Ag2 S Biocompatible Ensembles as Dual OCT Contrast Agents and NIR Ocular Imaging Probes.

Ag2 S nanoparticles (NPs) emerge as a unique system that simultaneously features in vivo near-infrared (NIR) imaging, remote heating, and low toxicity thermal sensing. In this work, their capabilities are extended into the fields of optical coherence tomography (OCT), as contrast agents, and NIR probes in both ex vivo and in vivo experiments in eyeballs. The new dual property for ocular imaging is obtained by the preparation of Ag2 S NPs ensembles with a biocompatible amphiphilic block copolymer. Rather than a classical ligand exchange, where surface traps may arise due to incomplete replacement of surface sites, the use of this polymer provides a protective extra layer that preserves the photoluminescence properties of the NPs, and the procedure allows for the controlled preparation of submicrometric scattering centers. The resulting NPs ensembles show extraordinary colloidal stability with time and biocompatibility, enhancing the contrast in OCT with simultaneous NIR imaging in the second biological window.

Relevance of Sugar Transport across the Cell Membrane.

Sugar transport through the plasma membrane is one of the most critical events in the cellular transport of nutrients; for example, glucose has a central role in cellular metabolism and homeostasis. The way sugars enter the cell involves complex systems. Diverse protein systems participate in the membrane traffic of the sugars from the extracellular side to the cytoplasmic side. This diversity makes the phenomenon highly regulated and modulated to satisfy the different needs of each cell line. The beautiful thing about this process is how evolutionary processes have diversified a single function: to move glucose into the cell. The deregulation of these entrance systems causes some diseases. Hence, it is necessary to study them and search for a way to correct the alterations and utilize these mechanisms to promote health. This review will highlight the various mechanisms for importing the valuable sugars needed to create cellular homeostasis and survival in all kinds of cells.

Optical detection of atherosclerosis at molecular level by optical coherence tomography: An in vitro study.

There is an urgent need for contrast agents to detect the first inflammation stage of atherosclerosis by cardiovascular optical coherence tomography (CV-OCT), the imaging technique with the highest spatial resolution and sensitivity of those used during coronary interventions. Gold nanoshells (GNSs) provide the strongest signal by CV-OCT. GNSs are functionalized with the cLABL peptide that binds specifically to the ICAM-1 molecule upregulated in the first stage of atherosclerosis. Dark field microscopy and CV-OCT are used to evaluate the specific adhesion of these functionalized GNSs to activated endothelial cells. This adhesion is investigated under static and dynamic conditions, for shear stresses comparable to those of physiological conditions. An increase in the scattering signal given by the functionalized GNSs attached to activated cells is observed compared to non-activated cells. Thus, cLABL-functionalized GNSs behave as excellent contrast agents for CV-OCT and promise a novel strategy for clinical molecular imaging of atherosclerosis.

Self-Formation Assessed by Cumulative Summation Test Does Not Reach Recommended Thresholds for Optical Diagnosis of Colorectal Polyps ≤ 7 mm.

BACKGROUND AND AIMS: Accurate optical diagnosis of diminutive polyps would allow implementing a resect and discard strategy. We evaluated the learning curve of a single training session followed by self-education in subjects with no endoscopic experience. METHODS: Learning curves were evaluated in 38 subjects employing learning curve-cumulative summation (LC-CUSUM) tests, with each participant attending one training session regarding narrow band imaging and optical diagnosis and then individually assessing 100 lesions, receiving feedback after each diagnosis. Diagnostic accuracy was subsequently evaluated in 180 patients with lesions ≤ 7 mm. Evaluators predicted each polyp's histology and recommended a surveillance interval. Determinants of accuracy were explored using regression analysis. RESULTS: According to the LC-CUSUM curve, 20 evaluators (52.6%) reached diagnostic competence after 57 lesions (IQR 55-76.5). During the diagnostic performance assessment, 11,666 diagnoses and 6840 follow-up recommendations were generated. Considering high confidence diagnoses, accuracy was 81.3% (80.5-82.1%), negative predictive value (NPV) for rectosigmoid adenomas 78.6% (76.4-80.6%), and sensitivity for adenomas 86.6% (85.8-87.4%). Two (5.3%) evaluators reached a ≥ 90% accuracy, 3 (7.9%) presented a NPV for rectosigmoid adenomas ≥ 90%, and 18 (47.4%) a sensitivity for adenomas ≥ 90%. Multivariable logistic regression showed high confidence and size ≥ 5 mm as the strongest predictors of accuracy. Fifteen (39.5%) evaluators recommended a correct or reduced follow-up interval in over 90% of subjects. CONCLUSIONS: Self-formation after a single training session did not allow most evaluators to reach the required accuracy. LC-CUSUM tests did not identify competent evaluators. Despite these results, 86.7% of follow-up intervals would have been corrected or reduced.

Maitotoxin Is a Potential Selective Activator of the Endogenous Transient Receptor Potential Canonical Type 1 Channel in Xenopus laevis Oocytes.

Maitotoxin (MTX) is the most potent marine toxin known to date. It is responsible for a particular human intoxication syndrome called ciguatera fish poisoning (CFP). Several reports indicate that MTX is an activator of non-selective cation channels (NSCC) in different cell types. The molecular identity of these channels is still an unresolved topic, and it has been proposed that the transient receptor potential (TRP) channels are involved in this effect. In Xenopus laevis oocytes, MTX at picomolar (pM) concentrations induces the activation of NSCC with functional and pharmacological properties that resemble the activity of TRP channels. The purpose of this study was to characterize the molecular identity of the TRP channel involved in the MTX response, using the small interference RNA (siRNA) approach and the two-electrode voltage-clamp technique (TEVC). The injection of a specifically designed siRNA to silence the transient receptor potential canonical type 1 (TRPC1) protein expression abolished the MTX response. MTX had no effect on oocytes, even at doses 20-fold higher compared to cells without injection. Total mRNA and protein levels of TRPC1 were notably diminished. The TRPC4 siRNA did not change the MTX effect, even though it was important to note that the protein level was reduced by the silencing of TRPC4. Our results suggest that MTX could be a selective activator of TRPC1 channels in X. laevis oocytes and a useful pharmacological tool for further studies on these TRP channels.

Subtissue Imaging and Thermal Monitoring of Gold Nanorods through Joined Encapsulation with Nd-Doped Infrared-Emitting Nanoparticles.

Encapsulation of gold nanorods together with Nd-doped fluorescent nanoparticles in a biocompatible polymer creates multifunctional nanostructures, whose infrared fluorescence allows their subcutaneous localization in biological tissues while also adding the ability to measure the temperature from the emitted light in order to better monitor the light-to-heat conversion of the gold nanorods during photothermal therapy.

Enhancing optical forces on fluorescent up-converting nanoparticles by surface charge tailoring.

3D remote control of multifunctional fluorescent up-converting nanoparticles (UCNPs) using optical forces is being required for a great variety of applications including single-particle spectroscopy, single-particle intracellular sensing, controlled and selective light-activated drug delivery and light control at the nanoscale. Most of these potential applications find a serious limitation in the reduced value of optical forces (tens of fN) acting on these nanoparticles, due to their reduced dimensions (typically around 10 nm). In this work, this limitation is faced and it is demonstrated that the magnitude of optical forces acting on UCNPs can be enhanced by more than one order of magnitude by a controlled modification of the particle/medium interface. In particular, substitution of cationic species at the surface by other species with higher mobility could lead to UCNPs trapping with constants comparable to those of spherical metallic nanoparticles.

Non-invasive paper-based sensors containing rare-earth-doped nanoparticles for the detection of D-glucose.

Today, diabetes mellitus is one of the most common diseases that affects the population on a worldwide scale. Patients suffering from this disease are required to control their blood-glucose levels several times a day through invasive methods such as piercing their fingers. Our NaGdF4: 5% Er3+, 3% Nd3+ nanoparticles demonstrate a remarkable ability to detect D-glucose levels by analysing alterations in their red-to-green ratio, since this sensitivity arises from the interaction between the nanoparticles and the OH groups present in the D-glucose molecules, resulting in discernible changes in the emission of the green and red bands. These luminescent sensors were implemented and tested on paper substrates, offering a portable, low-cost and enzyme-free solution for D-glucose detection in aqueous solutions with a limit of detection of 22 mg/dL. With this, our study contributes to the development of non-invasive D-glucose sensors, holding promising implications for managing diabetes and improving overall patient well-being with possible future applications in D-glucose sensing through tear fluid.

Correlation of Plasmatic Amyloid Beta Peptides (Aß-40, Aß-42) with Myocardial Injury and Inflammatory Biomarkers in Acute Coronary Syndrome.

Background/Objective: Amyloid beta (ß) -40 levels increase with age and inflammation states and appear to be associated with clinical manifestations of acute coronary syndrome (ACS). We investigated the correlation of Aß peptides with myocardial injury and inflammation biomarkers in patients with or without ST elevation myocardial infarction (STEMI, NSTEMI). Methods: This singe-center, cross-sectional, observational, and correlation study included 65 patients with ACS (n = 34 STEMI, 29 males, age = 58 ± 12 years; n = 31 NSTEMI, 22 males, age = 60 ± 12 years) who were enrolled in the coronary care unit within 12 h after symptom onset from February 2022 to May 2023. Aß peptide levels and biochemical parameters were assessed. Results: NSTEMI patients had a higher prevalence of hypertension (p = 0.039), diabetes (p = 0.043), smoking (p = 0.003), and prior myocardial infarction (p = 0.010) compared to STEMI patients. We observed a higher level of Aß-42 in NSTEMI (p = 0.001) but no difference in Aß-40 levels. We also found a correlation between age and NT-proBNP with both Aß peptides (Aß-40, Aß-42) (p = 0.001, p = 0.002 respectively). Conclusions: Our results show that patients with NSTEMI had a higher prevalence of cardiovascular risk factors (hypertension, diabetes, smoking, and prior myocardial infarction). Considering these results, we propose that Aß-42 can add value to risk stratification in NSTEMI patients.

Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) predisposes to colorectal cancer (CRC). In the current studies, we used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3 α; which has pro-inflammatory and anti-apoptotic functions, and STAT3ß; which attenuates the effects of STAT3α). In the current study, we determined the contribution of STAT3 to IBD across all tissues by examining DSS-induced colitis in mice that express only STAT3α and in mice treated with TTI-101, a direct small-molecule inhibitor of both isoforms of STAT3. METHODS: We examined mortality, weight loss, rectal bleeding, diarrhea, colon shortening, apoptosis of colonic CD4+ T-cells, and colon infiltration with IL-17-producing cells following 7-day administration of DSS (5%) to transgenic STAT3α knock-in (STAT3ß-deficient; ΔßΔß) mice and wild-type (WT) littermate cage control mice. We also examined the effect of TTI-101 on these endpoints in DSS-induced colitis in WT mice. RESULTS: Each of the clinical manifestations of DSS-induced colitis examined was exacerbated in ΔßΔß transgenic versus cage-control WT mice. Importantly, TTI-101 treatment of DSS-administered WT mice led to complete attenuation of each of the clinical manifestations and also led to increased apoptosis of colonic CD4+ T cells, reduced colon infiltration with IL-17-producing cells, and down-modulation of colon mRNA levels of STAT3-upregulated genes involved in inflammation, apoptosis resistance, and colorectal cancer metastases. CONCLUSIONS: Thus, small-molecule targeting of STAT3 may be of benefit in treating IBD and preventing IBD-associated colorectal cancer.

C-Reactive Protein: The Quintessential Marker of Systemic Inflammation in Coronary Artery Disease-Advancing toward Precision Medicine.

Atherosclerotic cardiovascular disease (CVD) remains the leading cause of mortality worldwide. While conventional risk factors have been studied and managed, CVD continues to pose a global threat. Risk scoring systems based on these factors have been developed to predict acute coronary syndromes and guide therapeutic interventions. However, traditional risk algorithms may not fully capture the complexities of individual patients. Recent research highlights the role of inflammation, particularly chronic low-grade inflammation, in the pathogenesis of coronary artery disease (CAD). C-reactive protein (CRP) is an inflammatory molecule that has demonstrated value as a predictive marker for cardiovascular risk assessment, both independently and in conjunction with other parameters. It has been incorporated into risk assessment algorithms, enhancing risk prediction and guiding therapeutic decisions. Pharmacological interventions with anti-inflammatory properties, such as statins, glucagon-like peptide-1 agonists, and interleukin-1 inhibitors, have shown promising effects in reducing both cardiovascular risks and CRP levels. This manuscript provides a comprehensive review of CRP as a marker of systemic inflammation in CAD. By exploring the current knowledge surrounding CRP and its implications for risk prediction and therapeutic interventions, this review contributes to the advancement of personalized cardiology and the optimization of patient care.

3D Optical Coherence Thermometry Using Polymeric Nanogels.

In nanothermometry, the use of nanoparticles as thermal probes enables remote and minimally invasive sensing. In the biomedical context, nanothermometry has emerged as a powerful tool where traditional approaches, like infrared thermal sensing and contact thermometers, fall short. Despite the strides of this technology in preclinical settings, nanothermometry is not mature enough to be translated to the bedside. This is due to two major hurdles: the inability to perform 3D thermal imaging and the requirement for tools that are readily available in the clinics. This work simultaneously overcomes both limitations by proposing the technology of optical coherence thermometry (OCTh). This is achieved by combining thermoresponsive polymeric nanogels and optical coherence tomography (OCT)-a 3D imaging technology routinely used in clinical practice. The volume phase transition of the thermoresponsive nanogels causes marked changes in their refractive index, making them temperature-sensitive OCT contrast agents. The ability of OCTh to provide 3D thermal images is demonstrated in tissue phantoms subjected to photothermal processes, and its reliability is corroborated by comparing experimental results with numerical simulations. The results included in this work set credible foundations for the implementation of nanothermometry in the form of OCTh in clinical practice.

A CRAC-like motif in BAX sequence: relationship with protein insertion and pore activity in liposomes.

Several proteins that interact with cholesterol have a highly conserved sequence, corresponding to the cholesterol recognition/interaction amino acid consensus. Since cholesterol has been proposed to modulate both oligomerization and insertion of the pro-apoptotic protein BAX, we investigated the existence of such a motif in the BAX sequence. Residues 113 to 119 of the recombinant BAX α5-helix, LFYFASK, correspond with the sequence motif described for the consensus pattern, -L/V-(X)(1-5)-Y-(X)(1-5)-R/K. Functional characterization of the point mutations, K119A, Y115F, and L113A in BAX, was performed in liposomes supplemented with cholesterol, comparing binding, integration, and pore forming activities. Our results show that the mutations Y115F and L113A changed the cholesterol-dependent insertion observed in the wild type protein. In addition, substitutions in the BAX sequence modified the concentration dependency of carboxyfluorescein release in liposomes, although neither pore activity of the wild type or of any of the mutants significantly increased in cholesterol-enriched liposomes. Thus, while it is likely that the putative CRAC motif in BAX accounts for its enhanced insertion in cholesterol-enriched liposomes; the pore forming properties of BAX did not depend on cholesterol content in the membranes, albeit those mutations changed the pore channeling activity of the protein.

Persistent respiratory symptoms in clean-up workers 5 years after the Prestige oil spill.

OBJECTIVES: Fishermen who had participated in clean-up activities of the Prestige oil spill showed an excess risk of respiratory symptoms 1-2 years later, but the long-term persistence of these health effects is unclear. The aim of this study was to evaluate the persistence of these respiratory symptoms 5 years after clean-up work. METHODS: Subgroups of 501 fishermen who had been exposed to clean-up work and 177 non-exposed individuals were re-interviewed by telephone in 2008, including the same symptom questions as in the initial survey. Associations between participation in clean-up work and respiratory symptoms were assessed using log-binomial and multinomial regression analyses adjusting for sex, age and smoking. RESULTS: Information from 466 exposed (93%) and 156 non-exposed (88%) fishermen was obtained. The prevalence of lower respiratory tract symptoms (including wheeze, shortness of breath, cough and phlegm) had slightly decreased in both groups, but remained higher among the exposed (RR 1.4, 95% CI 1.1 to 1.9). The risk of having persistent respiratory symptoms (reported both at baseline and at follow-up) increased with the degree of exposure: RR ratio 1.7 (95% CI 0.9 to 3.1) and 3.3 (95% CI 1.8 to 6.2) for moderately and highly exposed, respectively, when compared with those without any symptoms. Findings for nasal symptoms and for respiratory medication usage were similar. CONCLUSIONS: Participation in clean-up activities of oil spills may result in respiratory symptoms that persist up to 5 years after exposure. Guidelines for preventive measures and a continued surveillance of clean-up workers of oil spills are necessary.

Substance P-Friend or Foe.

Substance P (SP), a neuropeptide and pain transmitter has multiple roles and is involved in various processes in the body [...].

Cardiovascular risk in the postnatal life of children born to women with systemic lupus erythematous.

Systemic lupus erythematous (SLE) is an autoimmune disease with clinical manifestations in multiple organs, primarily striking women of reproductive age. Women with SLE can became pregnant such as any other healthy woman and carrier their pregnancy to term due to the improvement of health systems, but their specific inflammatory conditions could affect the microenvironment in which the fetus grows, and influence the development of placenta and the fetal heart. Until now, there is very little evidence of any increased risk of postnatal cardiovascular disease (CVD) in the apparently healthy children from women with SLE, but it is this great variability in the effects of lupus on pregnant products is related to.

El lupus eritematoso sistémico (LES) es una enfermedad autoinmune que presenta diversas manifestaciones clínicas en múltiples órganos, y afecta principalmente a mujeres en edad reproductiva. Las mujeres con LES se pueden embarazar y llevar a término su embarazo, sin embargo, las condiciones inflamatorias específicas de la madre pueden modificar el microambiente en el que el embrión y el feto se desarrollan y afectar la formación y desarrollo de la placenta y el corazón fetal. Hasta ahora hay muy poca evidencia de que haya un mayor riesgo de enfermedad cardiovascular (ECV) en hijos aparentemente sanos de madres con LES, a pesar de que se sabe que hay un mayor riesgo de alteraciones cognitivas y neuronales, así como de desarrollar enfermedades autoinmunes en esos niños. El objetivo de esta revisión fue realizar una búsqueda bibliografía cruzando palabras clave acerca la enfermedad cardiovascular en hijos sanos de mujeres con LES. La evidencia mostró que la autoinmunidad materna puede favorecer la predisposición para el desarrollo de ECV en sus hijos, por medio de la modificación de señales que alteran el microambiente durante la gestación, lo que puede afectar la respuesta inmunitaria y cambios epigenéticos durante la vida posnatal.

Genetic and Small-Molecule Modulation of Stat3 in a Mouse Model of Crohn's Disease.

Crohn's disease (CD), is an inflammatory bowel disease that can affect any part of the gastro-intestinal tract (GI) and is associated with an increased risk of gastro-intestinal cancer. In the current study, we determined the role of genetic and small-molecule modulation of STAT3 in a mouse model of CD. STAT3 has 2 isoforms (α, ß) which are expressed in most cells in a 4:1 ratio (α: ß). STAT3α has pro-inflammatory and anti-apoptotic functions, while STAT3ß has contrasting roles. We used an animal model of CD consisting of intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid and examined the severity of CD in transgenic-mice that express only STAT3α (∆ß/∆ß), as well as in wild-type (WT) mice administered TTI-101 (formerly C188-9), a small molecule STAT3 inhibitor. We determined that clinical manifestations of CD, such as mortality, rectal-bleeding, colonic bleeding, diarrhea, and colon shortening, were exacerbated in ∆ß/∆ß transgenic versus cage-control WT mice, while they were markedly decreased by TTI-101 treatment of WT mice. TTI-101 treatment also increased apoptosis of pathogenic CD4+ T cells and reduced colon levels of IL-17-positive cells. Our results indicate that STAT3 contributes to CD and that targeting of STAT3 with TTI-101 may be a useful approach to treating CD.

Bismuth Selenide Nanostructured Clusters as Optical Coherence Tomography Contrast Agents: Beyond Gold-Based Particles.

Optical coherence tomography (OCT) is an imaging technique currently used in clinical practice to obtain optical biopsies of different biological tissues in a minimally invasive way. Among the contrast agents proposed to increase the efficacy of this imaging method, gold nanoshells (GNSs) are the best performing ones. However, their preparation is generally time-consuming, and they are intrinsically costly to produce. Herein, we propose a more affordable alternative to these contrast agents: Bi2Se3 nanostructured clusters with a desert rose-like morphology prepared via a microwave-assisted method. The structures are prepared in a matter of minutes, feature strong near-infrared extinction properties, and are biocompatible. They also boast a photon-to-heat conversion efficiency of close to 50%, making them good candidates as photothermal therapy agents. In vitro studies evidence the prowess of Bi2Se3 clusters as OCT contrast agents and prove that their performance is comparable to that of GNSs.

Eosin Y-Functionalized Upconverting Nanoparticles: Nanophotosensitizers and Deep Tissue Bioimaging Agents for Simultaneous Therapeutic and Diagnostic Applications.

Functionalized upconverting nanoparticles (UCNPs) are promising theragnostic nanomaterials for simultaneous therapeutic and diagnostic purposes. We present two types of non-toxic eosin Y (EY) nanoconjugates derived from UCNPs as novel nanophotosensitizers (nano-PS) and deep-tissue bioimaging agents employing light at 800 nm. This excitation wavelength ensures minimum cell damage, since the absorption of water is negligible, and increases tissue penetration, enhancing the specificity of the photodynamic treatment (PDT). These UCNPs are uniquely qualified to fulfil three important roles: as nanocarriers, as energy-transfer materials, and as contrast agents. First, the UCNPs enable the transport of EY across the cell membrane of living HeLa cells that would not be possible otherwise. This cellular internalization facilitates the use of such EY-functionalized UCNPs as nano-PS and allows the generation of reactive oxygen species (ROS) under 800 nm light inside the cell. This becomes possible due to the upconversion and energy transfer processes within the UCNPs, circumventing the excitation of EY by green light, which is incompatible with deep tissue applications. Moreover, the functionalized UCNPs present deep tissue NIR-II fluorescence under 808 nm excitation, thus demonstrating their potential as bioimaging agents in the NIR-II biological window.

Distinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy.

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8+ T cell axis in both blood and inflamed joints. CX3CR1hi CD8+ T cells in blood and CXCR3hi CD8+ T cells in synovial fluid, the most clonally expanded T cells, significantly share TCR repertoires. The migration of blood CX3CR1hi CD8+ T cells into joints is possibly mediated by CXCL9/10/11/16 expressed by myeloid cells. Furthermore, arthritis after combined CTLA-4 and PD-1 inhibitor therapy preferentially has enhanced Th17 and transient Th1/Th17 cell signatures. Our data provide insights into the mechanisms, predictive biomarkers, and therapeutic targets for arthritis-irAE.