachment, accelerating proliferation, and promoting extracellular matrix (ECM) formation. Quantitative analysis confirmed that LGHR surfaces exhibited the highest cell density, areal coverage, and metabolic activity, particularly during the initial stages of culture, emphasizing the synergistic effects of HA and RGD coatings in accelerating osseointegration. This novel approach offers robust improvements in implant-tissue integration, accelerating wound healing and enhancing tissue compatibility, with promising implications for orthopedic and dental applications.
Adrenomedullin-RAMP2 System Modulates Inflammation and Tissue Repair in Experimental Autoimmune Uveitis Via T-Cell and M2 Macrophage Regulation.
Invest Ophthalmol Vis Sci
Yorishige Matsuda, Megumu Tanaka, Yunlu Zhao +15 more
Adrenomedullin (AM), a peptide produced by various cells, exerts diverse physiological effects and is regulated by receptor activity-modifying proteins (RAMP2 and 3). Experimental autoimmune uveitis (EAU) is a well-established model for studying human autoimmune uveitis. Hence, we investigated the pathophysiological roles of the AM-RAMP system in uveitis using an optimized EAU mouse model.
Growth hormone-releasing hormone receptor (GHRH-R) and its signaling.
Rev Endocr Metab Disord
Gabor Halmos, Zsuzsanna Szabo, Nikoletta Dobos +2 more
The hypothalamic polypeptide growth hormone-releasing hormone (GHRH) stimulates the secretion of growth hormone (GH) from the pituitary through binding and activation of the pituitary type of GHRH receptor (GHRH-R), which belongs to the family of G protein-coupled receptors with seven potential membrane-spanning domains. Various splice variants of GHRH-R (SV) in human neoplasms and other extrapituitary tissues were demonstrated and their cDNA was sequenced. Among the SVs, splice variant 1 (SV1) possesses the greatest similarity to the full-length GHRH-R and remains functional by eliciting cAMP signaling and mitogenic activity upon stimulation by GHRH. In this review, we briefly discuss the activation, regulation, molecular mechanisms and signaling pathways of GHRH-Rs and their SVs in various tissues and also summarize the expression, biological activities and potential function of GHRH, its analogs and their receptors. A large body of work have extensively studied and evaluated potential clinical applications of agonists and antagonists of GHRH in diverse fields, including oncology, endocrinology, obesity, diabetes, other metabolic dysfunctions, cardiology, immune functions, mood disorders, Alzheimer's and lung disease, ophthalmology, inflammation, wound healing and other applications. These results strongly support the potential therapeutic use of GHRH analogs in human medicine in the near future.
Circulating Fibroblast Growth Factor-21 in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.
Curr Obes Rep
Ioanna Filimidou, Myrsini Orfanidou, Antonis Goulas +2 more
The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is multifactorial. Fibroblast growth factor-21 (FGF-21) has been proposed to be associated with NAFLD, but data on its circulating levels in patients with NAFLD are to date conflicting.
Effects of Tesamorelin on Neurocognitive Impairment in Persons With HIV and Abdominal Obesity.
J Infect Dis
Ronald J Ellis, Florin Vaida, Keren Hu +6 more
In people with HIV who are virally suppressed with antiretroviral therapy, abdominal obesity (AO) is linked to neurocognitive impairment (NCI), potentially due to visceral adiposity, inflammation, and reduced insulin-like growth factor 1 (IGF-1). Tesamorelin, a growth hormone-releasing hormone, reduces AO and increases IGF-1, suggesting that it might mitigate NCI in people with HIV and viral suppression.