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INTRODUCTION: Psoriatic arthritis (PsA) is a chronic immunoinflammatory disease of the enthesis and adjacent synovium, skin, and nail, which early diagnosis may be crucial for starting a prompt therapeutic intervention. Theoretically, early treatment offers the advantage of acting on the reduction of the articular damage progression since initial phases of the disease. AREAS COVERED: This review explores the challenges of clinical-diagnostic aspects and the underlying pathophysiology of early PsA phases, as well as the evidence evaluating the impact of early intervention on disease outcomes. EXPERT OPINION: Main instruments for early PsA diagnosis include recognizing synovial-entheseal inflammatory signs at onset, improving screening PsA high-risk subjects, and increasing disease knowledge of physicians and patients with psoriasis or familial history. PsA continues to significantly impact on the Quality of Life of patients affected by the disease, making necessary to deeply study clinical manifestations, risk factors, and underlying immunoinflammatory mechanisms, as well as to identify biomarkers for early identification. Additionally, it remains a need to increase more evidence on understanding how early treatment of PsA and of psoriasis might influence the course of the disease.
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INTRODUCTION: Psoriatic arthritis (PsA) is an immune-inflammatory disease that affects both joints and entheses, and with diverse extra-articular manifestations (psoriasis, inflammatory bowel disease (IBD), and uveitis). A wide range of comorbid conditions, including cardiovascular diseases, obesity, metabolic syndrome (MetS), nonalcoholic fatty liver disease (NAFLD), mental health disorders (depression/anxiety), and osteoporosis are highly prevalent in course of PsA.Biological DMARDs (bDMARD), including TNF-inhibitors (TNFi), Interleukin (IL-17i) and IL-23i represent the cornerstone of the management of active disease. The use of these therapies obviously requires considering comorbidities presence, safety aspects and contraindications. AREAS COVERED: The aim of this review is to describe the inflammatory mechanisms behind PsA comorbidities, and the role of bDMARDs in the prevention and treatment of these conditions in course of PsA. EXPERT OPINION: Tailoring therapeutic strategies to the individual characteristics of each PsA patient can be an effective approach to manage comorbidities, maximizing the efficacy of bDMARDs, and reducing the incidence of AEs. Identifying targets within disease pathways can guide research into therapeutics that address both PsA and comorbidities simultaneously, but more studies are advocated for clarifying the potential prevention and management of bDMARDs used for PsA.
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Inflammatory bowel diseases (IBDs) are chronic intestinal disorders often characterized by a dysregulation of T cells, specifically T helper (Th) 1, 17 and T regulatory (Treg) repertoire. Increasing evidence demonstrates that dietary polyphenols from Mangifera indica L. extract (MIE, commonly known as mango) mitigate intestinal inflammation and splenic Th17/Treg ratio. In this study, we aimed to dissect the immunomodulatory and anti-inflammatory properties of MIE using a reverse translational approach, by initially using blood from an adult IBD inception cohort and then investigating the mechanism of action in a preclinical model of T cell-driven colitis. Of clinical relevance, MIE modulates TNF-α and IL-17 levels in LPS spiked sera from IBD patients as an ex vivo model of intestinal barrier breakdown. Preclinically, therapeutic administration of MIE significantly reduced colitis severity, pathogenic T-cell intestinal infiltrate and intestinal pro-inflammatory mediators (IL-6, IL-17A, TNF-α, IL-2, IL-22). Moreover, MIE reversed colitis-induced gut permeability and restored tight junction functionality and intestinal metabolites. Mechanistic insights revealed MIE had direct effects on blood vascular endothelial cells, blocking TNF-α/IFN-γ-induced up-regulation of COX-2 and the DP2 receptors. Collectively, we demonstrate the therapeutic potential of MIE to reverse the immunological perturbance during the onset of colitis and dampen the systemic inflammatory response, paving the way for its clinical use as nutraceutical and/or functional food.
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Colitis , Inflammatory Bowel Diseases , Mangifera , Adult , Humans , Animals , Tumor Necrosis Factor-alpha/metabolism , Endothelial Cells/metabolism , Intestinal Mucosa , Disease Models, AnimalABSTRACT
AIM: Several methods for assessing anastomotic integrity have been proposed, but the best is yet to be defined. The aim of this study was to compare the different methods to assess the integrity of colorectal anastomosis prior to ileostomy reversal. METHOD: A retrospective cohort analysis on patients between 1 January 2010 and 31 December 2020 with a defunctioning stoma for middle and low rectal anterior resection was performed. A propensity score matching comparison between patients who underwent proctoscopy alone and patients who underwent proctoscopy plus any other preoperative method to assess the integrity of colorectal anastomosis prior to ileostomy reversal (transanal water-soluble contrast enema via conventional radiology, transanal water-soluble contrast enema via CT, and magnetic resonance) was performed. RESULTS: The analysis involved 1045 patients from 26 Italian referral colorectal centres. The comparison between proctoscopy alone versus proctoscopy plus any other preoperative tool showed no significant differences in terms of stenoses (p = 0.217) or leakages (p = 0.103) prior to ileostomy reversal, as well as no differences in terms of misdiagnosed stenoses (p = 0.302) or leakages (p = 0.509). Interestingly, in the group that underwent proctoscopy and transanal water-soluble contrast enema the comparison between the two procedures demonstrated no significant differences in detecting stenoses (2 vs. 0, p = 0.98), while there was a significant difference in detecting leakages in favour of transanal water-soluble contrast enema via CT (3 vs. 12, p = 0.03). CONCLUSIONS: We can confirm that proctoscopy alone should be considered sufficient prior to ileostomy reversal. However, in cases in which the results of proctoscopy are not completely clear or the surgeon remains suspicious of an anastomotic leakage, transanal water-soluble contrast enema via CT could guarantee its detection.
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Rectal Neoplasms , Surgical Oncology , Humans , Proctoscopy , Ileostomy/methods , Retrospective Studies , Constriction, Pathologic/surgery , Rectal Neoplasms/diagnostic imaging , Rectal Neoplasms/surgery , Enema/methods , Contrast Media , Anastomosis, Surgical/adverse effects , Anastomosis, Surgical/methods , Anastomotic Leak/diagnostic imaging , Anastomotic Leak/etiology , Anastomotic Leak/surgery , Water , ItalyABSTRACT
Psoriasis is now considered to be the cutaneous phenotype of a systemic inflammatory condition, recognized under the term Psoriatic Disease (PsD). PsD has several extracutaneous manifestations, such as inflammatory articular and entheseal involvement, leading to psoriatic arthritis (PsA), and the less frequent intestinal and ocular manifestations with colitis/inflammatory bowel disease and uveitis, respectively. There have also been several reports of an increased frequency of comorbidities such as hypertension, diabetes, dyslipidemia, obesity, metabolic syndrome and cardiovascular manifestations during the course of PsD. The link between psoriasis and related comorbidities is considered a long-term disease sequela, often characterized by an unhealthy lifestyle and a consequence of systemic inflammation; hence, psoriasis requires adequate and prompt treatment, with the aim of controlling not only cutaneous manifestations but also extracutaneous manifestations and systemic inflammation. Pharmacological strategies for PsD have significantly increased over recent years. Recently, the targeted synthetic DMARDs, Janus kinase (JAK) inhibitors, tofacitinib and upadacitinib, were added to the therapeutic armamentarium for treating PsA, and deucravacitinib for psoriasis. These oral agents act directly on inflammatory mechanisms underlining the disease, as antagonists of the intracellular JAK signal pathway and, by STAT phosphorylation, inhibit gene proinflammatory cytokine transcription. JAK inhibitors represent a recent additional treatment strategy for PsD management and, among these, tofacitinib and upadacitinib have recently been approved for PsA, and deucravacitinib for psoriasis. In this review we describe ongoing and recent phase II and III randomized controlled trials (RCTs) evaluating the efficacy and safety of investigational JAK inhibitors in psoriasis and PsA.
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OBJECTIVES: Interleukin (IL) 17s cytokines are key drivers of inflammation that are functionally dysregulated in several human immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA), psoriasis and inflammatory bowel disease (IBD). Targeting these cytokines has some therapeutic benefits, but issues associated with low therapeutic efficacy and immunogenicity for subgroups of patients or IMIDs reduce their clinical use. Therefore, there is an urgent need to improve the coverage and efficacy of antibodies targeting IL-17A and/or IL-17F and IL-17A/F heterodimer. METHODS AND RESULTS: Here, we initially identified a bioactive 20 amino acid IL-17A/F-derived peptide (nIL-17) that mimics the pro-inflammatory actions of the full-length proteins. Subsequently, we generated a novel anti-IL-17 neutralising monoclonal antibody (Ab-IPL-IL-17) capable of effectively reversing the pro-inflammatory, pro-migratory actions of both nIL-17 and IL-17A/F. Importantly, we demonstrated that Ab-IPL-IL-17 has less off-target effects than the current gold-standard biologic, secukinumab. Finally, we compared the therapeutic efficacy of Ab-IPL-IL-17 with reference anti-IL-17 antibodies in preclinical murine models and samples from patients with RA and IBD. We found that Ab-IPL-IL-17 could effectively reduce clinical signs of arthritis and neutralise elevated IL-17 levels in IBD patient serum. CONCLUSIONS: Collectively, our preclinical and in vitro clinical evidence indicates high efficacy and therapeutic potency of Ab-IPL-IL-17, supporting the rationale for large-scale clinical evaluation of Ab-IPL-IL-17 in patients with IMIDs.
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Arthritis, Rheumatoid , Biological Products , Inflammatory Bowel Diseases , Humans , Mice , Animals , Interleukin-17 , Immunomodulating Agents , Cytokines , Inflammatory Bowel Diseases/drug therapy , Biological Products/pharmacology , Biological Products/therapeutic useABSTRACT
Inflammation of the adipose tissue contributes to the onset and progression of several chronic obesity-related diseases. The two most important lipophilic diterpenoid compounds found in the root of Salvia milthorrhiza Bunge (also called Danshen), tanshinone IIA (TIIA) and cryptotanshinone (CRY), have many favorable pharmacological effects. However, their roles in obesity-associated adipocyte inflammation and related sub-networks have not been fully elucidated. In the present study, we investigated the gene, miRNAs and protein expression profile of prototypical obesity-associated dysfunction markers in inflamed human adipocytes treated with TIIA and CRY. The results showed that TIIA and CRY prevented tumor necrosis factor (TNF)-α induced inflammatory response in adipocytes, by counter-regulating the pattern of secreted cytokines/chemokines associated with adipocyte inflammation (CCL2/MCP-1, CXCL10/IP-10, CCL5/RANTES, CXCL1/GRO-α, IL-6, IL-8, MIF and PAI-1/Serpin E1) via the modulation of gene expression (as demonstrated for CCL2/MCP-1, CXCL10/IP-10, CCL5/RANTES, CXCL1/GRO-α, and IL-8), as well as related miRNA expression (miR-126-3p, miR-223-3p, miR-124-3p, miR-155-5p, and miR-132-3p), and by attenuating monocyte recruitment. This is the first demonstration of a beneficial effect by TIIA and CRY on adipocyte dysfunction associated with obesity development and complications, offering a new outlook for the prevention and/or treatment of metabolic diseases.
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Chemokine CCL5 , MicroRNAs , Humans , Chemokine CCL5/metabolism , Chemokine CXCL10/metabolism , Interleukin-8/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Inflammation/drug therapy , Inflammation/genetics , Inflammation/metabolism , Tumor Necrosis Factor-alpha/metabolism , Adipocytes/metabolismABSTRACT
PURPOSE: Several risk factors affecting the adequacy of colon cleansing have been proposed during the last decades. However, less is known about the impact that atmospheric aspects could have on adequacy of the bowel cleansing. The study aimed to investigate if the atmospheric temperature could impact on the bowel cleansing during colonoscopy. METHODS: A prospective maintained database of the colonoscopies performed since 1st August 2017 to 31st March 2020 was retrospective reviewed. The primary outcome of the study was to identify if the atmospheric temperature was associated with inadequate colon cleansing during colonoscopy. Secondary outcome was to identify the other factors associated with an inadequate colon cleansing. RESULTS: One thousand two hundred twenty patients were enrolled. High atmospheric temperature (> 25 °C) significantly influenced the colon cleansing (p < 0.0001). Adequate colon cleansing was negatively influenced by gender (female patients were associated with higher colon cleansing rate, p = 0.013), diabetes (p < 0.0001), previous pelvic surgery (p = 0.001), use of Beta-Blocker (p = 0.001), anti-platelet (p = 0.017), angiotensin converting enzyme inhibitors (p = 0.001), the adoption of 4 L Poly Ethylene Glycol solution (p = 0.009), single-dose regimen (p < 0.0001) low patients' compliance (p < 0.0001), higher age and body mass index (p < 0.0001 and p = 0.025), lower education levels (p < 0.0001). On the contrary, admission to the ward to perform bowel preparation positively impacted on colon cleansing (p = 0.002). CONCLUSION: Atmospheric temperature could play an important role in the colon cleansing during colonoscopy, being high temperature (> 25 °C) associated with lower rate of adequate bowel cleansing. However, being this relationship never studied before, these results must be confirmed by other studies.
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Cathartics , Colon , Female , Humans , Cathartics/adverse effects , Colonoscopy/methods , Polyethylene Glycols/adverse effects , Prospective Studies , Retrospective Studies , TemperatureABSTRACT
INTRODUCTION: Psoriatic arthritis (PsA) is a chronic inflammatory disease affecting about one-third of subjects with psoriasis. Several treatment modalities targeting Janus Kinase pathways and intracellular inflammatory cascade are now available and under clinical investigation to treat this disease. AREAS COVERED: This review describes ongoing and recently completed phase 2 and 3 randomized clinical trials (RCTs) evaluating the efficacy and safety of approved JAK (Tofacitinib and Upadacitinib) and investigational JAK inhibitors (JAK1 inhibitors: Filgotinib and Ivarmacitinib (SHR0302); TYK2 inhibitors: Brepocitinib (PF-06700841) Deucravacitinib (BMS-986165), and NDI-034858) in PsA through February 2023. EXPERT OPINION: Current standard of care has significantly improved the quality of life in PsA. Recently approved JAK inhibitors for PsA have addressed many of the unmet needs of PsA, particularly of those with severe phenotypes. Preliminary results from several RCTs have reported good and fast efficacy and an acceptable safety profile of investigational JAK inhibitors in PsA. Additional clinical trials and long-term outcome data on these agents are necessary for increasing available therapeutic options for PsA.
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Antirheumatic Agents , Arthritis, Psoriatic , Janus Kinase Inhibitors , Psoriasis , Humans , Arthritis, Psoriatic/drug therapy , Janus Kinase Inhibitors/therapeutic use , Psoriasis/drug therapy , Janus Kinases , Antirheumatic Agents/therapeutic useABSTRACT
The functional disease of the esophago-gastric junction (EGJ) is one of the most common health problems. It often happens that patients suffering from GERD need surgical management. The laparoscopic fundoplication has been considered the gold standard surgical treatment for functional diseases of the EGJ. The aim of our meta-analysis is to investigate functional outcomes after robotic fundoplication compared with conventional laparoscopic fundoplication. A prospective search of online databases was performed by two independent reviewers using the search string "robotic and laparoscopic fundoplication", including all the articles from 1996 to December 2021. The risk of bias within each study was assessed with the Cochrane ROBINS-I and RoB 2.0 tools. Statistical analysis was performed using Review Manager version 5.4. In addition, sixteen studies were included in the final analysis, involving only four RCTs. The primary endpoints were functional outcomes after laparoscopic (LF) and robotic fundoplication (RF). No significant differences between the two groups were found in 30-day readmission rates (p = 0.73), persistence of symptomatology at follow-up (p = 0.60), recurrence (p = 0.36), and reoperation (p = 0.81). The laparoscopic fundoplication represents the gold standard treatment for the functional disease of the EGJ. According to our results, the robotic approach seems to be safe and feasible as well. Further randomized controlled studies are required to better evaluate the advantages of robotic fundoplication.
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The application of a multi-step scientific workflow revealed an unprecedented class of PGE2/leukotriene biosynthesis inhibitors with in vivo activity. Specifically, starting from a combinatorial virtual library of â¼4.2 × 105 molecules, a small set of compounds was identified for the synthesis. Among these, four novel 2-aminoacyl-1,3,4-thiadiazole derivatives (3, 6, 7, and 9) displayed marked anti-inflammatory properties in vitro by strongly inhibiting PGE2 biosynthesis, with IC50 values in the nanomolar range. The hit compounds also efficiently interfered with leukotriene biosynthesis in cell-based systems and modulated IL-6 and PGE2 biosynthesis in a lipopolysaccharide-stimulated J774A.1 macrophage cell line. The most promising compound 3 showed prominent in vivo anti-inflammatory activity in a mouse model, with efficacy comparable to that of dexamethasone, attenuating zymosan-induced leukocyte migration in mouse peritoneum with considerable modulation of the levels of typical pro-/anti-inflammatory cytokines.
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Italian Research Group for Gastric Cancer (GIRCG), during the 2013 annual Consensus Conference to gastric cancer, stated that laparoscopic or robotic approach should be limited only to early gastric cancer (EGC) and no further guidelines were currently available. However, accumulated evidences, mainly from eastern experiences, have supported the application of minimally invasive surgery also for locally advanced gastric cancer (AGC). The aim of our study is to give a snapshot of current surgical propensity of expert Italian upper gastrointestinal surgeons in performing minimally invasive techniques for the treatment of gastric cancer in order to answer to the question if clinical practice overcome the recommendation. Experts in the field among the Italian Research Group for Gastric Cancer (GIRCG) were invited to join a web 30-item survey through a formal e-mail from January 1st, 2020, to June 31st, 2020. Responses were collected from 46 participants out of 100 upper gastrointestinal surgeons. Percentage of surgeons choosing a minimally invasive approach to treat early and advanced gastric cancer was similar. Additionally analyzing data from the centers involved, we obtained that the percentage of minimally invasive total and partial gastrectomies in advanced cases augmented with the increase of surgical procedures performed per year (p = 0.02 and p = 0.04 respectively). It is reasonable to assume that there is a widening of indications given by the current national guideline into clinical practice. Propensity of expert Italian upper gastrointestinal surgeons was to perform minimally invasive surgery not only for early but also for advanced gastric cancer. Of interest volume activity correlated with the propensity of surgeons to select a minimally invasive approach.
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Laparoscopy , Robotic Surgical Procedures , Stomach Neoplasms , Humans , Stomach Neoplasms/surgery , Gastrectomy/methods , Surveys and Questionnaires , Minimally Invasive Surgical Procedures/methods , Robotic Surgical Procedures/methods , Laparoscopy/methodsABSTRACT
The increasing resistance of fungi to conventional antifungal drugs has prompted worldwide the search for new compounds. In this work, we investigated the antifungal properties of acylated Temporin L derivatives, Pent-1B and Dec-1B, against Candida albicans, including the multidrug-resistant strains. Acylated peptides resulted to be active both on reference and clinical strains with MIC values ranging from 6.5 to 26 µM, and they did not show cytotoxicity on human keratinocytes. In addition, we also observed a synergistic or additive effect with voriconazole for peptides Dec-1B and Pent-1B through the checkerboard assay on voriconazole-resistant Candida strains. Moreover, fluorescence-based assays, NMR spectroscopy, and confocal microscopy elucidated a potential membrane-active mechanism, consisting of an initial electrostatic interaction of acylated peptides with fungal membrane, followed by aggregation and insertion into the lipid bilayer and causing membrane perturbation probably through a carpeting effect.
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Antifungal Agents , Candida albicans , Drug Resistance, Multiple, Fungal , Humans , Antifungal Agents/pharmacology , Antimicrobial Cationic Peptides/pharmacology , Candida albicans/drug effects , Microbial Sensitivity Tests , Voriconazole/pharmacologyABSTRACT
Pilonidal Sinus is a benign, chronic disease that affects the hair follicles of the natal cleft of the sacrococcygeal area. Its ideal treatment is controversial, especially in complex or recurrent cases. The aim of this study is to evaluate the use of minimally invasive endoscopic approach in this setting. We enrolled patients affected by complex or recurrent sacrococcygeal pilonidal sinus from January 2015 through December 2020 who underwent Video-Assisted Ablation of Pilonidal Sinus. All patients enrolled were re-evaluated once a year with a standard physical examination. The patients included were 38. Recurrence rate at 1-, 3- and 5-years follow-ups were 28.9%, 22.2% and 38.1% respectively. Of interest, the mean (SD) distance from the most lateral orifice to the midline was higher in group of patients with recurrence and the multivariate analysis demonstrated that it was the limiting factor, which influences the recurrence rate. In complex or recurrent pilonidal sinus disease with pits off the midline the endoscopic approach should not be the first choice. This makes us think that these cases should have their own classification to be identified and guide surgeons in choosing the appropriate approach.
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Pilonidal Sinus , Humans , Pilonidal Sinus/surgery , Pilonidal Sinus/diagnosis , Retrospective Studies , Chronic Disease , Recurrence , Treatment OutcomeABSTRACT
Alzheimer's disease (AD) is one of the most prevalent forms of neurodegenerative disorders. Previously, we have shown that in vivo administration of an IL-17 neutralizing antibody (IL-17Ab) rescues amyloid-ß-induced neuro-inflammation and memory impairment, demonstrating the pivotal role of IL-17 in AD-derived cognitive deficit. Recently, AD has been recognized as a more intriguing pathology affecting vascular networks and platelet function. However, not much is known about peripheral vascular inflammation and how pro-inflammatory circulating cells/mediators could affect peripheral vessels' function. This study aimed to evaluate whether IL-17Ab treatment could also impact peripheral AD features, such as systemic inflammation, peripheral vascular dysfunction, and related pro-thrombotic state in a non-genetic mouse model of AD. Mice were injected intracerebroventricularly with Aß1-42 peptide (3 µg/3 µl). To evaluate the systemic/peripheral protective profile of IL-17Ab, we used an intranasal administration of IL-17Ab (1 µg/10 µl) at 5, 12, and 19 days after Aß1-42 injection. Circulating Th17/Treg cells and related cyto-chemokines, haematological parameters, vascular/endothelial reactivity, platelets and coagulation function in mice were evaluated. IL-17Ab treatment ameliorates the systemic/peripheral inflammation, immunological perturbance, vascular/endothelial impairment and pro-thrombotic state, suggesting a key role for this cytokine in fostering inflammatory processes that characterize the multifaced aspects of AD.
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Alzheimer Disease , Animals , Mice , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Amyloid beta-Peptides , Cytokines , Disease Models, Animal , Inflammation/drug therapy , Inflammation/pathology , Interleukin-17 , Peptide Fragments/pharmacologyABSTRACT
BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They are 1% of all gastrointestinal cancer and 60% of them affects the stomach. Up to 10% to 30% of GISTs are malignant. They occur in people over the age of 50 in both sexes. The most common symptoms of gastric GIST are bleeding, dyspepsia, vague abdominal pain or discomfort, and mass palpation. Some are asymptomatic and diagnosed incidentally. The first choice of treatment for primary localized gastric GISTs is surgery. The most suitable type of resection is not yet clear and it depends on size and location of tumor, especially for difficult localizations, such as subcardial, posterior wall and less curvature GISTs. METHODS: We report a rare case of a patient with subcardial gastric GIST treated with laparoscopic atypical quadrangular resection guided by intraoperative endoscopy. Furthermore, we performed a review of the literature about this topic. RESULTS: Despite the difficult localization an atypical resection of the gastric GIST was performed without breaking the lesion but preserving the lumen of the esofagogastrich junction. CONCLUSIONS: An atypical quadrangular resection for subcardial gastric GISTs, located along the posterior wall and lesser curvature, can be a safe and reliable alternative technique. However, we believe that it should be performed by an experienced surgeon and endoscopist to decrease the risk of mass's break and the narrowing of the cardial region's lumen. In our literature's knowledge there aren't cases treated with this technique. KEY WORDS: Gastric GIST, Gastrointestinal stromal tumors, Intraoperative endoscopy, Laparoscopic resection, Minimally invasive surgery.
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Gastrointestinal Stromal Tumors , Laparoscopy , Stomach Neoplasms , Surgeons , Female , Male , Humans , Gastrointestinal Stromal Tumors/surgery , Stomach Neoplasms/diagnosis , Stomach Neoplasms/surgeryABSTRACT
BACKGROUND AND AIMS: Atherosclerosis is widely accepted to be an inflammatory disease driven by lipid accumulation and leukocyte recruitment. More recently, galectins, a family of ß-galactoside binding proteins, have been shown to play a role in leukocyte recruitment among other immunomodulatory functions. Galectin (Gal) -9, a tandem repeat type galectin expressed by the endothelium in inflammatory environments, has been proposed to promote leukocyte recruitment. However, the role of Gal-9 in the context of monocyte recruitment remains elusive. METHODS AND RESULTS: Here, we characterise the immunomodulatory role of Gal-9 in context of atherosclerosis. We show that ApoE-/-Gal-9-/- mice have a significantly reduced aortic plaque burden compared to their ApoE-/- littermate controls after 12 weeks of high fat diet. RNA sequencing data from two independent studies reveal Lgals9 expression in leukocyte clusters isolated from murine atherosclerotic plaques. Additionally, soluble Gal-9 protein induces monocyte activation and a pro-inflammatory phenotype in macrophages. Furthermore, we show that immobilised recombinant Gal-9 acts as capture and adhesion molecule for CD14+ monocytes in a ß2-integrin and glycan dependent manner, while adhesion of monocytes to stimulated endothelium is reduced when Gal-9 is knocked down. Gal-9 also facilitates enhanced recruitment of leukocytes from peripheral arterial disease (PAD) patients compared to healthy young and aged controls. We further characterise the endothelium as source of circulating Gal-9, which is increased in plasma of PAD patients compared to healthy controls. CONCLUSIONS: These results highlight a pathological role for Gal-9 as promoter of monocyte recruitment and atherosclerotic plaque progression, making it a novel target in the prevention of plaque formation and progression.
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Atherosclerosis , Plaque, Atherosclerotic , Mice , Animals , Mice, Inbred C57BL , Cells, Cultured , Atherosclerosis/pathology , Plaque, Atherosclerotic/metabolism , Monocytes/metabolismABSTRACT
Temporin family is one of the largest among antimicrobial peptides (AMPs), which act mainly by penetrating and disrupting the bacterial membranes. To further understand the relationship between the physical-chemical properties and their antimicrobial activity and selectivity, an analogue of Temporin L, [Nle1, dLeu9, dLys10]TL (Nle-Phe-Val-Pro-Trp-Phe-Lys-Phe-dLeu-dLys-Arg-Ile-Leu-CONH2) has been developed in the present work. The design strategy consisted of the addition of a norleucine residue at the N-terminus of the lead peptide sequence, [dLeu9, dLys10]TL, previously developed by our group. This modification promoted an increase of peptide hydrophobicity and, interestingly, more efficient activity against both Gram-positive and Gram-negative strains, without affecting human keratinocytes and red blood cells survival compared to the lead peptide. Thus, this novel compound was subjected to biophysical studies, which showed that the peptide [Nle1, dLeu9, dLys10]TL is unstructured in water, while it adopts ß-type conformation in liposomes mimicking bacterial membranes, in contrast to its lead peptide forming α-helical aggregates. After its aggregation in the bacterial membrane, [Nle1, dLeu9, dLys10]TL induced membrane destabilization and deformation. In addition, the increase of peptide hydrophobicity did not cause a loss of anti-inflammatory activity of the peptide [Nle1, dLeu9, dLys10]TL in comparison with its lead peptide. In this study, our results demonstrated that positive net charge, optimum hydrophobic-hydrophilic balance, and chain length remain the most important parameters to be addressed while designing small cationic AMPs.
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INTRODUCTION: Despite progressive improvements in technical skills and instruments that have facilitated surgeons performing intracorporeal gastro-jejunal and jejuno-jejunal anastomoses, one of the big challenging tasks is handsewn knot tying. We analysed the better way to fashion a handsewn intracorporeal enterotomy closure after a stapled anastomosis. METHODS: All 579 consecutive patients from January 2009 to December 2019 who underwent minimally invasive partial gastrectomy for gastric cancer were retrospectively analysed. Different ways to fashion intracorporeal anastomoses were investigated: robotic versus laparoscopic approach; laparoscopic high definition versus three-dimensional versus 4K technology; single-layer versus double-layer enterotomies. Double-layer enterotomies were analysed layer by layer, comparing running versus interrupted suture; the presence versus absence of deep corner suture; and type of suture thread. RESULTS: Significantly lower rates of bleeding (p = 0.011) and leakage (p = 0.048) from gastro-jejunal anastomosis were recorded in the double-layer group. Barbed suture thread was significantly associated with reduced intraluminal bleeding and leakage rates both in the first (p = 0.042 and p = 0.010) and second layer (p = 0.002 and p = 0.029). CONCLUSIONS: Double-layer sutures using barbed suture thread both in first and second layer to fashion enterotomy closure result in lower intraluminal bleeding and anastomotic leak rates.