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Background: Glaucoma is a progressive optic neuropathy characterized by the neurodegeneration and death of retinal ganglion cells (RGCs), leading to blindness. Current glaucoma interventions reduce intraocular pressure but do not address retinal neurodegeneration. In this effort, to identify new pharmacological targets for glaucoma management, we employed a network pharmacology approach. Methods: We first retrieved transcriptomic data from GEO, an NCBI database, and carried out GEO2R (an interactive web tool aimed at comparing two or more groups of samples in a GEO dataset). The GEO2R statistical analysis aimed at identifying the top differentially expressed genes (DEGs) and used these as input of STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) app within Cytoscape software, which builds networks of proteins starting from input DEGs. Analyses of centrality metrics using Cytoscape were carried out to identify nodes (genes or proteins) involved in network stability. We also employed the web-server software MIRNET 2.0 to build miRNA-target interaction networks for a re-analysis of the GSE105269 dataset, which reports analyses of microRNA expressions. Results: The pharmacological targets, identified in silico through analyses of the centrality metrics carried out with Cytoscape, were rescored based on correlations with entries in the PubMed and clinicaltrials.gov databases. When there was no match (82 out of 135 identified central nodes, in 8 analyzed networks), targets were considered "potential innovative" targets for the treatment of glaucoma, after further validation studies. Conclusions: Several druggable targets, such as GPCRs (e.g., 5-hydroxytryptamine 5A (5-HT5A) and adenosine A_2B receptors) and enzymes (e.g., lactate dehydrogenase A or monoamine oxidase B), were found to be rescored as "potential innovative" pharmacological targets for glaucoma treatment.

Pyrazolo[3,4-b]pyridine scaffolds have been heavily exploited in the development of nitrogen-containing heterocycles with numerous therapeutic applications in the field of medicinal and pharmaceutical chemistry. The present work describes the synthesis of eighteen biaryl pyrazolo[3,4-b]pyridine ester (6a-i) and hydrazide (7a-i) derivatives via the Suzuki cross-coupling reaction. These derivatives were subsequently screened for their therapeutic potential to inhibit the diabetic α-amylase enzyme, which is a key facet of the development of anti-diabetic agents. Initially, the ethyl 4-(4-bromophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate 4 was synthesized through a modified Doebner method under solvent-free conditions, providing an intermediate for further derivatization with a 60% yield. This intermediate 4 was subjected to Suzuki cross-coupling, reacting with electronically diverse aryl boronic acids to obtain the corresponding pyrazolo[3,4-b]pyridine ester derivatives (6a-i). Following this, the biaryl ester derivatives (6a-i) were converted into hydrazide derivatives (7a-i) through a straightforward reaction with hydrazine monohydrate and were characterized using ¹H-NMR, ¹³C-NMR, and LC-MS spectroscopic techniques. These derivatives were screened for their α-amylase inhibitory chemotherapeutic efficacy, and most of the biaryl ester and hydrazide derivatives demonstrated promising amylase inhibition. In the (6a-i) series, the compounds 6b, 6c, 6h, and 6g exhibited excellent inhibition, with almost similar IC₅₀ values of 5.14, 5.15, 5.56, and 5.20 μM, respectively. Similarly, in the series (7a-i), the derivatives 7a, 7b, 7c, 7d, 7f, 7g, and 7h displayed excellent anti-diabetic activities of 5.21, 5.18, 5.17, 5.12, 5.10, 5.16, and 5.19 μM, respectively. These in vitro results were compared with the reference drug acarbose (IC₅₀ = 200.1 ± 0.15 μM), demonstrating better anti-diabetic inhibitory activity in comparison to the reference drug. The in silico molecular docking study results were consistent with the experimental biological findings, thereby supporting the in vitro pharmaceutical efficacy of the synthesized derivatives.

Background/Objectives: Heterodimer peptides targeting more than one receptor can be advantageous, as tumors can simultaneously express more than one receptor type. For human breast cancer, a promising biological target is tumor angiogenesis through α_vβ₃ integrin expression. Another promising target is Neuropeptide Y receptors, considering Y₁R is overexpressed in 90% of human breast tumors. This article details the development and preclinical evaluation, both in vitro and in vivo, of a novel heterodimer peptide dual-receptor-targeting probe, [^99mTc]HYNIC-cRGDfk-NPY, designed for imaging breast tumors. Methods: Female BALB/c healthy mice were used to perform biodistrubution studies and female SCID mice were subcutaneously injected with MCF-7 and MDA-MB-231 tumor cells. [^99mTc]HYNIC-cRGDfk-NPY was intravenously administered to the mice, followed by ex vivo biodistribution studies and small-animal SPECT/CT imaging. Nonspecific tracer uptake in both models was determined by coinjecting an excess of unlabeled HYNIC-cRGDfk-NPY (100 µg) along with the radiolabeled tracer. Results: Imaging and biodistribution data demonstrate good uptake to estrogen receptor-positive (MCF-7) and triple-negative (MDA-MB-231) tumor models. The in vivo tumor uptakes of radiolabeled conjugate were 9.30 ± 3.25% and 4.93 ± 1.01% for MCF-7 and MDA-MB231, respectively. The tumor/muscle ratios were 5.65 ± 0.94 for the MCF-7 model and 7.78 ± 3.20 for MDA-MB231. Conclusions: [^99mTc]HYNIC-cRGDfk-NPY demonstrated rapid blood clearance, renal excretion, and in vivo tumor uptake, highlighting its potential as a tumor imaging agent.

Background: Cardiovascular diseases rank as the top global cause of mortality, particularly acute myocardial infarction (MI). MI arises from the blockage of a coronary artery, which disrupts blood flow and results in tissue death. Among therapeutic approaches, bioactives from medicinal plants emerge as promising for the development of new medicines. Objectives: This study explored the effects of naringenin (NAR 100 mg/kg), a flavonoid found in citrus fruits, in normotensive (NTR) and spontaneously hypertensive (SHR) rats, both subjected to isoproterenol (ISO 85 mg/kg)-induced MI. Results: Post-treatment assessments indicated that NAR reduced blood pressure and minimized clot formation, particularly notable in the SHR group, which helps mitigate damage related to hypertension and ISO exposure. Additionally, NAR effectively restored KCl-induced contractility in the aortas of both NTR and SHR groups. NAR treatment reduced reduced glutathione (GSH) and lipid hydroperoxides (LOOH) values and recovered the activity of the antioxidant enzymes catalase (CAT) and glutathione-s-transferase (GST) in NTR groups. Moreover, myocardial damage assessed through histological analyses was reduced in groups treated with NAR. Conclusions: The results highlight significant pathophysiological differences between the groups, suggesting that NAR has protective potential against ISO-induced cardiac damage, warranting further investigation into its protective effects and mechanisms.

Background: Acquired resistance and adverse effects are some of the challenges faced by thousands of Luminal A breast cancer patients under tamoxifen (TMX) treatment. Some authors associate the overexpression of HOXB7 with TMX resistance in this molecular subtype, and the knockdown of this gene could be an effective strategy to regain TMX sensitivity. Therefore, we used calcium phosphate hybrid nanoparticles (HNP) for the delivery of short interfering RNA molecule (siRNA) complementary to the HOXB7 gene and evaluated the RNA interference (RNAi) effects associated with TMX treatment in breast cancer in vivo.

Methods: HNP were prepared by the self-assembly of a methoxy-poly (ethylene glycol)-block-poly (L-glutamic acid) copolymer (PEG-pGlu) and the coprecipitation of CaPO₄ to incorporate siRNA. The in vitro cell viability and migration were evaluated prior to in vivo experiments. Further, animals bearing early-stage and advanced Luminal A breast cancer were treated with HNP-siHOXB7, HNP-siHOXB7 + TMX, and TMX. Antitumoral activity and gene expression were evaluated following histopathological, hematological, and biochemical analysis.

Results: The HNP were efficient in delivering the siRNA in vitro and in vivo, whilst HOXB7 silencing associated with TMX administration promoted controlled tumor growth, as well as a higher survival rate and reduction in immuno- and hepatotoxicity.

Conclusions: Therefore, our findings suggest that HOXB7 can be an interesting molecular target for Luminal A breast cancer, especially associated with hormone therapy, aiming for adverse effect mitigation and higher therapeutic efficacy.

Background: Prokinetic agents are effective in increasing gastrointestinal (GI) contractility and alleviating constipation, often caused by slow intestinal motility. Lubiprostone (LUB), known for activating CLC-2 chloride channels, increases the chloride ion concentration in the GI tract, supporting water retention and stool movement. Despite its therapeutic efficacy, the exact mechanisms underlying its pharmacological action are poorly understood. Here, we investigated whether LUB activates the canonical transient receptor potential cation channel type 4 (TRPC4) through stimulation with E-type prostaglandin receptor (EP) type 3.

Methods: Using isotonic tension recordings on mouse colon strips, we examined LUB-induced contractility in both proximal and distal colon segments. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to determine mRNA levels of EP1-4 receptor subtypes in distal colonic muscular strips and isolated myocytes. The effects of a TRPC4 blocker and EP3 antagonist on LUB-stimulated contractions were also evaluated.

Results: LUB showed significant contraction in the distal segment compared to the proximal segment. EP3 receptor mRNA levels were highly expressed in the distal colon tissue, which correlated with the observed enhanced contraction. Furthermore, LUB-induced spontaneous contractions in distal colon muscles were reduced by a TRPC4 blocker or EP3 antagonist, indicating that LUB-stimulated EP3 receptor activation may lead to TRPC4 activation and increased intracellular calcium in colonic smooth muscle.

Conclusions: These findings suggest that LUB improves mass movement through indirect activation of the TRPC4 channel in the distal colon. The segment-specific action of prokinetic agents like LUB provides compelling evidence for a personalized approach to symptom management, supporting the defecation reflex.

Background This systematic review is registered with CRD42024507397 protocol number and aims to compare the known data about retatrutide on long-term cardiovascular (CV) protection with tirzepatide, an incretin with recent proven CV benefits. Material and Methods The inclusion criteria were (i) original full-text articles that are randomized control or clinical trials; (ii) published within the last ten years; (iii) published in English; and (iv) conducted on adult human populations. The exclusion criteria were articles deruled on cell cultures or mammals. Studies were selected if they (1) included patients with type 2 diabetes mellitus (DM) and CV risk; (2) patients that received either tirzepatide or retatrutide; and (3) provided sufficient information such as the corresponding 95% confidence intervals or at least a sufficient p-value. Studies were excluded if they were a letter to the editor, expert opinions, case reports, meeting abstracts, or reviews; redundant publications; or needed more precise or complete data. Results The seven included studies were assessed for bias with the Newcastle Ottawa scale, heterogenous, and emphasized the potential CV beneficial effect of type 2 DM (T2DM) therapies (glycemia, glycated A1c hemoglobin, body weight, lipid profile, blood pressure and renal parameter). Discussions Further, longer follow-up studies are necessary to verify the long-term CV protection, standardize the specific aspects of CV risk, and compare with subjects without T2DM for a more integrative interpretation of the CV effects independent of the improvement of metabolic activity.

Arthospira platensis and Spirulina platensis microalgae are a rich source of pro-health metabolites (% d.m.): proteins (50.0-71.3/46.0-63.0), carbohydrates (16.0-20.0/12.0-17.0), fats (0.9-14.2/6.4-14.3), polyphenolic compounds and phenols (7.3-33.2/7.8-44.5 and 4.2/0.3 mg GAE/g), and flavonoids (1.9/0.2 QUE/g) used in pharmaceutical and cosmetic formulations. This review summarises the research on the chemical profile, therapeutic effects in dermatological problems, application of Arthrospira and Spirulina microalgae, and contraindications to their use. The pro-health properties of these microalgae were analysed based on the relevant literature from 2019 to 2024. The antiviral mechanism of microalgal activity involves the inhibition of viral replication and enhancement of immunity. The anti-acne activity is attributed to alkaloids, alkanes, phenols, alkenes, phycocyanins, phthalates, tannins, carboxylic and phthalic acids, saponins, and steroids. The antibacterial activity generally depends on the components and structure of the bacterial cell wall. Their healing effect results from the inhibition of inflammatory and apoptotic processes, reduction of pro-inflammatory cytokines, stimulation of angiogenesis, and proliferation of fibroblasts and keratinocytes. The photoprotective action is regulated by amino acids, phlorotannins, carotenoids, mycosporins, and polyphenols inhibiting the production of tyrosinase, pro-inflammatory cytokines, and free oxygen radicals in fibroblasts and the stimulation of collagen production. Microalgae are promising molecular ingredients in innovative formulations of parapharmaceuticals and cosmetics used in the prophylaxis and therapy of dermatological problems. This review shows the application of spirulina-based commercial skin-care products as well as the safety and contraindications of spirulina use. Furthermore, the main directions for future studies of the pro-health suitability of microalgae exerting multidirectional effects on human skin are presented.

Background/Objectives: Increasing drugs' stability and adequately protecting them against degradation will ensure a decrease in their price and broader availability of pharmaceutical substances. This is of great importance, especially for drugs used to treat the most common diseases in the population, such as hypertension. The study examined two newly synthesized substances from the angiotensin I-converting enzyme inhibitor (ACEI) group as potential drugs. ACEIs are among the leading drugs used in the treatment of hypertension in the world. The chemical modifications of the tested substances applied concerned the places most susceptible to degradation. The presented work analyzed the compatibility of new derivatives with selected excipients used in pharmacy. Methods: Thermogravimetric (TGA) and differential thermal analyses (c-DTA) were used as the main methods. In addition, non-thermal methods such as colorimetry analysis, Fourier-transform infrared (FTIR) and UV spectroscopy were used. Results: Based on the conducted studies, it can be concluded that the incompatibility of IND-1 with glucose anhydrous and lactose monohydrate occurs only when the mixture is stored at higher temperatures. For the remaining IND-1 and IND-2 mixtures with excipients, compatibility was demonstrated. Conclusions: The obtained results confirmed the usefulness of the applied thermal analyses (TGA and c-DTA) for assessing the compatibility of the tested potential drugs with excipients. However, in the case of incompatibility reactions of substances occurring under the influence of elevated temperatures, such as the Maillard reaction, it is necessary to use non-thermal methods to obtain the right result.

Background: Renal replacement therapy (RRT), widely used in the treatment of renal injury during sepsis, aims to eliminate the toxins and proinflammatory cytokines involved in the pathomechanism underlying septic shock. Dialysis filters are characterized by a high adsorption potential for cytokines in RRT in the case of septic renal injury. For the treatment of sepsis with antibiotics, it is of key importance to achieve the desired values of PK/PD indices. Continuous renal replacement therapy (CRRT) may affect antimicrobial clearance, increasing their elimination in some cases. Methods: The aim of this study was to determine the degree of adsorption for linezolid on three different types of filters used in CRRT. In our in vitro study, a continuous veno-venous hemofiltration (CVVH) was conducted using three types of filters: polysulfone (PS), polyethyleneimine-treated polyacrylonitrile (PAN PEI), and non-PEI-treated polyacrylonitrile (PAN). Each type of filter was used in three CVVH cycles, involving the use of 600 mg of linezolid dissolved in 700 mL of bovine blood or in 700 mL of 0.9% NaCl. In each case, the total volume of the obtained solution was 1000 mL. Blood samples were collected at particular time points to measure their drug concentration. The differences in mean drug/NaCl adsorption and drug/blood adsorption were determined using a one-way ANOVA with multiple comparisons via Tukey's post hoc test; a p-value of <0.05 was considered significant. Results: A significant adsorption of linezolid was found for PAN PEI filters, both in samples obtained from bovine blood and 0.9% NaCl solutions, at the endpoint. In PAN PEI samples, the concentration of linezolid in 0.9% NaCl solutions decreased from 594.74 μg/mL to 310.66 μg/mL after 120 min (the difference was established at 52%). In blood samples, the initial concentration was 495.18 μg/mL, which then decreased to 359.84 μg/mL (73% of the beginning value). No significant adsorption was demonstrated on PAN or PS filters. Conclusion: There is a need for in vivo research to confirm the effect of filter type on linezolid concentration in patients undergoing CRRT.