Pharmaceuticals, Volume 17, Issue 6 (June 2024) – 116 articles

Amyloid aggregates have attracted significant interest in regard to diverse biomedical applications, particularly in the field of drug delivery. Here, we report novel amyloid aggregates based on a 12-amino-acid peptide from the amyloidogenic region of the receptor-interacting kinase 3 (RIP3) protein and a thermoresponsive triblock copolymer, namely, Pluronic F127 (RIP3/F127). Physicochemical characterization was performed to determine the aggregation size, morphology, and stimuli-responsive properties. The potential of the aggregates as a drug depot was assessed in lung cancer cells, using Doxorubicin (Dox) as a model drug. The results show that RIP3 and RIP3/F127 exhibit amyloidogenic properties. Further, the RIP3/F127 amyloids exhibited significant ultrasound-responsive properties compared to amyloid aggregates without Pluronic F127. Moreover, the RIP3/F127/Dox amyloid formulations that were subjected to ultrasound treatment exhibited greater toxicity to lung cancer cells compared to that of Dox alone at equal concentrations. Overall, the results from this proof-of-concept study show that amyloidogenic peptide aggregates with stimuli-responsive properties can be utilized as efficient drug delivery depots. Full article

Alectinib HCl (ALBHCl) is a tyrosine kinase inhibitor used for non-small cell lung carcinoma (NSCLC). The aim of this study is to unlock some of the physicochemical properties of ALBHCL that serve as a database for any future studies. A solubility study of ALBHCL was performed in different solvents. Also, photostability was tested in the solution and solid states, and the order of reaction and rate constant were calculated. In addition to the pH solubility relation, the pH-rate relation at different temperatures was also studied, and the profiles were constructed. A solubility study was also performed in different media for the purpose of optimizing suitable sink conditions for the in vitro dissolution testing of solid dosage forms. Solubility tests in multiple solvents and pH conditions revealed that the highest solubility was in DMSO, methanol, and chloroform, with acidic media yielding the maximum solubility but degrading at rather low pH levels. ALBHCL proved unstable at high temperatures and under light exposure, with varying stability across different pH levels. The optimal dissolution media for in vitro oral dosage form evaluation were determined, achieving sink conditions at pH levels of 6.8 and 4.5 with specific additives. This study enhances the existing database on ALBHCL’s physicochemical properties, emphasizing the importance of pH optimization in pharmaceutical processes and providing valuable insights into its pharmaceutical application. Full article

Polyphenols are the most prevalent naturally occurring phytochemicals in the human diet and range in complexity from simple molecules to high-molecular-weight polymers. They have a broad range of chemical structures and are generally categorized as “neuroprotective”, “anti-inflammatory”, and “antioxidant” given their main function of halting disease onset and promoting health. Research has shown that some polyphenols and their metabolites can penetrate the blood–brain barrier and hence increase neuroprotective signaling and neurohormonal effects to provide anti-inflammatory and antioxidant effects. Therefore, multi-targeted modulation of polyphenols may prevent the progression of neuropsychiatric disorders and provide a new practical therapeutic strategy for difficult-to-treat neuropsychiatric disorders. Therefore, multi-target modulation of polyphenols has the potential to prevent the progression of neuropsychiatric disorders and provide a new practical therapeutic strategy for such nervous system diseases. Herein, we review the therapeutic benefits of polyphenols on autism-spectrum disorders, anxiety disorders, depression, and sleep disorders, along with in vitro and ex vivo experimental and clinical trials. Although their methods of action are still under investigation, polyphenols are still seldom employed directly as therapeutic agents for nervous system disorders. Comprehensive mechanistic investigations and large-scale multicenter randomized controlled trials are required to properly evaluate the safety, effectiveness, and side effects of polyphenols. Full article

Gastrointestinal parasitism is a major health and welfare problem in ruminants. Synthetic chemical anthelmintic drugs have led to the emergence of resistance in gastrointestinal strongyles, inducing the search for alternatives to control the infections that affect ruminants. The objective of this work was to evaluate the anthelmintic potential of plant extracts against Haemonchus contortus Rudolphi. Three plants of the Guadeloupean biodiversity, Momordica charantia L., Carica papaya L. and Sargassum spp., were selected based on their high polyphenolic content and natural abundance. The phytochemistry of plants was explored, a biological assay against the parasite H. contortus was carried out, and several hypotheses about the way of action were proposed by an innovative electrochemical screening method. Full article

Venous thromboembolism (VTE) represents one of the leading causes of death during pregnancy. The greatest risk for it is the presence of medical or family history of VTE, stillbirth, cesarean section and selected thrombophilia. Appropriate thromboprophylaxis has the potential to decrease the risk of VTE in at-risk pregnant patients by 60–70%. Based on this, the authors reviewed the PubMed, Web of Science and Scopus databases to identify the possibilities of thromboprophylaxis in pregnant patients with a high risk of VTE. Moreover, they summarized its management in specific situations, such as cesarean delivery or neuraxial blockade. Currently, low-molecular-weight heparins (LMWH) are the preferred drugs for anticoagulant thromboprophylaxis in the course of pregnancy and postpartum due to easy administration and a lower rate of adverse events. Full article

The emergence of antibiotic resistance, caused by the improper use of antibiotics, is a significant challenge in combating infectious diseases, leading to millions of annual fatalities. The occurrence of antimicrobial side effects catalyzes the investigation of novel antimicrobial compounds and sources of drugs. Consequently, the research on biological activity that is conducted on plants, plant extracts, and compounds that are produced from plant components is of utmost significance. In this study, CtAC/MNPs were obtained by the reaction of activated carbon (AC) obtained from the fruits of the Celtis tournefortii (Ct) plant and magnetic nanoparticles (MNPs), and a CtAC/MNPs-Ag nanocomposite was synthesized by the reduction in silver ions added to the reaction. The synthesized CtAC/MNPs and CtAC/MNPs-Ag nanocomposites were analyzed spectroscopically (FTIR, XRD), microscopically (SEM, EDX), optically (DLS), electrochemically (zeta potential) and magnetically (VSM). The antibacterial activities of CtAC/MNPs and CtAC/MNPs-Ag nanocomposites against S. aureus and E. coli were investigated by microdilution method using minimal inhibitory concentration (MIC) and disk diffusion methods. Antioxidant activity study, including total phenolic content and DPPH and cuprac assays, revealed the remarkable effect of the CtAC/MNPs-Ag nanocomposite. This study has the advantages of obtaining CtAC/MNPs and CtAC/MNPs-Ag nanocomposites in a short time without requiring energy, and most importantly, the reaction takes place without using any toxic substances. In addition, according to the data obtained in the study, the CtAC/MNPs-Ag nanocomposite is thought to shed light on biomedical research. Full article

G-quadruplexes (G4s) are guanine-rich non-canonical secondary structures of nucleic acids that were identified in vitro almost half a century ago. Starting from the early 1980s, these structures were also observed in eukaryotic cells, first at the telomeric level and later in regulatory regions of cancer-related genes, in regulatory RNAs and within specific cell compartments such as lysosomes, mitochondria, and ribosomes. Because of the involvement of these structures in a large number of biological processes and in the pathogenesis of several diseases, including cancer, the interest in G4 targeting has exponentially increased in the last few years, and a great number of novel G4 ligands have been developed. Notably, G4 ligands represent a large family of heterogeneous molecules that can exert their functions by recognizing, binding, and stabilizing G4 structures in multiple ways. Regarding anti-cancer activity, the efficacy of G4 ligands was originally attributed to the capability of these molecules to inhibit the activity of telomerase, an enzyme that elongates telomeres and promotes endless replication in cancer cells. Thereafter, novel mechanisms through which G4 ligands exert their antitumoral activities have been defined, including the induction of DNA damage, control of gene expression, and regulation of metabolic pathways, among others. Here, we provided a perspective on the structure and function of G4 ligands with particular emphasis on their potential role as antitumoral agents. In particular, we critically examined the problems associated with the clinical translation of these molecules, trying to highlight the main aspects that should be taken into account during the phases of drug design and development. Indeed, taking advantage of the successes and failures, and the more recent technological progresses in the field, it would be possible to hypothesize the development of these molecules in the future that would represent a valid option for those cancers still missing effective therapies. Full article

The discovery of new peptides and their derivatives is an outcome of ongoing efforts to identify a peptide with significant biological activity for effective usage as a possible therapeutic agent. Spinorphin peptides have been documented to exhibit numerous applications and features. In this study, biologically active peptide derivatives based on novel peptide analogues of spinorphin conjugated with 5,5′-dimethyl (Dm) and 5,5′-diphenyl (Ph) hydantoin derivatives have been successfully synthesized and characterized. Scanning electron microscopy (SEM) and spectral methods such as UV-Vis, FT-IR (Fourier Transform Infrared Spectroscopy), CD (Circular Dichroism), and fluorimetry were used to characterize the microstructure of the resulting compounds. The results revealed changes in peptide morphology as a result of the restructuring of the aminoacidic sequences and aromatic bonds, which is related to the formation of intermolecular hydrogen bonds between tyrosyl groups and the hydantoin moiety. Electrochemical and fluorescence approaches were used to determine some physicochemical parameters related to the biological behavior of the compounds. The biological properties of the spinorphin derivatives were evaluated in vivo for anticonvulsant activity against the psychomotor seizures at different doses of the studied peptides. Both spinorphin analog peptides with Ph and Dm groups showed activity against all three phases of the seizure in the intravenous Pentylenetetrazole Seizure (ivPTZ) test. This suggests that hydantoin residues do not play a crucial role in the structure of spinorphin compounds and in determining the potency to raise the seizure threshold. On the other hand, analogs with a phenytoin residue are active against the drug-resistant epilepsy test (6-Hz test). In addition, bioactivity analyses revealed that the new peptide analogues have the potential to be used as antimicrobial and antioxidant compounds. These findings suggest promising avenues for further research that may lead to the development of alternative medicines or applications in various fields beyond epilepsy treatment. Full article

Background: Due to its rapid resistance development and ability to form biofilms, treatment of Pseudomonas aeruginosa infections is becoming more complicated by the day. Drug combinations may help reduce both resistance and biofilm formation. Methods: Using the microtiter plate assay, we investigated the in vitro inhibition of biofilm formation and the disruption of preformed biofilms in multidrug-resistant and extensively drug-resistant clinical isolates of P. aeruginosa in the presence of peak plasma levels of eight antipseudomonal antibiotics alone and in combination with fosfomycin: ceftazidime, piperacillin/tazobactam, cefepime, imipenem, gentamicin, amikacin, ciprofloxacin and colistin. Results: Combination therapy was significantly superior to monotherapy in its inhibition of biofilm formation. The highest inhibition rates were observed for combinations with colistin, cefepime and ceftazidime. Conclusion: Our results support fosfomycin combination therapy as an enhanced prophylactic option. Moreover, combinations with β-lactam antibiotics and colistin demonstrated a more potent inhibition effect on biofilm formation than protein synthesis inhibitors. Full article

Ethanol extracts obtained from 13 poplar propolis samples originating from various European countries by traditional maceration were tested for total polyphenols, flavonoid content, and antioxidant activity. Moreover, the content of 18 polyphenolic compounds (from the group of phenolic acids and flavonoids) was determined using the HPLC method. The inhibitory effect of six selected extracts with the highest activity was assessed by well-diffusion method against five strains (Bifidobacterium spp., L. rhamnosus, L. acidophilus, E. coli, and Bacteroides spp.) of intestinal bacteria self-isolated from the faeces of obese probands with the use of selective media. It was found that the antioxidant activity of propolis varied depending on geographical origin and even among samples from the same region, which indicates that some other factors also influence propolis quality. The samples of different geographical origin varied mainly in the share of individual phenolic compounds, and it was not possible to find a characteristic marker of origin, excluding the galangin present in the Polish samples only. Assessing the inhibitory activity of propolis (in the range of 70 mg to 10 µg per mL) indicated that the concentration of 100 µg/mL was found as being safe for tested fecal bacteria (Bifidobacterium spp., L. rhamnosus, L. acidophilus, E. coli, and Bacteroides spp.). As no negative effect of low doses of propolis on the intestinal microflora was found, it can be suggested that its use in recommended doses brings only beneficial effects to the body. Full article

In the New World, dogs are considered the main reservoir of visceral leishmaniasis (VL). Due to inefficacies in existing treatments and the lack of an efficient vaccine, dog culling is one of the main strategies used to control disease, making the development of new therapeutic interventions mandatory. We previously showed that Tanespimycin (17-AAG), a Hsp90 inhibitor, demonstrated potential for use in leishmaniasis treatment. The present study aimed to test the safety of 17-AAG in dogs by evaluating plasma pharmacokinetics, dose-proportionality, and the tolerability of 17-AAG in response to a dose-escalation protocol and multiple administrations at a single dose in healthy dogs. Two protocols were used: Study A: four dogs received variable intravenous (IV) doses (50, 100, 150, 200, or 250 mg/m²) of 17-AAG or a placebo (n = 4/dose level), using a cross-over design with a 7-day “wash-out” period; Study B: nine dogs received three IV doses of 150 mg/m² of 17-AAG administered at 48 h intervals. 17-AAG concentrations were determined by a validated high-performance liquid chromatographic (HPLC) method: linearity (R² = 0.9964), intra-day precision with a coefficient of variation (CV) ≤ 8%, inter-day precision (CV ≤ 20%), and detection and quantification limits of 12.5 and 25 ng/mL, respectively. In Study A, 17-AAG was generally well tolerated. However, increased levels of liver enzymes–alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)–and bloody diarrhea were observed in all four dogs receiving the highest dosage of 250 mg/m². After single doses of 17-AAG (50–250 mg/m²), maximum plasma concentrations (Cmax) ranged between 1405 ± 686 and 9439 ± 991 ng/mL, and the area under the curve (AUC) plotting plasma concentration against time ranged between 1483 ± 694 and 11,902 ± 1962 AUC 0–8 h μg/mL × h, respectively. Cmax and AUC parameters were dose-proportionate between the 50 and 200 mg/m² doses. Regarding Study B, 17-AAG was found to be well tolerated at multiple doses of 150 mg/m². Increased levels of liver enzymes–ALT (28.57 ± 4.29 to 173.33 ± 49.56 U/L), AST (27.85 ± 3.80 to 248.20 ± 85.80 U/L), and GGT (1.60 ± 0.06 to 12.70 ± 0.50 U/L)–and bloody diarrhea were observed in only 3/9 of these dogs. After the administration of multiple doses, Cmax and AUC 0–48 h were 5254 ± 2784 μg/mL and 6850 ± 469 μg/mL × h in plasma and 736 ± 294 μg/mL and 7382 ± 1357 μg/mL × h in tissue transudate, respectively. In conclusion, our results demonstrate the potential of 17-AAG in the treatment of CVL, using a regimen of three doses at 150 mg/m², since it presents the maintenance of high concentrations in subcutaneous interstitial fluid, low toxicity, and reversible hepatotoxicity. Full article

Millions of patients suffer from type 1 diabetes (T1D) and its associated complications. Nevertheless, the pursuit of a cure for T1D has encountered significant challenges, with a crucial impediment being the lack of biomarkers that can accurately predict the progression of T1D and reliable therapeutic targets for T1D. Hence, there is an urgent need to discover novel protein biomarkers and therapeutic targets, which holds promise for targeted therapy for T1D. In this study, we extracted summary-level data on 4907 plasma proteins from 35,559 Icelanders and 2923 plasma proteins from 54,219 UK participants as exposures. The genome-wide association study (GWAS) summary statistics on T1D and T1D with complications were obtained from the R9 release results from the FinnGen consortium. Summary-data-based Mendelian randomization (SMR) analysis was employed to evaluate the causal associations between the genetically predicted levels of plasma proteins and T1D-associated outcomes. Colocalization analysis was utilized to investigate the shared genetic variants between the exposure and outcome. Moreover, transcriptome analysis and a protein–protein interaction (PPI) network further illustrated the expression patterns of the identified protein targets and their interactions with the established targets of T1D. Finally, a Mendelian randomization phenome-wide association study evaluated the potential side effects of the identified core protein targets. In the primary SMR analysis, we identified 72 potential protein targets for T1D and its complications, and nine of them were considered crucial protein targets. Within the group were five risk targets and four protective targets. Backed by evidence from the colocalization analysis, the protein targets were classified into four tiers, with MANSC4, CTRB1, SIGLEC5 and MST1 being categorized as tier 1 targets. Delving into the DrugBank database, we retrieved 11 existing medications for T1D along with their therapeutic targets. The PPI network clarified the interactions among the identified potential protein targets and established ones. Finally, the Mendelian randomization phenome-wide association study corroborated MANSC4 as a reliable target capable of mitigating the risk of various forms of diabetes, and it revealed the absence of adverse effects linked to CTRB1, SIGLEC5 and MST1. This study unveiled many protein biomarkers and therapeutic targets for T1D and its complications. Such advancements hold great promise for the progression of drug development and targeted therapy for T1D. Full article

The SARS-CoV-2 infection has been associated with important mortality, particularly in immunocompromised patients, including solid organ transplant (SOT) recipients. Remdesivir (RDV) is an antiviral drug that has proven to be effective in reducing the replication of the virus in host cells, by which it may reduce the progression of symptoms and, consequently, the length of hospital stay and mortality. Randomized controlled trials have evaluated its use in the general population but never in SOT recipients. For the first time in this review, the safety and efficacy of RDV is evaluated in this specific population. The literature research was conducted using PubMed/MEDLINE and Scopus databases from 1 January 2020 to 24 November 2023, and 23 studies were analyzed. Although no clinical studies specifically evaluating this population have been conducted yet, RDV is likely safe for SOT patients when compared to the general population, so prescribers should consider utilizing RDV in SOT patients who are at high risk for progression to severe COVID-19. Future research will allow for the confirmation of the observed results and the acquisition of broader and clearer data regarding the safety and efficacy of the drug in this specific setting. Full article

The extensive use of rodenticides poses a severe threat to non-target species, particularly birds of prey and scavengers. In this study, a GC-MS/MS-based method was used to unlock the cause of bird deaths in Poland. Organs (liver, heart, kidney, and lungs) collected during autopsies of two rooks (Corvus frugilegus) and one carrion crow (Corvus corone corone), as well as fecal samples, were analyzed for the presence of anticoagulant coumarin derivatives, i.e., warfarin and bromadiolone. As for warfarin, the highest concentration was found in crow samples overall, with concentrations in the feces and lungs at 5.812 ± 0.368 µg/g and 4.840 ± 0.256 µg/g, respectively. The heart showed the lowest concentration of this compound (0.128 ± 0.01 µg/g). In the case of bromadiolone, the highest concentration was recorded in the liver of a rook (16.659 ± 1.499 µg/g) and this concentration significantly exceeded the levels in the other samples. By revealing the reality of the threat, these discoveries emphasize the need to regulate and monitor the trade in rodenticides. Full article

Prime editing shows potential as a precision genome editing technology, as well as the potential to advance the development of next-generation nanomedicine for addressing neurological disorders. However, turning in prime editors (PEs), which are macromolecular complexes composed of CRISPR/Cas9 nickase fused with a reverse transcriptase and a prime editing guide RNA (pegRNA), to the brain remains a considerable challenge due to physiological obstacles, including the blood–brain barrier (BBB). This review article offers an up-to-date overview and perspective on the latest technologies and strategies for the precision delivery of PEs to the brain and passage through blood barriers. Furthermore, it delves into the scientific significance and possible therapeutic applications of prime editing in conditions related to neurological diseases. It is targeted at clinicians and clinical researchers working on advancing precision nanomedicine for neuropathologies. Full article

Growing evidence suggests that activators of nuclear factor erythroid-derived 2-like 2 (Nrf2), such as sulforaphane, may represent promising novel pharmacological targets for conditions related to oxidative stress, including depressive disorder. Therefore, we conducted a study to explore the behavioral and biochemical effects of repeated (14 days) sulforaphane (SFN) treatment in the olfactory bulbectomy (OB) animal model of depression. An open field test (OFT), splash test (ST), and spontaneous locomotor activity test (LA) were used to assess changes in depressive-like behavior and the potential antidepressant-like activity of SFN. The OB model induced hyperactivity in mice during the OFT and LA as well as a temporary loss of self-care and motivation in the ST. The repeated administration of SFN (10 mg/kg) effectively reversed these behavioral changes in OB mice across all tests. Additionally, a biochemical analysis revealed that SFN (10 mg/kg) increased the total antioxidant capacity in the frontal cortex and serum of the OB model. Furthermore, SFN (10 mg/kg) significantly enhanced superoxide dismutase activity in the serum of OB mice. Overall, the present study is the first to demonstrate the antidepressant-like effects of repeated SFN (10 mg/kg) treatment in the OB model and indicates that these benefits may be linked to improved oxidative status. Full article

Bee-collected pollen (BCP) and bee bread (BB) are honey bee products known for their beneficial biological properties. The main goal of this study was to investigate BB microbiota and its contribution to bioactivity exerted by BB. The microbiota of BB samples collected at different maturation stages was investigated via culture-independent (Next Generation Sequencing, NGS) and culture-dependent methods. Microbial communities dynamically fluctuate during BB maturation, ending in a stable microbial community structure in mature BB. Bee bread bacterial isolates were tested for phenotypes and genes implicated in the production and secretion of enzymes as well as antibacterial activity. Out of 309 bacterial isolates, 41 secreted hemicellulases, 13 cellulases, 39 amylases, 132 proteinases, 85 Coomassie brilliant blue G or R dye-degrading enzymes and 72 Malachite Green dye-degrading enzymes. Furthermore, out of 309 bacterial isolates, 42 exhibited antibacterial activity against Staphylococcus aureus, 34 against Pseudomonas aeruginosa, 47 against Salmonella enterica ser. Typhimurium and 43 against Klebsiella pneumoniae. Artificially fermented samples exerted higher antibacterial activity compared to fresh BCP, strongly indicating that BB microbiota contribute to BB antibacterial activity. Our findings suggest that BB microbiota is an underexplored source of novel antimicrobial agents and enzymes that could lead to new applications in medicine and the food industry. Full article

Vanadium compounds are known to exert insulin-enhancing activity, normalize elevated blood glucose levels in diabetic subjects, and show significant activity in models of insulin resistance (IR). Faced with insulin resistance, the present work investigates the antidiabetic performance of a known oxidovanadium(IV)-based coordination compound—[V^IVO(octd)]—and effects associated with glucocorticoid-induced insulin resistance in mice. The effects of [V^IVO(octd)] were evaluated in a female Swiss mice model of insulin resistance induced by seven days of dexamethasone treatment in comparison with groups receiving metformin treatment. Biological assays such as hematological, TyG index, hepatic lipids, glycogen, oxidative stress in the liver, and oral glucose tolerance tests were evaluated. [V^IVO(octd)] was characterized with ⁵¹V NMR, infrared spectroscopy (FTIR), electron paramagnetic resonance (EPR), electronic absorption spectroscopy, and mass spectrometry (ESI–FT–MS). The [V^IVO(octd)] oral treatment (50 mg/kg) had an antioxidant effect, reducing 50% of fast blood glucose (p < 0.05) and 25% of the TyG index, which is used to estimate insulin resistance (p < 0.05), compared with the non-treated group. The oxidovanadium–sulfur compound is a promising antihyperglycemic therapeutic, including in cases aggravated by insulin resistance induced by glucocorticoid treatment. Full article

The aim of this study is to evaluate the anti-HPV potential of a Moringa olifera Lam seed, Nigella sativa L. seed, and Musa Acuminata peel herbal mixture in the form of polymer film-forming systems. A clinical trial conducted in outpatient clinics showed that the most significant outcome was wart size and quantity. Compared to the placebo group, the intervention group’s size and number of warts were considerably better according to the results. Chemical profiling assisted by LC-HRMS led to the dereplication of 49 metabolites. Furthermore, network pharmacology was established for the mixture of three plants; each plant was studied separately to find out the annotated target genes, and then, we combined all annotated genes of all plants and filtered the genes to specify the genes related to human papilloma virus. In a backward step, the 24 configured genes related to HPV were used to specify only 30 compounds involved in HPV infection based on target genes. CA2 and EGFR were the top identified genes with 16 and 12 edges followed by PTGS2, CA9, and MMP9 genes with 11 edges each. A molecular docking study for the top active identified compounds of each species was conducted in the top target HPV genes, CA2 and EGFR, to investigate the mode of interaction between these compounds and the targets’ active sites. Full article

Accidental poisonings by ingesting conjunctival fluid mixed with eye drops commonly involve alpha-2 adrenergic receptor agonists and tetrahydrozoline. These substances are recognized in commonly reported ingestions. Victims of all ages, otherwise in good health, often present as pale and lethargic to the emergency department (ED) after unintentionally ingesting topical eye medication. While eye drop poisoning cases in childhood include accidents during the play and poisonings in adults mean either suicide attempts or side effects caused by the systemic absorption of the substance, fluid of the ocular surface is a risk to all age groups. With this in mind, this study aimed to summarize data in the literature on tetrahydrozoline and alpha-2 adrenergic receptor agonists as dangerous medications, even when administered in low-bioavailability forms, such as eye drops. With this aim, a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review of relevant studies was conducted. A search of PubMed, Scopus, Web of Science, and EBSCOhost yielded nine studies that met the rigorous inclusion criteria. The primary studies were subject to a meta-analysis once a quality appraisal of the studies and a narrative synthesis of the extracted data had been conducted. The author hopes that this information will provide observations that will lead to better designs for over-the-counter eye drops, off-label drug usage policies, and parental attention. Full article

Diabetes, a multifactorial metabolic disorder, demands the discovery of multi-targeting drugs with minimal side effects. This study investigated the multi-targeting antidiabetic potential of quercetin and kaempferol. The druggability and binding affinities of both compounds towards multiple antidiabetic targets were explored using pharmacokinetic and docking software (AutoDock Vina 1.1.2). Our findings showed that quercetin and kaempferol obey Lipinski’s rule of five and exhibit desirable ADMET (absorption, distribution, metabolism excretion, and toxicity) profiles. Both compounds showed higher binding affinities towards C-reactive protein (CRP), interleukin-1 (IL-1), dipeptidyl peptidase-4 (DPP-IV), peroxisome proliferator-activated receptor gamma (PPARG), protein tyrosine phosphatase (PTP), and sodium–glucose co-transporter-1 (SGLT-1) compared to metformin (the positive control). Both quercetin and kaempferol inhibited α-amylase activity (in vitro) up to 20.30 ± 0.49 and 37.43 ± 0.42%, respectively. Their oral supplementation significantly reduced blood glucose levels (p < 0.001), improved lipid profile (p < 0.001), and enhanced total antioxidant status (p < 0.01) in streptozotocin–nicotinamide (STZ-NA)-induced diabetic mice. Additionally, both compounds significantly inhibited the proliferation of Huh-7 and HepG2 (cancer cells) (p < 0.0001) with no effect on the viability of Vero cell line (non-cancer). In conclusion, quercetin and kaempferol demonstrated higher binding affinities towards multiple targets than metformin. In vitro and in vivo antidiabetic potential along with the anticancer activities of both compounds suggest promise for further development in diabetes management. The combination of both drugs did not show a synergistic effect, possibly due to their same target on the receptors. Full article

TRPV1 channels are polymodal cation channels located predominantly on primary afferent neurons that are activated by inflammatory mediators, capsaicin (the active component in chili peppers), and noxious heat. TRPV1 channel antagonists are potential new analgesic agents, but their development has been hindered by the finding that they also produce loss of thermal homeostasis and response to noxious heat. Results from recent studies of the TRPV1 channel indicate that it might be possible to develop TRPV1 channel antagonists that inhibit pain without affecting noxious heat sensation. TRPV1 channels are also present in the central nervous system (CNS) and have been implicated in learning, memory, and behaviour. TRPV1 channel modulators have been proposed to have possible therapeutic potential in the treatment of neurological and psychiatric conditions. However, further understanding of the role of TRPV1 channels in the CNS is required before therapeutic advances in the treatment of neuropsychiatric conditions with TRPV1 channel modulators can be made. Full article

Nanoscale ultrasound contrast agents have attracted considerable interest in the medical imaging field for their ability to penetrate tumor vasculature and enable targeted imaging of cancer cells by attaching to tumor-specific ligands. Despite their potential, traditional chemically synthesized contrast agents face challenges related to complex synthesis, poor biocompatibility, and inconsistent imaging due to non-uniform particle sizes. To address these limitations, bio-synthesized nanoscale ultrasound contrast agents have been proposed as a viable alternative, offering advantages such as enhanced biocompatibility, consistent particle size for reliable imaging, and the potential for precise functionalization to improve tumor targeting. In this study, we successfully isolated cylindrical gas vesicles (GVs) from Serratia. 39006 and subsequently introduced the GVs-encoding gene cluster into Escherichia coli using genetic engineering techniques. We then characterized the contrast imaging properties of two kinds of purified GVs, using in vitro and in vivo methods. Our results demonstrated that naturally isolated GVs could produce stable ultrasound contrast signals in murine livers and tumors using clinical diagnostic ultrasound equipment. Additionally, heterologously expressed GVs from gene-engineered bacteria also exhibited good ultrasound contrast performance. Thus, our study presents favorable support for the application of genetic engineering techniques in the modification of gas vesicles for future biomedical practice. Full article

Tuberculosis (TB) is an airborne bacterial infection caused by Mycobacterium tuberculosis (M. tb), resulting in approximately 1.3 million deaths in 2022 worldwide. Oral therapy with anti-TB drugs often fails to achieve therapeutic concentrations at the primary infection site (lungs). In this study, we developed a dry powder inhalable formulation (DPI) of clofazimine (CFZ) to provide localized drug delivery and minimize systemic adverse effects. Poly (lactic acid-co-glycolic acid) (PLGA) microparticles (MPs) containing CFZ were developed through a single emulsion solvent evaporation technique. Clofazimine microparticles (CFZ MPs) displayed entrapment efficiency and drug loading of 66.40 ± 2.22 %w/w and 33.06 ± 1.45 µg/mg, respectively. To facilitate pulmonary administration, MPs suspension was spray-dried to yield a dry powder formulation (CFZ SD MPs). Spray drying had no influence on particle size (~1 µm), zeta potential (−31.42 mV), and entrapment efficiency. Solid state analysis (PXRD and DSC) of CFZ SD MPs studies demonstrated encapsulation of the drug in the polymer. The drug release studies showed a sustained drug release. The optimized formulation exhibited excellent aerosolization properties, suggesting effective deposition in the deeper lung region. The in vitro antibacterial studies against H37Ra revealed improved (eight-fold) efficacy of spray-dried formulation in comparison to free drug. Hence, clofazimine dry powder formulation presents immense potential for the treatment of tuberculosis with localized pulmonary delivery and improved patient compliance. Full article

Nowadays, lipidomics plays a crucial role in the investigation of novel biomarkers of various diseases. Its implementation into the field of clinical analysis led to the identification of specific lipids and/or significant changes in their plasma levels in patients suffering from cancer, Alzheimer’s disease, sepsis, and many other diseases and pathological conditions. Profiling of lipids and determination of their plasma concentrations could also be helpful in the case of drug therapy management, especially in combination with therapeutic drug monitoring (TDM). Here, for the first time, a combined approach based on the TDM of colistin, a last-resort antibiotic, and lipidomic profiling is presented in a case study of a critically ill male patient suffering from Pseudomonas aeruginosa-induced pneumonia. Implementation of innovative analytical approaches for TDM (online combination of capillary electrophoresis with tandem mass spectrometry, CZE-MS/MS) and lipidomics (liquid chromatography–tandem mass spectrometry, LC-MS/MS) was demonstrated. The CZE-MS/MS strategy confirmed the chosen colistin drug dosing regimen, leading to stable colistin concentrations in plasma samples. The determined colistin concentrations in plasma samples reached the required minimal inhibitory concentration of 1 μg/mL. The complex lipidomics approach led to monitoring 545 lipids in collected patient plasma samples during and after the therapy. Some changes in specific individual lipids were in good agreement with previous lipidomics studies dealing with sepsis. The presented case study represents a good starting point for identifying particular individual lipids that could correlate with antimicrobial and inflammation therapeutic management. Full article

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal form of pancreatic cancer characterized by therapy resistance and early metastasis, resulting in a low survival rate. Histone deacetylase (HDAC) inhibitors showed potential for the treatment of hematological malignancies. In PDAC, the overexpression of HDAC 2 is associated with the epithelial–mesenchymal transition (EMT), principally accompanied by the downregulation of the epithelial marker E-cadherin and increased metastatic capacity. The effector cytokine transforming growth factor-β (TGF β) is known to be a major inducer of the EMT in PDAC, leading to high metastatic and invasive potential. In addition, the overexpression of HDAC 6 in PDAC is associated with reduced apoptosis. Here, we have demonstrated that a novel HDAC 2/6 inhibitor not only significantly increased E-cadherin expression in PANC-1 cells (5.5-fold) and in 3D PDAC co-culture spheroids (2.5-fold) but was also able to reverse the TGF-β-induced downregulation of E-cadherin expression. Moreover, our study indicates that the HDAC inhibitor mediated re-differentiation resulting in a significant inhibition of tumor cell invasion by approximately 60% compared to control. In particular, we have shown that the HDAC inhibitor induces both apoptosis (2-fold) and cell cycle arrest. In conclusion, the HDAC 2/6 inhibitor acts by suppressing invasion via upregulating E-cadherin mediated by HDAC 2 blockade and by inducing cell cycle arrest leading to apoptosis via HDAC 6 inhibition. These results suggest that the HDAC 2/6 inhibitor might represent a novel therapeutic strategy for the treatment of PDAC tumorigenesis and metastasis. Full article

Background: Peru is one of the most biodiverse countries in the world, which is reflected in its wealth of knowledge about medicinal plants. However, there is a lack of information regarding intestinal absorption and the permeability of natural products. The human colon adenocarcinoma cell line (Caco-2) is an in vitro assay used to measure apparent permeability. This study aims to develop a quantitative structure–property relationship (QSPR) model using machine learning algorithms to predict the apparent permeability of the Caco-2 cell in natural products from Peru. Methods: A dataset of 1817 compounds, including experimental log Papp values and molecular descriptors, was utilized. Six QSPR models were constructed: a multiple linear regression (MLR) model, a partial least squares regression (PLS) model, a support vector machine regression (SVM) model, a random forest (RF) model, a gradient boosting machine (GBM) model, and an SVM–RF–GBM model. Results: An evaluation of the testing set revealed that the MLR and PLS models exhibited an RMSE = 0.47 and R² = 0.63. In contrast, the SVM, RF, and GBM models showcased an RMSE = 0.39–0.40 and R² = 0.73–0.74. Notably, the SVM–RF–GBM model demonstrated superior performance, with an RMSE = 0.38 and R² = 0.76. The model predicted log Papp values for 502 natural products falling within the applicability domain, with 68.9% (n = 346) showing high permeability, suggesting the potential for intestinal absorption. Additionally, we categorized the natural products into six metabolic pathways and assessed their drug-likeness. Conclusions: Our results provide insights into the potential intestinal absorption of natural products in Peru, thus facilitating drug development and pharmaceutical discovery efforts. Full article

The treatment adherence of narcotics-addicted individuals with reduced incidences of relapse can be enhanced by a sustained drug release formulation of antinarcotics. So far, different drug formulations have been reported with sustained drug release periods of 28 and 35 days. To further enhance this duration, different formulations of injectable hydrogels (IHs) have been developed by combining low molecular weight (LMW) and high molecular weight (HMW) chitosan (CS) with guar gum (GG) and crosslinking them by sodium bi phosphate dibasic. The structural, morphological, and physicochemical properties of LMW-CS IH, and HMW-CS IH were evaluated using Fourier transform infrared spectroscopy (FT-IR), thermo-gravimetric analysis (TGA), scanning electron microscopy (SEM), and rheological, swelling, and biodegradation analysis. The HMW-CS IH showed high crosslinking, increased thermal stability, high mechanical strength, elevated swelling, and low biodegradation. The antinarcotic drugs naltrexone (NTX) and disulfiram (DSF) were loaded separately into the HMW-CS IH and LMW-CS IH. The release of NTX and DSF was investigated in phosphate buffer saline (PBS) and ethanol (0.3%, 0.4%, and 0.5%) over a 56-day period using an UV spectrophotometer. The drug release data were tested in zero-order, first-order, and Korsemeyer–Peppas mathematical models. In PBS, all prepared formulations followed non-Fickian drug release, while in ethanol, only NTX HMW-CS IH followed non-Fickian release in all three different concentrations of ethanol. Full article

Cannabis sativa is a plant of the Cannabaceae family, whose molecular composition is known for its vast pharmacological properties. Cannabinoids are the molecules responsible for Cannabis sativa potential effects, especially tetrahydrocannabinol and cannabidiol. Scientific development has shown interest in the potential of cannabidiol in various health conditions, as it has demonstrated lower adverse events and great pharmacological potential, especially when administered topically. The present study aims to carry out a scoping review, focusing on the use of cannabidiol, in vivo models, for topical administration. Thus, the methodological approach used by the Joanna Briggs Institute was applied, and the studies were selected based on previously established inclusion criteria. Even though more information regarding the dose to achieve pharmacological potential is still needed, cannabidiol demonstrated potential in treating and preventing different conditions, such as glaucoma, atopic dermatitis, epidermolysis bullosa, and pyoderma gangrenosum. Full article