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The renin-angiotensin system in healthy human platelets: expressed but inactive.
Platelets
François Panosetti, François M Cuenot, Damian S Saint Auguste +11 more
Platelets play a crucial role in arterial thrombus formation, offering potential for new antiplatelet therapies with reduced bleeding risk. Here, we investigated the role of the renin-angiotensin system (RAS) in human platelets and explored its potential link to COVID-19 coagulopathy. Experiments were performed ex vivo on healthy human platelets. The expression of RAS receptors (Mas, MrgD, ACE, ACE2, AT1 and AT2) was evaluated using western blot and immunofluorescence. Platelets were incubated in vitro with either Captopril or different RAS peptides including Alamandine, Angiotensin-I, Angiotensin-II, Angiotensin-(1-7), and Angiotensin-(1-9). Platelet adhesion was measured by spectrophotometry using BCECF fluorescence. Platelet activation and aggregation were analyzed using aggregometry after stimulation with extracellular matrix proteins. ACE and ACE2 activity were assessed using Fluorescent Peptides (FPS). We demonstrated that healthy human platelets express all the tested RAS receptors. However, RAS peptides did not modulate platelet adhesion or aggregation despite a wide range of concentrations tested. ACE activity was detected in platelet lysates, but it was not inhibited by Captopril, while ACE2 activity was undetectable. Our findings suggest that while RAS receptors are expressed in platelets, RAS peptides do not impact platelet function, at least in our experimental setting. COVID-19 coagulopathy may occur independently of the RAS.
Case Report of Nephrogenic Diabetes Insipidus with a Novel Mutation in the AQP2 Gene.
Int J Mol Sci
Alejandro Padilla-Guzmán, Vanessa Amparo Ochoa-Jiménez, Jessica María Forero-Delgadillo +3 more
Nephrogenic diabetes insipidus (NDI) is a rare hereditary disorder characterized by renal resistance to arginine vasopressin (AVP), resulting in the kidneys' inability to concentrate urine. Approximately 90% of NDI cases follow an X-linked inheritance pattern and are associated with pathogenic variants in the AVPR2 gene, which encodes the vasopressin receptor type 2. The remaining 10% are attributed to mutations in the AQP2 gene, which encodes aquaporin-2, and may follow either autosomal dominant or recessive inheritance patterns. We present the case of a male infant, younger than nine months of age, who was clinically diagnosed with NDI at six months. The patient presented recurrent episodes of polydipsia, polyuria, dehydration, hypernatremia, and persistently low urine osmolality. Despite adjustments in pharmacologic treatment and strict monitoring of urinary output, the clinical response remained suboptimal. Given the lack of improvement and the radiological finding of an absent posterior pituitary (neurohypophysis), the possibility of coexistent central diabetes insipidus (CDI) was raised, prompting a therapeutic trial with desmopressin. Nevertheless, in the absence of clinical improvement, desmopressin was discontinued. The patient's management was continued with hydrochlorothiazide, ibuprofen, and a high-calorie diet restricted in sodium and protein, resulting in progressive clinical stabilization. Whole-exome sequencing identified a novel homozygous missense variant in the AQP2 gene (c.398T > A; p.Val133Glu), classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria: PM2 (absent from population databases), PP2 (missense variant in a gene with a low rate of benign missense variation), and PP3 (multiple lines of computational evidence supporting a deleterious effect)]. NDI is typically diagnosed during early infancy due to the early onset of symptoms and the potential for severe complications if left untreated. In this case, although initial clinical suspicion included concomitant CDI, the timely initiation of supportive management and the subsequent incorporation of molecular diagnostics facilitated a definitive diagnosis. The identification of a previously unreported homozygous variant in AQP2 contributed to diagnostic confirmation and therapeutic decision-making. The diagnosis and comprehensive management of NDI within the context of polyuria-polydipsia syndrome necessitates a multidisciplinary approach, integrating clinical evaluation with advanced molecular diagnostics. The novel AQP2 c.398T > A (p.Val133Glu) variant described herein was associated with early and severe clinical manifestations, underscoring the importance of genetic testing in atypical or treatment-refractory presentations of diabetes insipidus.
Oat Fiber Alleviates Loperamide-Induced Constipation in Mice by Modulating Intestinal Barrier Function.
Nutrients
Yufei Shi, Yuchao Han, Jie Jiang +8 more
Objective: To investigate the effects of oat fiber on animal constipation and elucidate its underlying mechanisms. Methods: Male BALB/c mice were randomly allocated into five groups: control group (CON), model control group (MODEL), low dose group (LOW), middle dose group (MIDDLE), high dose group (HIGH). Constipation was induced in the mice by intragastric administration of loperamide. Subsequently, the mice (except those in the CON and MODEL groups) were administered oat fiber intragastrically for 21 consecutive days. Results: Compared with the MODEL group, oat fiber significantly increased the number of fecal pellets, fecal wet weight, and fecal water content (p < 0.05), shortened the time to first black stool excretion (p < 0.05), and enhanced the small intestinal propulsion rate in constipated mice. Additionally, oat fiber significantly upregulated motilin (MTL) and gastrin (GAS) levels (p < 0.05), while downregulating vasoactive intestinal peptide (VIP) and somatostatin (SS) levels (p < 0.05). It also significantly reduced the transcription level of Aquaporin 8 (AQP8) (p < 0.05), effectively alleviating intestinal mucosal injury and immune inflammation. The relative expression levels of TNF-α and IL-1β were significantly decreased in the oat fiber group (p < 0.05). Gut microbiota analysis revealed that oat fiber increased both the abundance and diversity of gut microbiota in constipated mice. Specifically, oat fiber was found to enhance the relative abundance of Firmicutes while reducing that of Bacteroidetes. At the genus level, it promoted the proliferation of Lachnospiraceae_NK4A136_group and Roseburia. Conclusions: Oat fiber alleviates constipation in mice by modulating gastrointestinal regulatory peptides, gut microbiota, aquaporin and mitigating intestinal barrier damage and immune-inflammatory responses.
Safety Choice Drivers of the Coming Treatment Options for Non-Cirrhotic Metabolic Steatohepatitis.
Liver Int
Alessandra Mangia, Luca V C Valenti
Metabolic dysfunction associated steatohepatitis (MASH), formerly known as NASH, represents one of the leading causes of chronic liver disease worldwide. Its high prevalence is driven by insulin resistance, obesity and type 2 diabetes (T2D) and is associated with cardiovascular disease. The main driver of liver damage is fat accumulation in hepatocytes leading to inflammation and fibrosis development. People with MASH and clinically significant fibrosis (stage F2/F3) are 'at risk' of progressing to cirrhosis and hepatocellular carcinoma and are considered in need of treatment. Metabolic drivers of MASH originating outside the liver, for example, from the adipose tissue and the gut, and genetic heterogeneity contribute to making the prevalent pathogenetic factor difficult to dissect at an individual level. In this scenario, the Food and Drug Administration's conditional approval of the liver-directed thyroid hormone receptor beta agonist Resmetirom as the first pharmacological treatment for MASH last March 2024 and the expected extension of the glucagon-like protein-1 receptor agonist Semaglutide indication from diabetes and obesity to MASH mark a key milestone. Both drugs are also under evaluation by the European Medicines Agency. The proven efficacy of these compounds in clinical trials needs to be balanced against safety profiles and patient preferences. To investigate future trajectories and possible uses as mono-therapy or in combination, we examined available results of clinical trials and real-life studies. Despite the need to await the final results of outcome studies to exclude any possible challenges for both compounds, safety profiles and external factors including reimbursement policies or supply limitations may currently guide the individual choice.
The Mystery Actor in the Neuroendocrine Theater: Who Really Knows Obestatin? Central Focus on Hypothalamic-Pituitary Axes.
Int J Mol Sci
Michał Szlis, Anna Wójcik-Gładysz, Alina Gajewska +1 more
The available literature data indicate that obestatin, a peptide derived from the preproghrelin precursor, may modulate neuroendocrine function, particularly in appetite regulation and somatotrophic/gonadotrophic pathways. This review synthesizes animal studies assessing the influence of obestatin on central neuroendocrine systems. Obestatin has been shown to affect the hypothalamic appetite-regulating center through neuropeptides such as neuropeptide Y and agouti-related peptide, yet findings remain inconsistent between species. In rodents, its effects on food intake and energy balance are inconclusive, whereas sheep models demonstrate significant alterations in orexigenic gene expression and peptide immunoreactivity. Regarding the somatotrophic axis, obestatin showed no significant effect on growth hormone (GH) secretion in rodents; however, in sheep, it modulated growth hormone-releasing hormone and somatostatin mRNA expression, elevated pituitary GH synthesis, and increased circulating GH levels. Studies involving the gonadotrophic axis demonstrated the presence of obestatin in Leydig and pituitary cells, with in vitro evidence suggesting its ability to modulate intracellular pathways implicated in gonadoliberin, luteinizing hormone, and follicle-stimulating hormone release. The collective findings discussed in this article indicate that obestatin interacts with multiple hypothalamic-pituitary axes, though its effects vary depending on species and experimental conditions. This review highlights the complexity of obestatin's central actions and the need for further research to elucidate its functional relevance in neuroendocrine regulation.
Safety and efficacy of once-weekly efruxifermin versus placebo in metabolic dysfunction-associated steatohepatitis (HARMONY): 96-week results from a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial.
Lancet
Mazen Noureddin, Juan P Frias, Guy W Neff +15 more
Efruxifermin is a bivalent fibroblast growth factor 21 analogue in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). This trial aimed to prospectively assess the safety and efficacy of efruxifermin administration for 96 weeks in individuals with MASH and moderate (stage 2; F2) or severe (stage 3; F3) fibrosis.
ACE2/Angiotensin-(1-7)/Mas and the brain.
Brain Res
Maria José Campagnole-Santos, Marco Antônio Peliky Fontes, Thiago Verano-Braga +3 more
It is well known that the renin-angiotensin system (RAS) plays a key role in regulating blood pressure and hydroelectrolyte balance. In addition to angiotensin (Ang) II, Ang-(1-7) has emerged as an important component of this system. Here we review evidence regarding the presence and actions of ACE2/Ang-(1-7)/Mas receptor pathway within the central nervous system, where the RAS possesses a crucial role in controlling cardiovascular, metabolic and stress-coping behavior functions. The involvement of this non-canonical RAS pathway in the brain mechanisms related to hypertension will also be discussed.
Molecular-Level Understanding of Membrane Disruption Behaviors of Antimicrobial Peptides by Gradient Boosting Algorithm-Assisted Raman Spectroscopy.
J Chem Inf Model
Chao Li, Qing-Qing Zhou, Tong Yu +11 more
Antimicrobial peptides (AMPs) can rapidly kill bacteria via disrupting the integrity of the cytoplasmic membrane. Although the understanding of the interaction between AMPs and phospholipid membrane is essential for related drug designs, the in situ observation of this process is still challenging, especially at the molecular level. Herein, we develop a new analytical methodology named gradient boosting algorithm-assisted Raman spectroscopy (GB-Raman) for revealing the membrane disruption mechanism of AMPs. The analytical process consists of three steps: first, collecting the Raman spectra of phospholipid membrane in the physiological environment without or with AMPs as two data sets; then, using the well-trained gradient boosting algorithm to automatically extract Raman spectral differences between the two data sets; finally, speculating the membrane disruption mechanisms of AMPs based on the molecular structure information offered by the above spectral differences. When using a well-studied AMP named magainin 2 as a proof of concept, the GB-Raman revealed that the intensity ratio of two vC-C peaks of lipid acyl chains (I1084/I1072) in the phospholipid membrane was increased and their locations were red-shifted after interacting with magainin 2. These spectral changes indicated the disturbance of lipid hydrophobic chain ordering caused by magainin 2, which was matched by previous studies. Another AMP named cathelicidin-BF (BF-30) with an unknown membrane disruption mechanism was also explored. The extracted Raman spectral differences originated from the decrease in the intensity of vC-O-C peak, δC-H peak, and vC-C peaks of lipid acyl chains after interacting with BF-30, implying that BF-30 may disrupt phospholipid membrane like detergents. The above speculation was further verified by other technologies such as isothermal titration calorimetry (ITC). This study opens a new avenue to research on AMPs and provides deep insight into their membrane disruption behaviors, leading to great potential in drug development against bacterial resistance.
Protein phosphatase 6 regulates metabolic dysfunction-associated steatohepatitis via the mTORC1 pathway.
J Hepatol
Zhengshuai Liu, Shuang Wei, Yang Jiang +15 more
Metabolic dysfunction-associated steatohepatitis (MASH) is a serious chronic liver disease for which therapeutic options are limited. Although fibroblast growth factor 21 (FGF21) analogs have shown therapeutic promise for MASH in multiple preclinical and clinical studies, their underlying mechanisms of action remain elusive.
Combined Cold Exposure and Exercise Improves NAFLD: Mechanistic Insights.
Med Sci Sports Exerc
Xue Geng, Zhijian Rao, Jianhong Zhang +7 more
Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the global population and poses a remarkably serious threat to human health.
Availability and characteristics of clinical trials for neuroendocrine tumors: Is there an unmet need?
Eur J Cancer
Philipp Melhorn, Amirhossein Sadeghi, Markus Raderer +1 more
Therapeutic advances in neuroendocrine tumors (NET) have been incremental over recent decades. Similar to other rare diseases, the number of trials that can be offered to NET patients is generally limited.
New Names, New Drugs, Better Outcomes in Steatotic Liver Disease.
Br J Hosp Med (Lond)
Matthew Peverelle, Mzamo Mbelle, Deepak Joshi
Steatotic liver disease (SLD) is a growing cause of chronic liver disease, with potential progression to cirrhosis, hepatocellular carcinoma (HCC), and liver failure. Previously known as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), new terminology, including metabolic-dysfunction associated steatotic liver disease (MASLD) and metabolic-dysfunction associated steatohepatitis (MASH), was introduced to improve diagnostic clarity and reduce stigmatization. MASLD is now recognized as the hepatic manifestation of the metabolic syndrome and is the most common cause of liver disease in the UK, affecting up to 20% of adults. The incidence of MASLD-related cirrhosis and HCC is expected to rise significantly by 2030, highlighting the need for early diagnosis and treatment. For over two decades, effective medical therapies for MASLD were elusive. However, recent trials of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), thyroid hormone receptor-β (THR-β) agonist resmetirom, and fibroblast growth factor 21 (FGF21) agonists have shown promising results in reversing steatohepatitis and potentially fibrosis. These agents potentially offer new disease-modifying treatment options for MASLD, with GLP-1 RAs particularly effective in achieving weight loss and all drugs showing promising histological benefits in patients with MASH. This review summarizes nomenclature changes, provides an update on the UK's SLD burden, with a particular focus on MASLD and MASH, and discusses new therapeutic strategies for managing this complex and increasingly prevalent condition.
Management of Arginine Vasopressin Deficiency (Central Diabetes Insipidus) in Neonates and Infants.
Horm Res Paediatr
Hannah Pearlstein, Allie Dayno, Jessica Zook +4 more
Arginine vasopressin deficiency (AVP-D), previously called central diabetes insipidus (central DI), is the inability to concentrate urine despite elevated serum osmolality (i.e., volume depletion) related to inadequate production of the posterior pituitary hormone vasopressin. Without treatment, which typically consists of fluids and pharmacologic vasopressin analogs, AVP-D can quickly lead to hypernatremia and dehydration. Management of AVP-D in neonates and infants is particularly challenging for many reasons: their inability to communicate thirst, their limited renal concentrating capacity, the obligate fluids required for nutrition that may cause hyponatremia with anti-diuretic therapy, the lack of FDA-approved formulation of vasopressin analog in this age, the potential need for growth-related adjustments in nutrition, fluids, and vasopressin analogs, and a limited evidence base. Despite these challenges, multiple groups have reported experiences with the available pharmacologic options, including alternative formulations of desmopressin (buccal, standard oral tablet, orally disintegrating tablet [melt], subcutaneous) and thiazide diuretics.
MASLD Pharmacotherapy: Current Standards, Emerging Treatments, and Practical Guidance for Indian Physicians.
J Assoc Physicians India
Ashish Kumar
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), has become a significant public health issue worldwide, with a pronounced impact in India due to the escalating rates of obesity and type 2 diabetes mellitus (T2DM) driving its prevalence. This condition spans a range of hepatic disorders, from uncomplicated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), accompanied by differing levels of hepatic fibrosis, heightening the likelihood of progression to cirrhosis, liver cancer, and cardiovascular complications. While lifestyle modification remains the cornerstone of MASLD management, pharmacologic therapies are increasingly recognized as essential for patients with progressive disease or those at higher risk of complications. Recent insights into the pathogenesis of MASLD have led to the development of innovative therapies targeting key mechanisms such as hepatic steatosis, insulin resistance, inflammation, and hepatic fibrosis. Several pharmacological agents have shown encouraging results in clinical trials, including thyroid hormone receptor-β agonist resmetirom, glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide, peroxisome proliferator-activated receptor (PPAR) agonists such as pioglitazone and saroglitazar, sodium-glucose cotransporter-2 inhibitors (SGLT2i), and vitamin E. Furthermore, emerging therapies, including the dual incretin agonist tirzepatide and fibroblast growth factor (FGF) analogs, hold the potential to transform future treatment strategies. This review provides a comprehensive overview of current and evolving pharmacologic options for MASLD, with a focus on practical recommendations tailored for Indian physicians. A structured treatment algorithm for noncirrhotic MASLD (F0-F3 fibrosis) is presented, incorporating only drugs currently available in India and stratified based on diabetes status and hepatic fibrosis severity. Given India's vast and diverse patient population, ensuring access to cost-effective therapies remains a challenge, necessitating a pragmatic approach that balances efficacy, affordability, and real-world feasibility. This review serves as a practical clinical guide, equipping physicians with evidence-based recommendations to optimize MASLD management in routine practice.
Cushing's syndrome with diabetes insipidus in pregnancy: a case report.
BMC Endocr Disord
Shinnosuke Hata, Nobuyoshi Shinokawa, Yuki Harada +6 more
Cushing's syndrome (CS) during pregnancy is a rare condition associated with significant maternal and fetal complications, including hypertension, diabetes, preeclampsia, and preterm birth. Diabetes insipidus (DI) in pregnancy is a rare but often diagnosed condition, and its effective management is crucial for maintaining maternal health during pregnancy and childbirth. This case report describes the rare coexistence of DI and CS during pregnancy, highlighting the unique complexities in diagnosis and management.
Multiplexed MALDI fingerprints for rapid detection of spontaneous bacterial peritonitis.
Diagn Microbiol Infect Dis
Qiong Wu, Bo Wei, Han Zhang +9 more
The efficient diagnosis of spontaneous bacterial peritonitis (SBP) has been hindered by the low sensitivity of current clinical indicators. A rapid and accurate detection method for SBP is essential to enable early diagnosis and prompt intervention.
Sublingual Administration of Desmopressin Oral Disintegrating Tablet in a Neonate With Central Diabetes Insipidus.
Cureus
Daisuke Watanabe, Hideaki Yagasaki, Mari Tsukahara +2 more
Precise titration of desmopressin (1-deamino-8-D-arginine vasopressin; DDAVP) is essential for managing neonatal central diabetes insipidus (CDI). Although oral administration is increasingly considered an alternative to the traditional intranasal route, the differences between DDAVP formulations and administration methods are often unclear in clinical practice. This complicates efforts to establish effective sublingual treatment protocols using oral disintegrating tablets (ODTs) in neonates. Here, we present the case of a Japanese neonate with CDI, semilobar holoprosencephaly, and a cleft lip and palate. The patient exhibited hypotonic polyuria, hypernatremia, elevated serum osmolality, and low plasma arginine vasopressin (AVP) levels within the first week of life. At 30 days of age, we dissolved a 60-µg DDAVP ODT in 5 mL of water and administered it sublingually. The initial dose of 3 µg/kg/day was titrated to 2 µg/kg/day based on the patient's clinical response. Close monitoring enabled fine adjustment of dosing. The patient achieved a stable fluid balance and did not exhibit signs of hyponatremia, seizures, or other adverse events. This case supports the potential utility of sublingual DDAVP ODTs in neonates and underscores the necessity of establishing standardized preparation and dosing protocols, which will require further clinical experience.
'Un-thirsty' hypernatremia.
Endocrinol Diabetes Metab Case Rep
Markus Koster, Katrin Ledergerber, Michael Brändle
A 38-year-old man was admitted because of transient somnolence. Five weeks previously, he had suffered a subarachnoid hemorrhage from a ruptured aneurysm of the anterior communicating artery (ACOM), which was treated by craniotomy and clipping. He had recovered well, although loss of short-term memory and a forehead paresis on the side of craniotomy persisted. Clinical examination on admission showed no new neurological deficits. Cerebral computed tomography with angiography revealed no bleeding or infarction and correctly positioned clips. Laboratory examination showed severe hypernatremia (179 mmol/L). The patient was admitted to the intensive care unit (ICU) and treated with oral fluids and 5% glucose intravenously. Remarkably, he denied being thirsty and had to be encouraged to drink. Urine osmolality quickly fell to 294 mOsm/kg, polyuria of up to 400 mL/h was measured, and serum sodium remained elevated. Therefore, diabetes insipidus (DI) was obvious. After application of desmopressin acetate, urine output dropped to around 50 mL/h, confirming central DI or vasopressin deficiency (VD). Desmopressin acetate dose and volume management were continuously adjusted to blood sodium to restore euvolemia. Drinking volume needed to be supervised because of persistent lack of thirst and amnesia of being told to drink. Adipsic VD (aAVP-D) is a rare syndrome characterized by the combination of VD and loss of thirst in response to hypernatremia. It usually occurs within days after cell damage of osmoreceptors, for example after disruption of blood supply as in clipping of an ACOM aneurysm. Management includes titrated desmopressin acetate replacement, fixed water intake, weight monitoring, patient education and sodium monitoring.
Discovery of natural orexin 2 receptor antagonists from Valeriana species: A potential approach for insomnia treatment.
Chronobiol Int
Aparna G Shenoy, Vishal Ravi, Suhail Subair +3 more
The orexinergic system, comprising orexin-A and orexin-B neuropeptides that bind to OX1R and OX2R receptors, plays a critical role in regulating sleep-wake cycles, appetite, and alertness. OX2R is particularly important for promoting arousal and non-rapid eye movement (NREM) sleep and has been linked to sleep disorders such as insomnia and narcolepsy. Although OX2R antagonists like suvorexant have shown therapeutic promise, they are often associated with side effects including cognitive impairment and dependence, highlighting the need for safer alternatives. This study employed an in-silico approach to identify natural OX2R antagonists from Valeriana species. Phytochemicals were screened based on molecular docking and favourable ADME/T profiles. Molecular dynamics (MD) simulations and post-MD analysis confirmed stable binding of hesperidine and valerosidate to OX2R. Principal component analysis (PCA) revealed minimal conformational variability while gibbs free energy landscape (FEL) analysis and MM-PBSA binding free energy calculations further supported the strong binding of hesperidine and valerosidate to OX2R, comparable to suvorexant. These findings support hesperidine and valerosidate as promising, naturally derived OX2R antagonists, and warrant further invitro and invivo investigations for potential therapeutic application in insomnia treatment.
Intergenerational Postoperative Neurocognitive Disorder in a Rat Model: Initiating Mechanisms and Pharmacological Prevention.
Anesthesiology
Ling-Sha Ju, Zeeshan A Khan, Nikolaus Gravenstein +3 more
Vulnerability to perioperative neurocognitive disorder (PND) and the mechanisms initiating PND, which may serve as targets for prevention, are incompletely understood. This study hypothesized that sevoflurane can induce persistent upregulation of the hypothalamic-pituitary-adrenal axis, inflammation, and behavioral deficits in young adult male rats by stimulating hypothalamic arginine vasopressin (AVP) production via Na + -K + -Cl - (NKCC1) Cl - importer/γ-aminobutyric acid type A receptor signaling. These changes may also result in neurocognitive deficits in the offspring of exposed rats ( i.e. , intergenerational PND).