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The heart hosts tissue resident macrophages which are capable of modulating cardiac inflammation and function by multiple mechanisms. At present, the consequences of phenotypic diversity in macrophages in the heart are incompletely understood. The contribution of cardiac M2-polarized macrophages to the resolution of inflammation and repair response following myocardial infarction remains to be fully defined. In this study, the role of M2 macrophages was investigated utilising a specific CSF-1 receptor signalling inhibition strategy to achieve their depletion. In mice, oral administration of GW2580, a CSF-1R kinase inhibitor, induced significant decreases in Gr1lo and F4/80hi monocyte populations in the circulation and the spleen. GW2580 administration also induced a significant depletion of M2 macrophages in the heart after 1 week treatment as well as a reduction of cardiac arginase1 and CD206 gene expression indicative of M2 macrophage activity. In a murine myocardial infarction model, reduced M2 macrophage content was associated with increased M1-related gene expression (IL-6 and IL-1β), and decreased M2-related gene expression (Arginase1 and CD206) in the heart of GW2580-treated animals versus vehicle-treated controls. M2 depletion was also associated with a loss in left ventricular contractile function, infarct enlargement, decreased collagen staining and increased inflammatory cell infiltration into the infarct zone, specifically neutrophils and M1 macrophages. Taken together, these data indicate that CSF-1R signalling is critical for maintaining cardiac tissue resident M2-polarized macrophage population, which is required for the resolution of inflammation post myocardial infarction and, in turn, for preservation of ventricular function.

Background: Sortilin1 (SORT1) is a ubiquitously expressed transporter involved in sorting or clearing proteins and is pathologically linked to tissue fibrosis and calcification. Targeting SORT1 may have potential clinical efficacy in controlling or reversing cardiovascular fibrosis and/or calcification. Hence, this study assessed the protein–protein network of human SORT1 and its targetability using known nutra-/pharmaceuticals. Material and methods: Network proteins of human SORT1 were identified using the String database, and the affinity of the protein–protein interaction of this network was analysed using Chimera software (Chimera-1.17.3-mac64). The tissue-specific expression profile of SORT1 was evaluated and assessed for enrichment in different cell types, including immune cells. A library of in-house small molecules and currently used therapeutics for cardiovascular diseases were screened using AutoDock Vina to assess the targetability of human SORT1. The concentration affinity (CA) ratio of the small molecules was estimated to assess the clinical feasibility of targeting SORT1. Results: IGF2R, NTRK2, GRN and GGA1 were identified as high-affinity interaction networks of SORT1. Of these high-affinity interactions, IGF2R and GRN can be considered relevant networks in regulating tissue fibrosis or the microcalcification process due to their influence on T-cell activation, inflammation, wound repair, and the tissue remodelling process. The tissue cell-type enrichment indicated major expression of SORT1 in adipocytes, specialised epithelial cells, monocytes, cardiomyocytes, and thyroid glandular cells. The binding pocket analysis of human SORT1 showed twelve potential drug interaction sites with varying binding scores (0.86 to 5.83) and probability of interaction (0.004 to 0.304). Five of the drug interaction sites were observed to be targetable at the therapeutically feasible concentration of the small molecules evaluated. Empagliflozin, sitagliptin and lycopene showed a superior affinity and CA ratio compared to established inhibitors of SORT1. Conclusion: IGF2R and GRN are relevant networks of SORT1, regulating tissue fibrosis or the microcalcification process. SORT1 can be targeted using currently approved small-molecule therapeutics (empagliflozin and sitagliptin) or widely used nutraceuticals (lycopene), which should be evaluated in a randomised clinical trial to assess their efficacy in reducing the cardiac/vascular microcalcification process.

Lycopene exhibits a broad spectrum of biological activities with potential therapeutic applications. Despite its established antioxidant and anti-inflammatory properties, the molecular basis for its pharmacological actions remains incompletely defined. Here we investigated the molecular targets, pharmacodynamic feasibility, and tissue-specific expression of lycopene targets using a computational pharmacology approach combined with affinity and protein–protein interaction (PPI) analyses. Lycopene-associated human protein targets were predicted using a Swiss target screening platform. Molecular docking was used to estimate binding affinities, and concentration-affinity (CA) ratios were calculated based on physiologically relevant plasma concentrations (75–210 nM). PPI networks of lycopene targets were constructed to identify highly connected targets, and tissue expression analysis was assessed for high-affinity targets using protein-level data from the Human Protein Atlas database. Of the 94 predicted targets, 37% were nuclear receptors and 18% were Family A G Protein Coupled Receptors (GPCRs). Among the top 15 high-affinity targets, nuclear receptors and GPCRs comprised 40% and 26.7%, respectively. Twenty targets had affinities < 10 μM, with six key targets (MAP2K2, SCN2A, SLC6A5, SCN3A, TOP2A, and TRIM24) showing submicromolar binding. CA ratio analysis identified MAP2K2, SCN2A, and SLC6A5 as pharmacodynamically feasible targets (CA > 1). PPI analysis revealed 32 targets with high interaction and 9 with significant network connectivity. Seven targets (TRIM24, GRIN1, NTRK1, FGFR1, NTRK3, CHRNB4, and PIK3CD) showed both high affinity and centrality in the interaction network. The expression profiling of submicromolar targets revealed widespread tissue distribution for MAP2K2 and SCN3A, while SCN2A, TOP2A, and TRIM24 showed more restricted expression patterns. This integrative analysis identifies a subset of lycopene targets with both high affinity and pharmacological feasibility, particularly MAP2K2, SCN2A, and TRIM24. Lycopene appears to exert its biological effects through modulation of interconnected signalling networks involving nuclear receptors, GPCRs, and ion channels. These findings support the potential of lycopene as a multi-target therapeutic agent and provide a rationale for future experimental and clinical validation.

Background: Intravenous cannulation (IVC) is a routine yet distressing procedure in pediatric patients, often provoking significant anxiety and procedural pain. Although eutectic mixtures such as eutectic mixture of local anesthetic cream are widely used, their delayed onset limits their applicability in time-sensitive settings. Ethyl chloride vapocoolant spray and 10% lignocaine spray have been proposed as rapid-onset alternatives, yet direct comparative evidence in children is scarce.Purpose: This study aimed to compare the analgesic efficacy, onset of action, and ease of IVC between ethyl chloride vapocoolant spray and 10% lignocaine spray in pediatric patients undergoing elective surgery.Methods: A prospective, randomized, double-blinded trial was conducted in a tertiary care hospital between 2022 and 2024 following ethics approval (IEC:279/2022) and trial registration (CTRI/2023/08/056580). Sixty children aged 8–17 years (American Society of Anesthesiologists [ASA] I–II) scheduled for elective procedures were randomized to receive either 3 sprays of 10% lignocaine (group L) or ethyl chloride spray (group E) before IVC. Pain was assessed using the visual analogue scale (ASA=0–100 mm), ease of cannulation with a 4-point Likert scale, and procedural time was recorded. Failed cannulations, adverse events, and rescue analgesia requirements were noted. Data were analyzed using IBM SPSS Statistics ver. 22.0 with a significance threshold of P<0.05.Results: Group E demonstrated significantly lower VAS scores (30.43±0.9 mm) compared to group L (70.03±1.07 mm, P<0.001). Mean cannulation time was shorter in group E (16.07±2.41 seconds) than group L (24.57±4.42 seconds, P<0.001). Ease of cannulation was superior in group E, with 100% of patients reporting no difficulty, whereas only 67.8% in group L reported the same (P= 0.002). No adverse effects or serious complications were observed in either group.Conclusion: Ethyl chloride vapocoolant spray provides significantly superior dermal analgesia, faster onset, and improved ease of IVC compared to 10% lignocaine spray in children aged 8–17 years. Its rapid action and safety profile make it a valuable alternative in pediatric anesthesia practice, particularly in time-sensitive clinical settings.

Date palms, along with their fruits' dietary consumption, possess enormous medicinal and pharmacological activities manifested in their usage in a variety of ailments in the various traditional systems of medicine. In recent years, the identification of progenitor cells in the adult organ systems has opened an altogether new approach to therapeutics, due to the ability of these cells to repair the damaged cells/tissues. Hence, the concept of developing therapeutics, which can mobilize endogenous progenitor cells, following tissue injury, to enhance tissue repair process is clinically relevant. The present study investigates the potential of date of palm fruit extracts in repairing tissue injury following myocardial infarction (MI) potentially by mobilizing circulating progenitor cells. Extracts of four different varieties of date palm fruits common in Saudi Arabia eastern provision were scrutinized for their total flavonoid, total phenolic, antioxidant capacity, as well as their effects on two different rodent MI models. High concentrations of phenolic and flavonoid compounds were observed in date palm fruit extracts, which contributed to the promising antioxidant activities of these extracts and the observed high protective effect against various induced MI. The extracts showed ability to build up reserves and to mobilize circulating progenitor cells from bone marrow and peripheral circulation to the site of myocardial infraction. Date palm fruit extracts have the potential to mobilize endogenous circulating progenitor cells, which can promote tissue repair following ischemic injury.

Simultaneous and collocated measurements of spectrally resolved scattering and absorption coefficients and mass concentration of near‐surface composite aerosols in the marine atmosphere over the Bay of Bengal (BOB), along with incoming shortwave (0.3–3 μm) global solar radiation and columnar spectral aerosol optical depths (AOD), were made on a research cruise during the winter phase of the Integrated Campaign for Aerosols, Gases and Radiation Budget (W‐ICARB). The aerosol radiative properties revealed distinct spatial features associated with the contrasting outflows from Indo‐Gangetic Plain (IGP) and East Asia. Both scattering and absorption coefficients depicted very high values (>200 and >15 Mm−1) over the northwestern and southeastern BOB and extremely low values (<50 and <10 Mm−1) over the central BOB. The mean value of the total scattering coefficient at 550 nm (∼123.7 ± 85.3 Mm−1) over the entire BOB during winter was higher than the mean values (∼94 ± 47 Mm−1) reported for the premonsoon season. While SSA at 550 nm showed very low values (<0.8) over a very large region in the central BOB and moderately low values over the southern BOB (∼0.85–0.9), the columnar AOD varied from the least values of ∼0.1 over the northeastern BOB to the highest values of ∼0.8 over the northwestern BOB. While significant cooling was observed at the top of the atmosphere and surface over the northwestern BOB, the atmospheric forcing was found to be significantly high (∼15 W m−2) over the southern BOB, where the aerosol radiative forcing efficiency (ARFE) at the surface was also found to be high. Examination of the Moderate Resolution Imaging Spectroradiometer (MODIS)‐derived fire count along with the advection pathways revealed a strong contribution from the emissions of biomass smoke from East Asia, which might be contributing to the enhanced aerosol induced warming over the southern BOB. However, the ARFE at the surface was low over the northwestern BOB, where the advection from IGP was predominant. Key Points The radiative properties of aerosols revealed heterogeneous spatial features Spatial distinctiveness associated with contrasting outflows Forcing efficiency of East Asian aerosols is higher than that from IGP

Monocyte/macrophages are implicated in initiation of angiogenesis, tissue/organ perfusion and atherosclerosis biology. We recently showed that chemokine receptor CX(3)CR1 is an essential regulator of monocyte/macrophage derived smooth muscle cell differentiation in the vessel wall after injury. Here we hypothesised the contribution of CX(3)CR1- CX(3)CL1 interaction to in vivo neovascularization and studied the functional consequences of genetic and pharmacologic targeting of CX(3)CR1 in formation, maturation and maintenance of microvascular integrity. Cells functionally deficient in CX(3)CR1 lacked matrix tunnelling and tubulation capacity in a 3D Matrigel assay. These morphogenic and cytokinetic responses were driven by CX(3)CL1-CX(3)CR1 interaction and totally abrogated by a Rho antagonist. To evaluate the role of CX(3)CR1 system in vivo, Matrigel plugs were implanted in competent CX(3)CR1(+/gfp) and functionally deficient CX(3)CR1(gfp/gfp) mice. Leaky microvessels (MV) were formed in the Matrigel implanted in CX(3)CR1(gfp/gfp) but not in CX(3)CR1(+/gfp) mice. In experimental plaque neovascularization immature MV phenotype was observed in CX(3)CR1(gfp/gfp) mice, lacking CX(3)CR1 positive smooth muscle-like cells, extracellular collagen and basement membrane (BM) laminin compared to competent CX(3)CR1(+/gfp) mice. This was associated with increased extravasation of platelets into the intima of CX(3)CR1(gfp/gfp) but not functionally competent CX(3)CR1 mice. Pharmacologic targeting using CX(3)CR1 receptor antagonist in wild type mice resulted in formation of plaque MV with poor BM coverage and a leaky phenotype. Our data indicate a hitherto unrecognised role for functional CX(3)CR1 in Matrigel and experimental plaque neovascularization in vivo, which may buttress MV collectively in favour of a more stable non-leaky phenotype.

Atherosclerosis is associated with alterations in nitric oxide (NO)/cGMP signaling. In early stages of the disease, inflammatory and possibly other cells produce reactive oxygen species that scavenge vasoprotective NO. In addition to the oxidative stress, expression and activity of enzymes downstream to NO formation may also be affected. Here, we show in the aortas of chronically hypercholesterolemic rabbits (a model of late-stage atherosclerosis), both subunits and specific activity of the NO receptor soluble guanylyl cyclase (sGC) were significantly reduced, whereas overall NO synthase activity was unaffected. These changes were most prominent in the neointimal layer, wherein cGMP-dependent protein kinase I (cGK) levels also were reduced. Additionally, a protein ( p38nt) that was constitutively tyrosine-nitrated was detected, and its expression was significantly reduced in atherosclerotic aorta. Phosphorylation of the cGK substrate vasodilator-stimulated phosphoprotein (VASP) at Ser-239, an established biochemical endpoint of NO/cGMP signaling, also was reduced. Thus, late-stage atherosclerosis is associated not only with enhanced NO breakdown but also with altered NO reception and cGMP signaling. Preferential down-regulation in neointima suggests a direct connection of these changes to neointimal proliferation and vascular dysfunction and provides a rationale for future pharmacotherapy using classical and novel sGC activators.

First ever in‐situ measurements of black carbon (BC) aerosols in the troposphere (up to 9 km) made over central India and the resulting atmospheric impact as revealed by the environment lapse rate are presented. The altitude distribution of BC showed multiple peaks; two surprisingly large peaks, one at ∼4.5 km, and another above 8 km. Associated with these, rapid decrease in the environmental lapse rate and a sharp increase in the atmosphere stability were observed, probably caused by the atmospheric warming by the BC layers. This important observation calls for extensive high altitude profiling of BC to quantify the resultant warming, increase in stability and consequent increase in BC lifetime. Key Points First ever in‐situ measurements of free‐tropospheric BC aerosols over India Substantial amount of BC found even at an altitude of 8 km Large BC‐induced warming at around 8 km have implications to cirrus clouds

Escobar syndrome is a rare autosomal recessive disorder characterized by flexion joint and digit contractures, skin webbing, cleft palate, deformity of spine and cervical spine fusion. Associated difficult airway is mainly due to micrognathia, retrognathia, webbing of neck and limitation of the mouth opening and neck extension. We report a case of a 1 year old child with Escobar syndrome posted for bilateral hamstrings to quadriceps transfer. The child had adequate mouth opening with no evidence of cervical spine fusion, yet we faced difficulty in intubation which was ultimately overcome by securing a proseal laryngeal mask airway (PLMA) and then by intubating with an endotracheal tube railroaded over a paediatric fibreoptic bronchoscope passed through the lumen of a PLMA.