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[Wheat-grain moxibustion at the Guanyuan point to regulate low testosterone and hypothalamic-pituitary-gonadal axis in naturally aged mice].
Zhonghua Nan Ke Xue
Meng-Fan Cui, Bing-Zhe Ma, Zhi-Yang Yin +3 more
To investigate the effects of wheat-grain moxibustion at the Guanyuan point on testosterone (T) synthesis and the hypothalamic-pituitary-gonadal (HPG) axis in naturally aged mice.
Endogenous opiates and behavior: 2024.
Peptides
Richard J Bodnar
This paper is the forty-seventh consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2024 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Emerging Use of BPC-157 in Orthopaedic Sports Medicine: A Systematic Review.
HSS J
Nikhil Vasireddi, Henrik Hahamyan, Michael J Salata +4 more
Background: Body protection compound-157 (BPC-157) is a naturally occurring gastric peptide that promotes mucosal integrity and homeostasis. Preclinical studies show its potential for promoting healing in musculoskeletal injuries such as fractures, tendon ruptures, ligament tears, and muscle injuries. Despite lacking US Food and Drug Administration approval and its use being banned in professional sports, it is increasingly used by clinicians and athletes. Purpose: We sought to (1) provide a comprehensive synthesis of the BPC-157 literature from an orthopedic sports medicine perspective and (2) elucidate the mechanism of action, musculoskeletal effects, metabolism, and safety profile. Methods. We conducted a systematic review of English-language literature, published from database inception to June 3, 2024, from PubMed, Cochrane, and Embase. We searched PROSPERO to identify any current or unpublished reviews. Studies reporting BPC-157's mechanism, musculoskeletal outcomes, metabolism, and safety were included. Articles were screened in 3 phases by 2 reviewers. In cases of a disagreement between the 2 reviewers, blinding was removed, and eligibility was determined by group consensus, with a third author making the final decision. Results. A total of 544 articles from 1993 to 2024 were identified. After duplicates were removed, 36 studies were included (35 preclinical studies, 1 clinical study). The studies suggest that BPC-157 enhances growth hormone receptor expression and several pathways involved in cell growth and angiogenesis, while reducing inflammatory cytokines. In preclinical models, BPC-157 improved functional, structural, and biomechanical outcomes in muscle, tendon, ligament, and bony injuries. In a retrospective study of musculoskeletal pain following intraarticular injection of BPC-157 for unspecified chronic knee pain, 7 of 12 patients reported relief for >6 months. BPC-157 is metabolized in the liver, with a half-life of less than 30 minutes, and is cleared by the kidneys. Preclinical safety studies showed no adverse effects across several organ systems. No clinical safety data were found. Conclusion: This systematic review of level IV and level V studies suggests that BPC-157 shows promise for promoting recovery from musculoskeletal injuries. Adverse effects are possible due to unregulated manufacturing, contamination, or unknown clinical safety. We recommend that clinicians counsel athletes to understand their organizations' rules to remain compliant with medication/supplement safety and testing standards.
Role of G-protein-coupled receptor kinase 4 on the dysfunction of renal Mas receptor in hypertension.
PLoS One
Lin Chen, Jiayao Chen, Jindong Wan +5 more
The angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor axis plays an important role in the regulation of blood pressure. G protein-coupled receptor kinase 4 (GRK4) has attracted more attentions by modulating G protein-coupled receptors and blood pressure. However, it remains unknown whether renal Mas receptor is regulated by GRK4 and its role in the pathogenesis of hypertension. Compared with Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs) exhibited impaired Mas receptor-mediated diuresis and natriuresis, which was accompanied with increased phosphorylation levels of Mas receptors. Similarly, the phosphorylation of renal Mas receptor was increased and its-induced renal effects were decreased in human (h) GRK4γ 142V transgenic mice relative to wild-type littermates. There was a colocalization and a direct interaction of renal Mas receptor and GRK4, which were increased in SHRs and confirmed by rigid protein-protein docking. In vitro studies found that treatment with the Mas receptor agonist AVE0991 inhibited Na+-K+-ATPase activity in WKY renal proximal tubule (RPT) cells, which was failed in SHR cells. GRK4 silencing decreased the phosphorylation of Mas receptor and improved the impaired Mas receptor-mediated inhibition of Na+-K+-ATPase activity in SHR RPT cells. Further study showed that ultrasound-targeted microbubble destruction-targeted renal GRK4 depletion decreased Mas receptor phosphorylation and improved its-induced diuresis and natriuresis in SHRs. These suggest that GRK4 contributes to increased renal Mas receptor phosphorylation and dysfunction in hypertension, indicating that targeting GRK4 may be a viable therapeutic approach for hypertension.
An Enzyme-Cleavable Cage on Integrin Adhesive Ligand Regulates Stem Cell Fate in An External Stimulus-Free Manner.
Langmuir
Shuhou Yang, Jiacheng Lei, Kaikai Zheng +8 more
The interaction between integrins and their receptors is essential for cell adhesion, acting as a critical link for cells to sense and respond to signals from the extracellular matrix (ECM). While various stimuli-responsive systems, such as electrical, optical, enzymatic, and magnetic systems, have been employed to modulate the binding of arginine-glycine-aspartic acid (RGD) to integrins, these triggers often pose risks of cellular damage. Here, the cRGD ligands are passivated by conjugating amide cages with varying electron densities on the side chain of aspartic acid in cRGD peptides in order to undergo spontaneous hydrolysis of the cages via MSC exocrine enzymes during cell adhesion. This modification allows precise control over enzyme-mediated cage degradation and cRGD activation as the varying electron densities affect the stability of the amide cages. Our approach enables controllable spatiotemporal integrin activation, thereby regulating cell spreading and differentiation while minimizing the risks associated with external stimuli.
Editorial Commentary: Testosterone, Growth Hormone, and Vitamin D Supplementation Is Not Routinely Indicated for Orthopaedic Surgery Patients.
Arthroscopy
Travis J Dekker
Endocrinologists and family medicine physicians prescribe testosterone replacement therapy (TRT) for decreased levels of androgens in aging males. Benefits include improvements in mood, cognition, libido, energy, and quality of life. In orthopaedic surgery patients of both sexes, benefits could also include improvements in functional outcomes, bone mineral density, lean body mass, and early mobilization. A challenge is that patients may request supplementation with TRT and other supplements, including vitamin D (which may benefit fracture healing, bone metabolism, muscle recovery, and healing of tendons and wounds) and growth hormones (specifically BPC 157, which may optimize endurance training, metabolism, tissue repair, and surgical recovery). However, TRT and other supplements have risks and may not be indicated. TRT is not recommended for routine use in the perioperative management of orthopaedic surgery patients.
Thymopentin-integrated self-assembling nanoplatform for enhanced photo-immunotherapy in diabetic wound healing.
J Colloid Interface Sci
Runze Wang, Wenting Cheng, Hailong Tian +4 more
Diabetic wounds represent a significant clinical challenge owing to infection, oxidative stress, and immune dysregulation. In this study, a multifunctional photoimmunotherapy nanoplatform (I-P-T NPs) was developed through the self-assembly of the near-infrared photosensitizer IR820, the immunomodulatory agent thymopentin (TP5), and the antioxidant phloretin (Phl) via intermolecular hydrogen bonding and hydrophobic interactions. This nanoplatform integrates photothermal therapy (PTT), immune modulation, and reactive oxygen species scavenging to address the infection-oxidation-immunosuppression triad in diabetic wounds. The I-P-T NPs exhibited robust photothermal conversion under 808 nm irradiation, generating localized hyperthermia with antibacterial effects. In vitro experiments demonstrated that I-P-T NPs promoted M2 macrophage polarization, reduced oxidative stress, enhanced endothelial and keratinocyte migration, and suppressed pro-inflammatory cytokine release. Additionally, the nanoplatform displayed potent antibacterial activity against both Gram-positive and Gram-negative bacteria. In a streptozotocin-induced diabetic mouse model with infected wounds, topical application of I-P-T NPs combined with photothermal treatment accelerated wound closure, enhanced re-epithelialization and collagen deposition, and mitigated inflammation. The self-assembled design improved the solubility of Phl and enabled spatiotemporally controlled delivery of multiple therapeutic components. No significant systemic toxicity was observed, confirming the biocompatibility of I-P-T NPs. This study presents a novel nanoplatform that synergistically combines photothermal sterilization, TP5-mediated immune regulation, and Phl-driven antioxidant effects, offering a promising strategy for managing complex diabetic wounds. This modular design highlights the potential for translating multifunctional nanotherapies into clinical applications for the treatment of chronic wounds.
Triple Agonism Based Therapies for Obesity.
Curr Cardiovasc Risk Rep
Jonathan Goldney, Malak Hamza, Farhaana Surti +2 more
Glucagon-like peptide 1 (GLP-1) receptor agonists (RA) have transformed obesity and type 2 diabetes (T2D) management. Tirzepatide, the first dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) RA approved for both conditions, has paved the way for next-generation incretin-based therapies. Among these, triple agonists targeting GLP-1, GIP, and glucagon receptors represent a promising next step. This review outlines the rationale for their development and summarizes clinical trial data, focusing on retatrutide, the most advanced candidate.
Study of Intracellular Peptides of the Central Nervous System of Zebrafish (Danio rerio) in a Parkinson's Disease Model.
Int J Mol Sci
Louise O Fiametti, Camilla A Franco, Leticia O C Nunes +2 more
Although peptides have been shown to have biological functions in neurodegenerative diseases, their role in Parkinson's disease has been understudied. A previous study by our group, which used a 6-hydroxydopamine zebrafish model, suggested that nine intracellular peptides may play a part in this condition. In this context, our aim is to better understand the role of five of these nine peptides. The selection of peptides was made based on their precursor proteins, which are fatty acid binding protein 7, mitochondrial ribosomal protein S36, MARCKS-related protein 1-B, excitatory amino acid transporter 2 and thymosin beta-4. The peptides were chemically synthesized in solid phase and characterized by high-performance liquid chromatography and mass spectrometry. Circular dichroism was performed to determine the secondary structure of each peptide, which showed that all five peptides maintain a random structure in the aqueous solutions that were studied. Two molecules show a helical profile in trifluoroethanol, a known structuring agent. Cell viability by the MTT assay indicates that all five peptides are not cytotoxic in all concentrations tested in both mouse and human cell lines. Behavioral assay using a 6-OHDA zebrafish larvae model suggest that all peptides help in the recovery of motor function with 24 h treatment at two concentrations. Three peptides showed a complete recovery from the 6-OHDA-induced motor impairment. Further studies are needed to better understand the mechanism of action of these peptides and whether they are truly a potential ally against Parkinson's disease.
Review: Special Issue: Real-world evidence on the use of GLP1 receptor agonists: Emerging concepts in obesity management: focus on glucagon receptor agonist combinations.
Drugs Context
Sarah L Anderson
The global rise in obesity and its associated health risks has driven the need for more effective pharmacological treatments. Glucagon receptor (GCGR)-based multi-agonist drugs are emerging as promising treatments for obesity, with several in advanced stages of clinical development. Agents like mazdutide, pemvidutide, survodutide and retatrutide have demonstrated the ability to trigger significant weight loss in earlier phase trials, often surpassing the amount of weight loss obtained with existing therapies. Their potential to address obesity-related comorbidities, including type 2 diabetes mellitus and cardiovascular disease, positions them as important additions to future obesity treatment guidelines. As these GCGR-based multi-agonists advance through clinical trials, their impact on obesity management may be substantial, particularly for patients who have not achieved success with current medications or lifestyle interventions. Some are also being evaluated for cardiovascular outcomes, highlighting their relevance in populations at high risk with overweight and obesity. Key considerations as these drugs move forward in development to eventual approval include cost, access and long-term safety. This article is part of the Real-world evidence on the use of GLP1 receptor agonists Special Issue: https://www.drugsincontext.com/special_issues/real-world-evidence-on-the-use-of-glp1-receptor-agonists.
Assessment of Selected Biochemical Parameters of the Renin-Angiotensin-Aldosterone System in Repeat Convalescent Plasma Donors in the Context of Long-Term Changes Following SARS-CoV-2 Infection.
J Clin Med
Marta Stanek, Dorota Diakowska, Krzysztof Kaliszewski +1 more
Background: SARS-CoV-2 infection has been associated with long-term health consequences, including dysregulation of the renin-angiotensin-aldosterone system (RAAS). This study aimed to evaluate long-term changes in selected RAAS-related biochemical parameters in repeat convalescent plasma donors, focusing on enzymes and peptides involved in vascular regulation and inflammation. Methods: Thirty repeat convalescent plasma donors were enrolled, each providing four serum samples at defined time points post-infection. Samples were collected during Period 1 (≤60 days), Period 2 (61-90 days), Period 3 (91-120 days), and Period 4 (>120 days) after confirmed SARS-CoV-2 infection. The analyzed parameters included angiotensin I (Ang I), angiotensin II (Ang II), angiotensin 1-7 (Ang 1-7), angiotensin 1-9 (Ang 1-9), ACE, ACE2, ADAM10, and ADAM17. Concentrations were determined using ELISA assays. The control group consisted of pre-pandemic serum samples from healthy individuals. Results: An initial post-infection increase was observed in most parameters, particularly in Period 1. Over time, levels of several markers declined, yet Ang 1-7 and Ang 1-9 remained elevated compared to controls even beyond 120 days. Significant correlations (p < 0.05) were found between ADAM10, ADAM17, and angiotensin peptides, suggesting prolonged RAAS modulation. Metalloproteinases were notably elevated early after infection, potentially contributing to inflammatory and cardiovascular responses. Conclusions: The findings indicate a transient but measurable biochemical response of the RAAS following SARS-CoV-2 infection, with most parameters normalizing after 120 days. However, the sustained elevation of certain markers suggests a potential long-term impact on vascular homeostasis, warranting further investigation.
Structural and Functional Differences of Rhodostomin and Echistatin in Integrin Recognition and Biological Implications.
Proteins
Yi-Chun Chen, Chun-Hao Huang, Yao-Tsung Chang +5 more
Rhodostomin (Rho) and Echistatin (Ech) are RGD-containing disintegrins with different sizes, disulfide bond patterns, and amino acid sequences in their RGD loops and C-termini. Cell adhesion analyzes showed that Rho exhibited a 5.2-, 18.9-, 2.2-, and 1.7-fold lower inhibitory activity against integrins αvβ3, α5β1, αIIbβ3, and αvβ5 in comparison with those of Ech. In contrast, Rho exhibited an 8.8-fold higher activity than Ech in inhibiting integrin αvβ6. The swapping of Ech's RGD loop and C-terminal sequences into those of Rho cannot increase its integrins' inhibitory activities. Interestingly, the mutation of Ech into Rho's RGD loop PRGDMP sequence and C-terminal YH sequence caused an 8.2-fold higher activity in inhibiting integrin αvβ6. Structural analyzes of Rho and Ech showed that they have similar conformations in their RGD loop and different conformations in their C-terminal regions. Molecular docking found that not only the RGD loop but also the C-terminal region of Rho and Ech interacted with integrins, showing that the C-terminal region is also important for integrin recognition. The docking of Rho into integrin αvβ6 showed that the C-terminal H68 residue of Rho interacted with D129 of β6. In contrast, the docking of Ech into integrin α5β1 showed that the C-terminal H44 residue of Ech interacted with Q191 of β1. Ech exhibited 78.5- and 10.9-fold higher activities in inhibiting HUVEC proliferation and A375 melanoma cell migration than those of Rho. These findings demonstrate that the disulfide bond pattern, RGD loop, and C-terminal region of disintegrins may cause their functional differences. The functional and structural differences between Rho and Ech support their potential as scaffolds to design drugs targeting their respective integrins.
Orexin effect on physiological pulsations of the human brain.
Proc Natl Acad Sci U S A
Matti Järvelä, Janne Kananen, Heta Helakari +10 more
Sleep promotes cerebrospinal fluid (CSF) to interstitial fluid (ISF) exchange in the brain facilitated by brain pulsations. Especially brain vasomotion and arterial pulsations modulated by noradrenaline drive the intracranial fluid dynamics. Narcolepsy type 1 (NT1) entails lessened orexinergic output to wake-promoting systems including the noradrenergic locus coeruleus. As arousal state and noradrenergic signaling affect CSF-ISF clearance, we chose patients with NT1 as a human orexin-targeted model of sleep-related pathology bridging the gap between healthy awake and sleep with respect to CSF flow pulsations. We also investigated the sensitivity of magnetic resonance encephalography to detect flow with a phantom model and sought to replicate earlier pulsation findings in sleep. In this case-control study, we used fast functional MRI to map brain pulsations in groups of healthy sleeping controls (n = 13), healthy awake controls (n = 79), and awake NT1 (n = 21) patients. We measured the very low frequency (0.008 to 0.1) and cardiorespiratory frequencies and calculated in each frequency band the coefficient of variation, spectral power, and full band spectral entropy to obtain brain pulsation maps. We uncovered a brain pulsation profile from healthy waking to sleep to a sleep-related pathology NT1 prominently affected in the vascular-related vasomotor and brain arterial pulsations. Our results established how drivers of brain hydrodynamics are affected by a specific loss of key neurotransmitter governing arousal compared to healthy sleep. We also showed with a phantom model that MREG is sensitive to flow-related signal changes and solidified evidence of brain pulsations in the healthy states of sleep and wakefulness.
Ectopic GHRH production: revisiting a rare cause of acromegaly.
Rev Endocr Metab Disord
Matheo A M Stumpf, Nathalie Oliveira Santana, Marcio Carlos Machado +5 more
Growth Hormone-Releasing Hormone (GHRH) is a hypothalamic hormone that stimulates GH secretion by the anterior pituitary gland. Ectopic production of GHRH by neuroendocrine tumors (NETs) is a rare cause of acromegaly, with some clinical and biochemical features indistinguishable from pituitary adenoma origin. Some clues for this diagnosis include pituitary MRI harboring hyperplasia, increased serum GHRH and extra-pituitary tumor detected in whole body scans. The preferable treatment, when possible, should be surgical resection of the NET. In cases with residual tumor, somatostatin analogs could be used as an alternative for adjuvant therapy for both tumoral and biochemical control of IGF-1. Life-long follow-up is needed as some patients may develop persistent pituitary hyperplasia or GH-adenomas due to prolonged GHRH exposure, with elevated IGF-1 levels even without NET recurrence. In such scenarios, medical therapy should be provided for hyperplasia cases and transsphenoidal surgery to patients with pituitary adenoma. If available, genetic test for MEN1 mutations should always be performed.
New Approach Combination-Dosed Therapy for Nonalcoholic Steatohepatitis Versus Vitamin E: A Randomized Controlled Trial.
Clin Ther
Amr Y Zakaria, Rehab Badawi, Hasnaa Osama +2 more
There is currently no US Food and Drug Administration-approved remedy for nonalcoholic steatohepatitis (NASH). The present study evaluated the efficacy of N-acetyl cysteine (NAC) and rosuvastatin (RSV) compared with conventional vitamin E in patients with NASH.
Safety of Intravenous Infusion of BPC157 in Humans: A Pilot Study.
Altern Ther Health Med
Edwin Lee, Kailynd Burgess
For years, the peptide Body Protection Compound 157 (BPC-157) has been used to treat partial muscle or tendon tears. Few studies on humans have been published, with none on the intravenous use of BPC-157 in humans.
Diagnostic Dilemma of a Neuroendocrine Tumour Complicated by Simultaneous Retroperitoneal Fibrosis and Carcinoid Heart Disease in a Perimenopausal Woman.
Cureus
Mohammad Adjmal Rummun, Nosamudiana Obazee, Mimi Leung +5 more
Carcinoid tumours are rare, slow-growing neuroendocrine neoplasms that often remain asymptomatic until metastatic spread or the development of carcinoid syndrome. Carcinoid syndrome is characterised by flushing, diarrhoea, and bronchospasm due to the secretion of vasoactive hormones. These tumours commonly arise in the gastrointestinal tract but can also occur in other organs, namely, the lungs, genitourinary tract, and pancreas. Retroperitoneal fibrosis (RPF), a rare inflammatory disease, involves chronic inflammation leading to fibrous scarring and compression of surrounding structures like the ureters and blood vessels. Carcinoid heart disease secondary to fibrous valve thickening can also occur and causes high morbidity and mortality. This case report highlights a 52-year-old woman who developed a rare complication of RPF along with carcinoid heart disease secondary to a carcinoid tumour. Her symptoms, initially misdiagnosed as menopausal, included a four-year history of diarrhoea, uncontrolled hypertension, and flushing. She was admitted with abdominal pain, acute kidney injury, and bilateral hydronephrosis. Imaging and biochemical tests revealed a primary ileocecal carcinoid tumour with hepatic metastases, RPF causing ureteric obstruction, and elevated chromogranin A/B and urinary 5-hydroxyindoleacetic acid (5-HIAA) levels. Cardiac involvement included severe tricuspid regurgitation, pulmonary hypertension, and impaired left ventricular function, consistent with carcinoid heart disease. Management involved nephrostomy placement following failed bilateral ureteric stenting, octreotide infusions to prevent carcinoid crisis, and symptomatic control with lanreotide. The patient continues to receive multidisciplinary care from cardiology, urology, and oncology. This case underscores the complexity of diagnosing and managing carcinoid tumours with atypical presentations and rare complications like RPF.
A Royal Flush: Carcinoid Heart Disease Complicated by Severe Tricuspid and Pulmonic Valve Regurgitation.
Cureus
Syed Rafay H Zaidi, Nina Appareddy, Wallacy Garcia +4 more
Carcinoid heart disease (CHD) is a severe complication of metastatic neuroendocrine tumors (NETs), leading to fibrotic degeneration of right-sided heart valves. A 38-year-old male presented with progressive dyspnea, fatigue, abdominal bloating, diarrhea, and facial flushing. Imaging revealed hepatic metastases and mesenteric lymphadenopathy, and biochemical markers confirmed a NET of likely gastrointestinal origin. Echocardiography showed torrential tricuspid regurgitation, severe pulmonary insufficiency, right ventricular dilation, and a patent foramen ovale (PFO). The patient was started on long-acting lanreotide for carcinoid syndrome and optimized on heart failure therapy. Due to severe valvular dysfunction, he underwent tricuspid and pulmonic valve replacement with bioprosthetic valves and PFO closure under perioperative octreotide infusion. The patient also underwent transthoracic liver debulking and ablation, small bowel resection, and mesenteric dissection. Postoperatively, he showed symptomatic improvement and remains under multidisciplinary surveillance. This case highlights the importance of early recognition, multidisciplinary management, and surgical intervention in CHD to optimize outcomes. Early initiation of somatostatin analog therapy, guideline-directed medical therapy for heart failure, and timely surgical intervention can significantly improve symptom burden and survival.
High fat diet-induced loss of pituitary plasticity in aging female mice with ablated leptin signaling in somatotropes.
Front Endocrinol (Lausanne)
Tiffany K Miles, Angela K Odle, Stephanie D Byrum +7 more
Somatotropes lacking leptin receptors (LEPR) produce less growth hormone and are poorly responsive to growth hormone releasing hormone (GHRH). Transcriptomic analysis reveals that the mutant somatotropes contain progenitor cell markers (Sox9+) and multiple pituitary hormone transcripts-(Pomc, Prl, Lhb, Tshb and Cga), suggesting that the cells are progenitor cells. The resulting GH deficiency contributes to adult-onset obesity in the mutant, due to an increase in abdominal fat.
Vasopressin and its analogues in patients with septic shock: holy Grail or unfulfilled promise?
Crit Care
Quentin Lajoye, Arthur Orieux, Alexandre Boyer +2 more
The Surviving Sepsis Campaign (SSC) recommends norepinephrine as first-line vasopressor in patients with septic shock. For many years, there has been growing evidence that high doses of norepinephrine might have cardiac and immunological adverse effects and be associated with poorer outcomes. Current SSC guidelines therefore suggest adding vasopressin, a non-catecholaminergic vasopressor, as a second-line vasopressor rather than increasing the norepinephrine dose in patients requiring doses of norepinephrine base > 0.25-0.50 µg/kg/min, after excluding persistent hypovolemia and cardiac dysfunction. Vasopressin is a peptide hormone that causes vasoconstriction through its specific receptor, the arginine vasopressin receptor V1. Up to one-third of patients with septic shock may have vasopressin deficiency, which contributes to refractory septic shock. Vasopressin use is associated with a norepinephrine-sparing effect, which may in turn reduce the complications induced by high-doses of norepinephrine, by decreasing the vasopressor load: this is the concept of decatecholaminization. Nevertheless, the use of vasopressin in patients with septic shock has not yet demonstrated clear benefits in terms of patient outcomes, such as less cardiotoxicity, reduced use of renal replacement therapy or decreased mortality. The heterogeneity in the use of vasopressin and the definition of early vasopressin administration between different studies as well as many unresolved issues regarding the use of vasopressin in patients with septic shock could explain the absence of clear and relevant clinical benefits. Thus, the identification of subgroups of patients likely to benefit the most from vasopressin, the management of vasopressin administration (time to initiation, optimal doses, weaning strategy) and a better understanding of the interactions between vasopressin and corticosteroids represent major areas of research for future studies.