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Identification of glutamine as a potential therapeutic target in dry eye disease.
Signal Transduct Target Ther
Xiaoniao Chen, Chuyue Zhang, Fei Peng +12 more
Dry eye disease (DED) is a prevalent inflammatory condition significantly impacting quality of life, yet lacks effective pharmacological therapies. Herein, we proposed a novel approach to modulate the inflammation through metabolic remodeling, thus promoting dry eye recovery. Our study demonstrated that co-treatment with mesenchymal stem cells (MSCs) and thymosin beta-4 (Tβ4) yielded the best therapeutic outcome against dry eye, surpassing monotherapy outcomes. In situ metabolomics through matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) revealed increased glutamine levels in cornea following MSC + Tβ4 combined therapy. Inhibition of glutamine reversed the anti-inflammatory, anti-apoptotic, and homeostasis-preserving effects observed with combined therapy, highlighting the critical role of glutamine in dry eye therapy. Clinical cases and rodent model showed elevated expression of glutaminase (GLS1), an upstream enzyme in glutamine metabolism, following dry eye injury. Mechanistic studies indicated that overexpression and inhibition of GLS1 counteracted and enhanced, respectively, the anti-inflammatory effects of combined therapy, underscoring GLS1's pivotal role in regulating glutamine metabolism. Furthermore, single-cell sequencing revealed a distinct subset of pro-inflammatory and pro-fibrotic corneal epithelial cells in the dry eye model, while glutamine treatment downregulated those subclusters, thereby reducing their inflammatory cytokine secretion. In summary, glutamine effectively ameliorated inflammation and the occurrence of apoptosis by downregulating the pro-inflammatory and pro-fibrotic corneal epithelial cells subclusters and the related IκBα/NF-κB signaling. The present study suggests that glutamine metabolism plays a critical, previously unrecognized role in DED and proposes an attractive strategy to enhance glutamine metabolism by inhibiting the enzyme GLS1 and thus alleviating inflammation-driven DED progression.
CCN5 suppresses injury-induced vascular restenosis by inhibiting smooth muscle cell proliferation and facilitating endothelial repair via thymosin β4 and Cd9 pathway.
Eur Heart J
Qi Zhang, Hongda Li, Tao Zhuang +18 more
Members of the CCN matricellular protein family are crucial in various biological processes. This study aimed to characterize vascular cell-specific effects of CCN5 on neointimal formation and its role in preventing in-stent restenosis (ISR) after percutaneous coronary intervention (PCI).
Activation of APJ Receptors by CMF-019, But Not Apelin, Causes Endothelium-Dependent Relaxation of Spontaneously Hypertensive Rat Coronary Arteries.
J Cardiovasc Pharmacol
Santo Anto, Chengwen Sun, Stephen T O'Rourke
Receptors for the vasoactive adipokine apelin, termed APJ receptors, are G-protein-coupled receptors and are widely expressed throughout the cardiovascular system. APJ receptors can also signal through G-protein-independent pathways, including G-protein-coupled receptor kinase 2 (GRK2), which inhibits endothelial nitric oxide synthase (eNOS) activity and nitric oxide production in endothelial cells. Apelin causes endothelium-dependent, nitric oxide-mediated relaxation of coronary arteries from normotensive animals, but the effects of activating APJ receptor signaling pathways in hypertensive coronary arteries are largely unknown. We hypothesized that apelin-induced relaxation is impaired in coronary arteries from spontaneously hypertensive rats (SHR). Western blot and mRNA analysis revealed increased GRK2 expression in cultured SHR coronary endothelial cells. Apelin failed to cause relaxation in isolated SHR coronary arteries but, in the presence of apelin, relaxations to acetylcholine were impaired. Apelin had no effect on relaxation to diethylamine NONOate. The GRK2 inhibitor, CMPD101, increased apelin-induced phosphorylation of Akt and eNOS in SHR endothelial cells and restored relaxation to apelin in SHR arteries. CMPD101 also blocked the inhibitory effect of apelin on ACh-induced relaxation. Relaxations to the APJ receptor-biased agonist, CMF-019, which preferentially activates the G-protein-dependent pathway with minimal effect on GRK2, were similar in SHR and Wistar Kyoto coronary arteries. Immunoblot analysis in SHR coronary endothelial cells demonstrated that CMF-019 increased Akt and eNOS phosphorylation whereas apelin had no effect. Thus, APJ receptor signaling through GRK2 impairs nitric oxide production or release from SHR endothelial cells. APJ receptor-biased agonists, such as CMF-019, may be more effective than apelin in causing vasodilation of SHR coronary arteries.
The possible role of cerebrolysin in the management of vascular dementia: Leveraging concepts.
Neuroscience
Hayder M Al-Kuraishy, Ali I Al-Gareeb, Salwa H Zekry +4 more
Cerebrolysin (CBL) is a combination of neurotrophic peptides and amino acids derived from pig brains. CBL can cross the blood-brain barrier (BBB) and its biological effect is similar to the effect of endogenous neurotrophic effects. The mechanism of action of CBL is related to the induction of neurogenesis, neuroplasticity, neuroprotection, and neurotrophicity. Therefore, CBL may be effective against the development and progression of neurodegenerative diseases such as Alzheimer disease (AD) and cerebrovascular disorders such as vascular dementia (VD). Moreover, many studies highlighted that CBL is effective in the improvement of cognitive impairment in patients with neurodegenerative diseases. However, the underlying neuroprotective effects of CBL against the VD neuropathology were not fully elucidated. Thus, this review aims to discuss the possible therapeutic efficacy of CBL in the management of VD. In conclusion, CBL could be effective therapeutic strategy in preventing and treating VD by targeting neuroinflammation, BBB injury, and chronic cerebral hypoperfusion.
Hepatic and Pancreatic Cellular Response to Early Life Nutritional Mismatch.
Endocrinology
Shubhamoy Ghosh, Amit Ganguly, Manal Habib +4 more
To determine the basis for perinatal nutritional mismatch causing metabolic dysfunction-associated steatotic liver disease and diabetes mellitus, we examined adult phenotype, hepatic transcriptome, and pancreatic β-islet function. In prenatal caloric-restricted rats with intrauterine growth restriction (IUGR) and postnatal exposure to high fat with fructose (HFhf) or high carbohydrate, we investigated male and female IUGR-HFhf and IUGR-high carbohydrate, vs HFhf and control offspring. Males more than females displayed adiposity, glucose intolerance, insulin resistance, hyperlipidemia, and hepatomegaly with hepatic steatosis. Male hepatic triglyceride synthesis, de novo lipogenesis genes increased, while female lipolysis, β-oxidation, fatty acid efflux, and FGF21 genes increased. IUGR-HFhf males demonstrated reduced β-islet insulin and humanin, and type 1 diabetes mellitus human amniotic fluid increased humanin. Humanin suppression disabled glucose stimulated insulin, ATP production, with apoptotic diminished β-islet viability. Humanin and FGF21 may reverse perinatal nutritional mismatched phenotype by restoring functional β islets and preventing metabolic dysfunction-associated steatotic liver disease and diabetes mellitus.
Intranasal Delivery of a Ghrelin Mimetic Engages the Brain Ghrelin Signaling System in Mice.
Endocrinology
Renée Poelman, Marie V Le May, Erik Schéle +2 more
Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor (GHSR), promotes food intake and other feeding behaviors, and stimulates growth hormone (GH) release from the pituitary. Growth hormone secretagogues (GHS), such as GHRP-6 and MK-0677, are synthetic GHSR ligands that activate orexigenic neuropeptide Y neurons that coexpress agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus when administered systemically. Systemic GHRP-6 also stimulates GH release in humans and rats. Thus, GHS and ghrelin have therapeutic relevance in patients who could benefit from its orexigenic and/or GH-releasing effects. This study examined whether intranasal delivery of ghrelin, GHRP-6, or MK-0677 engages the brain ghrelin signaling system. Effective compounds and doses were selected based on increased food intake after intranasal application in mice. Only GHRP-6 (5 mg/kg) increased food intake without adverse effects, prompting detailed analysis of meal patterns, neuronal activation in the arcuate nucleus (via Fos mapping) and neurochemical identification of c-fos messenger RNA (mRNA)-expressing neurons using RNAscope. We also assessed the effect of intranasal GHRP-6 on serum GH levels. Intranasal GHRP-6 increased food intake by increasing meal frequency and size. Fos expression in the arcuate nucleus was higher in GHRP-6-treated mice than in saline controls. When examining the neurochemical identity of c-fos-mRNA-expressing neurons, we found coexpression with 63.5 ± 1.9% Ghsr mRNA, 79 ± 6.8% Agrp mRNA, and 11.4 ± 2.5% Ghrh mRNA, demonstrating GHRP-6's ability to engage arcuate nucleus neurons involved in food intake and GH release. Additionally, intranasal GHRP-6 elevated GH serum levels. These findings suggest that intranasal GHRP-6, but not ghrelin or MK-0677, can engage the brain ghrelin signaling system.
Self-assembled Palmitic Acid-modified Thymopentin Functions as a Delivery System of Nanovaccine for Cancer Immunotherapy.
Chembiochem
Danhong Chen, Xiaoyun Ye, Ran Xu +9 more
In clinical practice, thymopentin (TP-5) is a commonly utilized immunomodulatory peptide drug. The relatively short half-life of TP-5, however, significantly limits its applicability in immunotherapy. Inspired by the structure of the TLR2 ligand lipopeptide Pam3CSK4, fatty acid-modified TP-5 peptides were designed and synthesized in this study. Utilizing its amphiphilicity, they were sonicated to assemble into nanoparticles with the diameters of approximately 100 nm. Compared with TP-5, TP-5 monopalmitate-modified nanoparticle has immune-activating properties both in vivo and in vitro. It markedly increased TNF-α secretion from RAW264.7 cells and aided in the maturation of DCs. The immunogenicity of OVA model antigen was increased in vivo when capsulated by TP-5 lipopeptide nanoparticle, which considerably slowed the growth of B16-OVA melanoma. This fatty acid-modified TP-5 assembled nanoparticle offers a straightforward and useful delivery system for the design of innovative nanovaccine for cancer immunotherapy.
Predictors of Placebo Response in the Study of Oxytocin in Autism to Improve Reciprocal Social Behaviors.
J Child Adolesc Psychopharmacol
Alyssa Verdes, Suvekcha Bhattachan, Alexander Kolevzon +17 more
Background: Although randomized clinical trials (RCTs) have investigated several treatments for social communication difficulties and repetitive behavior in autism, none has yet shown consistent superiority over placebo. Placebo response in autism RCTs may impede the ability to detect meaningful treatment effects. Objective: We sought to identify individual-level predictors of placebo response in Study of Oxytocin in Autism to improve Reciprocal Social Behaviors (SOARS-B), a 24-week RCT of intranasal oxytocin for social impairment in autistic youth. In our primary analysis, we examined predictors of change in the Aberrant Behavior Checklist-modified Social Withdrawal (ABC-mSW) score at 24 weeks in SOARS-B participants taking placebo. Secondary analyses examined predictors of ABC-mSW change at 12 weeks and of Clinical Global Impressions-Improvement at 24 and 12 weeks. We also examined predictors of response among SOARS-B participants taking oxytocin. Methods: For each analysis, we first used lasso (least absolute shrinkage and selection operator) regression to identify potentially influential predictors from a large group that included demographic factors, rating scale data, and prescribed medications. We then estimated an unpenalized linear regression model for the outcome of interest that included only variables retained by the optimal lasso. We considered variables with statistically significant coefficients to be influential predictors. Results: Higher baseline ABC-mSW score was the only significant predictor of greater ABC-mSW change in the placebo group at 24 and 12 weeks. Conclusions: In SOARS-B, higher baseline severity on a measure of reciprocal social communication predicted greater placebo response. This is consistent with the finding that lower social communication adaptive functioning was associated with greater placebo response in recent RCTs of balovaptan for social impairment in autism. However, it contrasts with findings from a trial of citalopram for repetitive behavior in autism, in which lower baseline severity of a composite of autistic and mood symptoms predicted greater placebo response. This may indicate that different factors contribute to placebo response in different symptom domains.
Nano-viscosimetry analysis of membrane disrupting peptide magainin2 interactions with model membranes.
Biophys Chem
Sara Pandidan, Adam Mechler
The rapid spread of antibiotic-resistant strains of bacteria has created an urgent need for new alternative antibiotic agents. Membrane disrupting antimicrobial peptides (AMPs): short amino acid sequences with bactericidal and fungicidal activity that kill pathogens by permeabilizing their plasma membrane may offer a solution for this global health crisis. Magainin 2 is an AMP secreted by the African clawed frog (Xenopus laevis) that is described as a toroidal pore former membrane disrupting AMP. Magainin 2 is one of the most thoroughly studied AMPs, yet its mechanism of action is still largely hypothetical: visual evidence of the pore formation is lacking, and the molecular mechanism leading to pore formation is still debated. In the present study, quartz crystal microbalance (QCM) based viscoelastic fingerprinting analysis supported by dye leakage experiments and atomic force microscopy (AFM) imaging was used to glean deeper insights into the mechanism of action. The effect of membrane charge, acyl chain unsaturation and cholesterol concentration were also investigated. The results show lipid specific disruptive mechanism of magainin 2. QCM nano-viscometry measurements revealed the presence of distinct stages in the mechanism of magainin 2 action that, with dye leakage data, confirm the existence of an initial transient pore stage that may result in peptide flip-flop between the outer and inner membrane leaflets. There is evidence of a further mechanistic stage at high peptide concentrations that is consistent with membrane collapse into a peptide-lipid mixed phase that is distinct from the transient pore formation. The results confirm some of the earliest hypotheses about magainin 2 action, while also highlighting the membrane modulating effect of this peptide.
Adrenomedullin 2 attenuates anxiety-like behaviors by increasing IGF-II in amygdala and re-establishing blood-brain barrier.
Transl Psychiatry
Denian Wang, Zhi Yang, Pengfei Wu +6 more
Anxiety disorder, a prevalent mental health issue, is one of the leading causes of disability worldwide. Damage to the blood-brain barrier (BBB) is implicated in anxiety, but its regulatory mechanisms remain unclear. Herein, we show that adrenomedullin 2 (ADM2), a novel angiogenic growth factor, alleviates autistic and anxiety-like behaviors in mice. Based on transcriptome analysis and biochemical analyses, we found that ADM2 facilitates the expression of insulin-like growth factor 2 (IGF-II), which then triggers the activation of the AKT-GSK3β-mTOR signaling pathway via the IGF-II receptor (IGF-IIR), rather than the IGF-I receptor (IGF-IR). Furthermore, as evidenced by increased Evans blue staining and decreased VE-cadherin levels, the BBB exhibited dysfunction in ADM2 knockout mice with anxiety-like behaviors. In in vitro studies, ADM2 administration promoted the expression of VE-cadherin and decreased IGF-II leakage through the endothelial barrier in a BBB model. Taken together, ADM2 may alleviate anxiety-like behavior and social deficits by enhancing BBB integrity and increasing IGF-II levels in the brain. These findings highlight the potential of ADM2 as a therapeutic target for anxiety and related mental disorders.
Adrenomedullin 2/Intermedin Exerts Cardioprotective Effects by Regulating Cardiomyocyte Mitochondrial Function.
Hypertension
Yunlu Zhao, Takayuki Sakurai, Akiko Kamiyoshi +11 more
Adrenomedullin 2 (AM2) plays critical roles in regulating blood pressure and fluid balance. However, the specific involvement of AM2 in cardiac hypertrophy has not been comprehensively elucidated, warranting further investigation into its molecular mechanisms and therapeutic implications.
The interaction between orexin, sleep deprivation and Alzheimer's disease: Unveiling an Emerging Connection.
J Physiol Sci
Masoumeh Kourosh-Arami, Mahdi Ramezani, Alireza Komaki
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive decline and memory loss. Sleep-wake disorders are an extremely predominant and often disabling aspect of AD. Ox is vital in maintaining the sleep-wake cycle and promoting wakefulness. Dysfunction of Ox signaling has been associated with sleep disorders such as narcolepsy. In AD patients, the increase in cerebrospinal fluid Ox levels is related to parallel sleep deterioration. The relationship between AD and sleep disturbances has gained increasing attention due to their potential bidirectional influence. Disruptions in sleep patterns are commonly observed in AD patients, leading researchers to investigate the possible involvement of Ox in sleep disturbances characteristic of the disease. This review article explores the role of the Ox system in AD, and the intricate relationship between AD and sleep, highlighting the potential mechanisms, impact on disease pathology, and therapeutic interventions to improve sleep quality in affected individuals.
Enhancing fat graft survival: thymosin beta-4 facilitates mitochondrial transfer from ADSCs via tunneling nanotubes by upregulating the Rac/F-actin pathway.
Free Radic Biol Med
Xiaoyu Zhang, Yan Lin, Haoran Li +2 more
Autologous fat grafting is a widely used technique in plastic and reconstructive surgery, but its efficacy is often limited by the poor survival rate of transplanted adipose tissue. This study aims to enhance the survival of fat grafts by investigating the role of thymosin beta-4 (Tβ4) in facilitating mitochondrial transfer from adipose-derived stem cells (ADSCs) to adipocytes and newly formed blood vessels within the grafts via tunneling nanotubes (TNTs). We demonstrate that Tβ4 upregulates the Rac/F-actin pathway, leading to an increased formation of TNTs and subsequent transfer of mitochondria from ADSCs. This process mitigates oxidative stress, reduces apoptosis, and promotes revascularization, thereby improving the quality and volume retention of fat grafts. Our findings provide a novel mechanistic insight into the enhancement of fat graft survival and suggest that mitochondrial transplantation and Tβ4 are potential therapeutic strategies to improve clinical outcomes in autologous fat transfer procedures.
Are We Ready to Measure Skin Permeation of Modern Antiaging GHK-Cu Tripeptide Encapsulated in Liposomes?
Molecules
Karolina Ogórek, Kinga Nowak, Emilia Wadych +3 more
Cosmetically active compounds (CACs), both of lipophilic and hydrophilic origin, have difficulty reaching the deeper layers of the skin, and this shortcoming significantly reduces their efficacy. One such CAC that occurs naturally in the human body and displays many beneficial properties (via reducing fine lines and wrinkles, tightening skin, improving its elasticity, etc.) is the glycyl-L-histidyl-L-lysine tripeptide complex of copper (GHK-Cu). GHK-Cu is a fairly hydrophilic compound with limited permeation through the lipophilic stratum corneum. On the other hand, liposomes capable of encapsulating GHK-Cu may improve its permeation potential. The present review discusses various issues related to obtaining insight into the permeation of CACs through the skin. Methods for studying the transport of CACs encapsulated by liposomes and free GHK-Cu across the skin barrier are summarized. An analysis of the literature data reveals that the transport of liposomes containing GHK-Cu received little attention. This research gap gives an impetus to the methodological developments for assessing the effect of liposomes on GHK-Cu transportation and trafficking.
Female Syrian hamster analyses of bremelanotide, a US FDA approved drug for the treatment of female hypoactive sexual desire disorder.
Neuropharmacology
Johnathan M Borland, Abigail L Kohut-Jackson, Anna C Peyla +3 more
Hypoactive sexual desire disorder (HSDD) is the most reported sexual dysfunction among premenopausal women worldwide. Bremelanotide, trade name Vyleesi, has been approved by the United States Food and Drug Administration to treat HSDD. However, despite approval, very little is known about its neurobiological mechanism of action. In this study, we utilized a female Syrian hamster model to investigate the effects of bremelanotide on melanocortin receptor expression in the mesolimbic dopamine system and sexual reward. We found that the majority of melanocortin 3 and 4 (MC4R) receptor mRNA is expressed in dopamine neurons in the ventral tegmental area (VTA). Fewer neurons express MC4R in the nucleus accumbens (NAc) or dorsal striatum, where they rarely colocalize with neurons expressing dopamine D1 or D2 receptors. Instead, MC4R mRNA is expressed in nucleus accumbens interneurons. Neither the low nor the high dose of bremelanotide had an effect on the expression of melanocortin receptor mRNA in the mesolimbic dopamine system. Finally, sexual experience resulted in a conditioned place preference (CPP) in female Syrian hamsters, though bremelanotide treatment failed to enhance sexual reward in this test. The results of this study are discussed in conjunction with similar studies in rats, with the conclusion that bremelanotide does not act on the VTA-NAc reward circuit and does not enhance the rewarding effects of sexual interactions.
The Role and Mechanisms of the Hypocretin System in Zebrafish (Danio rerio).
Int J Mol Sci
Vyacheslav Dyachuk
Sleep is the most important physiological function of all animals studied to date. Sleep disorders include narcolepsy, which is characterized by excessive daytime sleepiness, disruption of night sleep, and muscle weakness-cataplexy. Narcolepsy is known to be caused by the degeneration of orexin-synthesizing neurons (hypocretin (HCRT) neurons or orexin neurons) in the hypothalamus. In mammals, HCRT neurons primarily regulate the sleep/wake cycle, nutrition, reward seeking, and addiction development. The hypocretin system of the brain is involved in a number of neurological disorders. The distinctive pathologies associated with the disruption of HCRT neurons are narcolepsy and cataplexy, which are caused by the loss of hypocretin neurons that produce HCRT. In Danio, the hypocretin system is also involved in the regulation of sleep and wakefulness. It is represented by a single hcrt gene that encodes the peptides HCRT1 and HCRT2, as well as one HCRT receptor (HCRTR), which is structurally closest to the mammalian HCRTR2. The overexpression of the hcrt gene in Danio rerio larvae causes wakefulness, whereas the physical destruction of HCRT cells or a pharmacological blockade of the type 2 hypocretin receptor leads to fragmentation of sleep in fish larvae, which is also observed in patients with narcolepsy. These data confirm the evolutionary conservatism of the hypocretin system. Thus, Danio rerio is an ideal model for studying the functions of HCRT neural networks and their functions.
Peripheral inflammation enhances opioid-induced gastrointestinal motility inhibition via up-regulating spinal mu opioid receptor.
Toxicol Appl Pharmacol
Zhonghua Zhang, Yaofeng Zhao, Dingnian Gou +8 more
Opioids are potent analgesics in clinical pain management but exert variable analgesia in different pain types. Opioid-induced constipation is a common side effect of opioid therapy, and whether opioids induce different gastrointestinal motility inhibitions in different pain types is unknown. In this study, we evaluated the antinociceptive effects and inhibition of upper gastrointestinal transit and colonic bead expulsion of morphine, DAMGO, and Deltorphin in mouse CFA chronic inflammatory pain, SNI chronic neuropathic pain, and carrageenan chronic inflammatory pain models. Furthermore, quantitative PCR and immunofluorescence were used to investigate the mechanisms underlying the altered inhibition. Results showed that intrathecal administration of morphine, DAMGO, and Deltorphin produced higher antinociceptive effects in the CFA and carrageenan groups than in the SNI group. Upper gastrointestinal transit inhibition was significantly enhanced in the carrageenan group by morphine and DAMGO; colonic bead expulsion inhibition was also enhanced in the CFA and carrageenan groups by morphine and DAMGO, but not in Deltorphin treatment. Additionally, mu (MOR) opioid receptor mRNA and MOR-expressing cell density in the lumbar spinal cord of CFA and carrageenan mice were increased, whereas delta opioid receptor expression remained unchanged in these groups. Finally, the pharmacological blockade of MOR completely prevented the enhanced upper gastrointestinal transit inhibition in the carrageenan group by morphine and DAMGO. Altogether, our results indicate that gastrointestinal motility inhibition induced by MOR agonists can be enhanced with upregulated spinal MOR expression in chronic inflammatory pain.
SHLP6: a novel NLRP3 and Cav1 modulating agent in Cu-induced oxidative stress and neurodegeneration.
Front Mol Neurosci
H Thamarai Kannan, Suganiya Umapathy, Ieshita Pan
Copper sulfate exposure induces oxidative stress by triggering excessive reactive oxygen species (ROS) production, leading to inflammatory responses, neuroinflammation, and cellular dysfunction. Small humanin-like peptide-6 (SHLP-6), a mitochondria-derived peptide with anti-aging and anti-cancer properties, has not been explored for its protective effects against copper sulfate toxicity. This study investigates the antioxidant, anti-inflammatory, and neuroprotective potential of SHLP-6 in zebrafish larvae exposed to copper sulfate.
Managing Ifosfamide-Induced Arginine Vasopressin Resistance: Diagnostic and Treatment Strategies.
Cureus
Avia A Williams, Arslan I Pir Muhammad, Rupam Ruchi +1 more
The early recognition of ifosfamide-related renal dysfunction, including arginine vasopressin resistance (previously referred to as diabetes insipidus), which is characterized by polyuria due to the inability of the collecting duct to concentrate urine, as well as direct proximal tubular injury, which is characterized by numerous metabolic disturbances including hypophosphatemia, metabolic acidosis, hypokalemia, and glucosuria, is paramount to timely initiation of treatment and titration of desmopressin. In this report, we present a case of a 42-year-old female with a history of spindle cell carcinoma of the left thigh, who was referred to the inpatient nephrology consult service for acute kidney injury, polyuria, and metabolic derangements following her sixth cycle of doxorubicin-ifosfamide chemotherapy. The patient was treated with supratherapeutic doses of desmopressin, with successful improvement of her polyuria. We review the pathophysiology of different forms of ifosfamide-associated nephrotoxicity, including arginine vasopressin resistance, the challenges of diagnosing arginine vasopressin disorders, and the utility of desmopressin in the management of arginine vasopressin resistance. This case also highlights the clinical implications of using copeptin in the diagnosis of arginine vasopressin resistance, leading to effective treatment and improving patient outcomes.
The novel ECM protein SNED1 mediates cell adhesion via the RGD-binding integrins α5β1 and αvβ3.
J Cell Sci
Dharma Pally, Nandini Kapoor, Alexandra Naba
The extracellular matrix (ECM) is a complex meshwork comprising over 100 proteins. It serves as an adhesive substrate for cells and, hence, plays crucial roles in health and disease. We have recently identified a novel ECM protein, SNED1, and have found that it is required for neural crest cell migration and craniofacial morphogenesis during development and in breast cancer, where it is necessary for the metastatic dissemination of tumor cells. Interestingly, both processes involve the dynamic remodeling of cell-ECM adhesions via cell surface receptors. Sequence analysis revealed that SNED1 contains two amino acid motifs, RGD and LDV, known to bind integrins, the largest class of ECM receptors. We thus sought to investigate the role of SNED1 in cell adhesion. Here, we report that SNED1 mediates breast cancer and neural crest cell adhesion via its RGD motif. We further demonstrate that cell adhesion to SNED1 is mediated by the RGD integrins α5β1 and αvβ3. These findings are a first step toward identifying the signaling pathways activated downstream of the SNED1-integrin interactions guiding craniofacial morphogenesis and breast cancer metastasis.