Search Results (33)

Diabetic neuropathy (DN) remains a major clinical burden, characterized by progressive sensory dysfunction, pain, and impaired quality of life. Despite the available symptomatic treatments, there is a pressing need for disease-modifying therapies. In recent years, preclinical research has highlighted the potential of repurposed pharmacological agents, originally developed for other indications, to target key mechanisms of DN. This narrative review examines the main pathophysiological pathways involved in DN, including metabolic imbalance, oxidative stress, neuroinflammation, ion channel dysfunction, and mitochondrial impairment. A wide array of repurposed drugs—including antidiabetics (metformin, empagliflozin, gliclazide, semaglutide, and pioglitazone), antihypertensives (amlodipine, telmisartan, aliskiren, and rilmenidine), lipid-lowering agents (atorvastatin and alirocumab), anticonvulsants (topiramate and retigabine), antioxidant and neuroprotective agents (melatonin), and muscarinic receptor antagonists (pirenzepine, oxybutynin, and atropine)—have shown promising results in rodent models, reducing neuropathic pain behaviors and modulating underlying disease mechanisms. By bridging basic mechanistic insights with pharmacological interventions, this review aims to support translational progress toward mechanism-based therapies for DN. Full article

This study evaluated the acute and developmental toxicity of selected hydrotropes, co-solvents, and surfactants commonly used in pharmaceutical and cosmetic formulations, using Artemia salina as a model organism. Two bioassays were employed: a lethality test and a hatching inhibition test. Compounds such as sodium lauryl sulfate (LC₅₀ < 0.05%), sodium xylenesulfonate (LC₅₀ = 0.79%), sodium p-toluensulfonate (LC₅₀ = 0.21%), N,N-dimethylbenzamide (LC₅₀ < 0.05%), and N,N-diethylnicotinamide (LC₅₀ = 0.05%) exhibited high toxicity at 48 h, inducing significant mortality and strong inhibition of hatching. Glycerin, propylene glycol, and dimethyl sulfoxide showed low toxicity across all concentrations. Lethal concentration values confirmed the high toxicity of sodium xylenesulfonate and N,N-dimethylbenzamide, with moderate effects observed for other compounds. The hatching inhibition test proved more sensitive than the lethality test, enabling the detection of embryotoxicity and developmental delays. Although more laborious, it provided detailed information into how the tested substances influenced developmental stage progression. Hierarchical clustering analysis grouped the substances based on toxicity patterns and clearly discriminated highly toxic surfactants from low-toxicity solvents. The results demonstrated that combining both bioassays offers a more comprehensive evaluation of toxicity, with the hatching test being particularly useful for identifying early developmental effects not evident in lethality testing alone. Full article

Improving the aqueous solubility of poorly soluble pharmaceuticals is essential for accurate pharmacotoxicological testing, but the biological safety of solubilizers and hydrotropic agents used for this purpose requires careful evaluation. This study assessed the acute toxicity, physiological parameters (heart rate, claw and appendage movement), behavioral responses (swimming speed), and embryotoxicity of 15 commonly used solubilizers and hydrotropes using Daphnia magna as a biological model. Compounds included surfactants (polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), sodium lauryl sulfate (SLS)), sulfonated hydrotropes (sodium xylene sulfonate (SXS), sodium benzenesulfonate (SBS), sodium p-toluenesulfonate (PTS), sodium 1,3-benzenedisulfonate (SBDS)), and solubilizing solvents (dimethyl sulfoxide (DMSO), glycerol (GLY), propylene glycol (PDO), dimethylformamide (DMF), N,N’-Dimethylbenzamide (DMBA), N,N-Diethylnicotinamide (DENA), N,N-Dimethylurea (DMU), urea). Acute lethality was evaluated across concentration ranges appropriate to each compound group (e.g., 0.0005–0.125% for surfactants; up to 5% for less toxic solvents). Surfactants exhibited extreme toxicity, with Tween 20 and SLS causing 100% lethality even at 0.0005%, while Tween 80 induced 40–50% lethality at that concentration. In contrast, DMSO, GLY, and PDO showed low acute toxicity, maintaining normal heart rate (202–395 bpm), claw and appendage movement, and swimming speed at ≤1%, though embryotoxicity became evident at higher concentrations (≥1–2%). SXS, SBS, PTS, and SBDS displayed clear dose-dependent toxicity but were generally tolerated up to 0.05%. DMBA, DENA, and DMU caused physiological suppression, including reduced heart rate (e.g., DMBA: 246 bpm vs. control 315 bpm) and impaired mobility. Behavioral assays revealed biphasic effects for DMSO and DMBA, with early stimulation (24 h) followed by inhibition (48 h). Embryotoxicity assays demonstrated significant morphological abnormalities and developmental delays at elevated concentrations, especially for DMSO, GLY, and PDO. Overall, DMSO, GLY, PDO, SXS, and DMF can be safely used at tightly controlled concentrations in Daphnia magna toxicity assays to ensure accurate screening without solvent-induced artifacts. Full article

The adverse effects of protein kinase inhibitors (PKIs) and other anticancer therapies were compared using FDA Adverse Events Reporting System (FAERS) data. The dataset included 159 FDA-approved anticancer drugs (71 PKIs, 88 nonPKIs) and analyzed 8216 unique adverse event (AE) terms. PKIs showed fewer systemic toxicities, with an average of 230.1 distinct AEs per drug, compared to 537.7 in nonPKIs. Hematologic AEs were significantly lower in PKIs (e.g., febrile neutropenia: 1.93% vs. 5.25%; thrombocytopenia: 2.18% vs. 3.87%), coupled with a lower incidence of infections (6.87% vs. 14.2%) and immunosuppressive effects. However, gastrointestinal and skin-related AEs were more common in PKIs (e.g., diarrhea: 13.95% vs. 8.36%). A higher proportion AEs in the PKI group (14.57%) were classified under “Investigations”, compared to the nonPKI group (9.87%). The frequency of “Skin and subcutaneous tissue disorders” AEs was twice as high in the PKI group. Clustering analysis grouped drugs by AE profiles, showing that PKIs formed more homogeneous clusters, while nonPKIs had broader variability. Multi-kinase inhibitors with VEGFR activity were linked to dermatologic AEs, likely due to EGFR inhibition in basal keratinocytes. Despite PKIs’ targeted mechanisms, resistance remains a challenge, requiring biomarker-driven strategies. This study highlights PKIs’ improved tolerability but emphasizes using personalized treatment approaches to optimize efficacy and safety. Full article

Background/Objectives: Drug-induced dysbiosis, particularly from antibiotics, has emerged as a significant contributor to chronic diseases by disrupting gut microbiota composition and function. Plant-derived secondary metabolites, such as polysaccharides, polyphenols, alkaloids, and saponins, show potential in mitigating antibiotic-induced dysbiosis. This review aims to consolidate evidence from preclinical studies on the therapeutic effects of secondary metabolites in restoring gut microbial balance, emphasizing their mechanisms and efficacy. Methods: A narrative review was conducted using PubMed, Scopus, and Web of Science. Studies were selected based on specific inclusion criteria, focusing on animal models treated with secondary metabolites for antibiotic-induced dysbiosis. The search terms included “gut microbiota”, “antibiotics”, and “secondary metabolites”. Data extraction focused on microbial alterations, metabolite-specific effects, and mechanisms of action. Relevant findings were systematically analyzed and summarized. Results: Secondary metabolites demonstrated diverse effects in mitigating the impact of dysbiosis by modulating gut microbial composition, reducing inflammation, and supporting host biological markers. Polysaccharides and polyphenols restored the Firmicutes/Bacteroidetes ratio, increased beneficial taxa such as Lactobacillus and Bifidobacterium, and suppressed pathogenic bacteria like Escherichia-Shigella. Metabolites such as triterpenoid saponins enhanced gut barrier integrity by upregulating tight junction proteins, while alkaloids reduced inflammation by modulating proinflammatory cytokines (e.g., TNF-α, IL-1β). These metabolites also improved short-chain fatty acid production, which is crucial for gut and systemic health. While antibiotic-induced dysbiosis was the primary focus, other drug classes (e.g., PPIs, metformin) require further investigation. Conclusions: Plant-derived secondary metabolites show promise in managing antibiotic-induced dysbiosis by restoring microbial balance, reducing inflammation, and improving gut barrier function. Future research should explore their applicability to other types of drug-induced dysbiosis and validate findings in human studies to enhance clinical relevance. Full article

Kounis syndrome (KS) is a rare condition where hypersensitivity reactions trigger coronary vasospasm, destabilization of atherosclerotic plaques, or stent thrombosis, posing diagnostic and therapeutic challenges due to its overlap with acute coronary syndrome (ACS) and the absence of specific guidelines. This study reviews cases of KS from the Institute of Cardiovascular Disease to highlight clinical presentations, triggers, and treatment strategies. We analyzed four cases of KS treated at our institution between 2019 and 2024. Detailed clinical histories, laboratory findings, imaging studies, and treatment plans were reviewed. Patients were classified by KS subtype based on coronary anatomy and pathophysiological mechanisms. Management strategies were tailored to each subtype, combining myocardial revascularization, antiplatelet therapy, and treatment for allergic reactions. The series included two cases of Type I KS in patients with structurally normal coronary arteries and two cases of Type II KS involving pre-existing atherosclerosis. No Type III KS was observed. Triggers included insect stings, antibiotics, iodinated contrast agents, and anesthetics. Coronary angiography confirmed the diagnosis in all cases. Treatments included percutaneous coronary interventions, dual antiplatelet therapy, and prophylactic antihistamines or corticosteroids. All patients experienced favorable outcomes, although diagnostic delays were noted in cases with atypical presentations. KS remains underdiagnosed, especially in emergency settings where it mimics ACS. Early recognition and multidisciplinary management involving allergology and cardiology are crucial. Future research should focus on safer diagnostic tools, understanding the pathophysiology, and developing evidence-based preventive strategies. Increasing the awareness of KS and its inclusion in ACS differentials are essential to improving patient outcomes and preventing recurrences. Full article

Chronic pain is a debilitating condition affecting millions worldwide, often resulting from complex interactions between the nervous and immune systems. Recent advances highlight the critical role of metabolite-sensing G protein-coupled receptors (GPCRs) in various chronic pain types. These receptors link metabolic changes with cellular responses, influencing inflammatory and degenerative processes. Receptors such as free fatty acid receptor 1 (FFAR1/GPR40), free fatty acid receptor 4 (FFAR4/GPR120), free fatty acid receptor 2 (FFAR2/GPR43), and Takeda G protein-coupled receptor 5 (TGR5/GPR131/GPBAR1) are key modulators of nociceptive signaling. GPR40, activated by long-chain fatty acids, exhibits strong anti-inflammatory effects by reducing cytokine expression. Butyrate-activated GPR43 inhibits inflammatory mediators like nitric oxide synthase-2 and cyclooxygenase-2, mitigating inflammation. TGR5, activated by bile acids, regulates inflammation and cellular senescence through pathways like NF-κB and p38. These receptors are promising therapeutic targets in chronic pain, addressing the metabolic and inflammatory factors underlying nociceptive sensitization and tissue degeneration. This review explores the molecular mechanisms of metabolite-sensing receptors in chronic pain, their therapeutic potential, and challenges in clinical application. By uncovering these mechanisms, metabolite-sensing receptors could lead to safer, more effective pain management strategies. Full article

Osteoarthritis (OA) is a degenerative joint disease characterized by the breakdown of cartilage and the subsequent inflammation of joint tissues, leading to pain and reduced mobility. Despite advancements in symptomatic treatments, disease-modifying therapies for OA remain limited. This narrative review examines the dual role of autophagy in OA, emphasizing its protective functions during the early stages and its potential to contribute to cartilage degeneration in later stages. By delving into the molecular pathways that regulate autophagy, this review highlights its intricate interplay with oxidative stress and inflammation, key drivers of OA progression. Emerging therapeutic strategies aimed at modulating autophagy are explored, including pharmacological agents such as AMP kinase activators, and microRNA-based therapies. Preclinical studies reveal encouraging results, demonstrating that enhancing autophagy can reduce inflammation and decelerate cartilage degradation. However, the therapeutic benefits of autophagy modulation depend on precise, stage-specific approaches. Excessive or dysregulated autophagy in advanced OA may lead to chondrocyte apoptosis, exacerbating joint damage. This review underscores the promise of autophagy-based interventions in bridging the gap between experimental research and clinical application. By advancing our understanding of autophagy’s role in OA, these findings pave the way for innovative and effective therapies. Nonetheless, further research is essential to optimize these strategies, address potential off-target effects, and develop safe, targeted treatments that improve outcomes for OA patients. Full article

Protein kinases are vital regulators in cell biology, modifying protein functions through phosphorylation. Protein kinase inhibitors (PKIs), which impede these kinases’ activities, have broadened their therapeutic scope from cancer treatment to autoimmune and viral diseases. Despite their clinical success, challenges such as drug resistance and tolerability of adverse events persist. This article used the Protein Kinase Inhibitor Database (PKIDB) and major pharmacovigilance databases to assess the adverse events (AEs) linked to FDA-approved protein kinase inhibitors. Methods were adopted to statistically identify outliers and construct a prototypical profile to generalize AE occurrences. A total of 66 inhibitors were analyzed, revealing substantial variability in the safety profiles. Cluster analysis identified distinct patterns of AEs based on kinase target classes, highlighting the importance of tailored therapeutic approaches. Statistical methods such as Tukey’s fences were used to identify drugs with unusual safety profiles, offering insights into both frequent and rare severe reactions. Real-world evidence complements clinical trial data, capturing AEs that might not be fully identified pre-approval. Full article

In recent years, the European market, including Romania, has witnessed a significant increase in the promotion of cannabidiol (CBD)-based products, often presented as effective treatments for various health conditions. This study investigates the inconsistencies between the health claims associated with these supplements and the evidence from clinical trials. To identify products available on the Romanian market, a systematic review of online pharmacies and websites that specialize in selling CBD-based products has been performed. Additionally, a systematic review of clinical trials has been conducted to assess the efficacy of CBD for the specified indications. Our analysis revealed that some claims, such as those related to post-traumatic stress disorder, lack substantial clinical evidence. Moreover, even when clinical support exists, the dosages recommended for the supplements are often significantly lower than those used in trials, raising concerns about their efficacy. These findings highlight the need for stricter regulatory oversight and more transparent communication to ensure that consumer expectations are aligned with scientific evidence, ultimately promoting informed decision-making and consumer safety. Full article

Background: Small molecules play a crucial role in the exploration of physiological pathways and in drug development by targeting deoxyribonucleic acid (DNA). DNA is a central focus for both endogenous and exogenous ligands, which interact directly or indirectly to regulate transcription and replication processes, thus controlling genetic expression in specific cells. Among these molecules, indole derivatives like tryptophan, serotonin, and melatonin are notable for their widespread presence in nature and significant biological effects. Tryptophan, an essential amino acid, serves as a vital structural element in proteins and a precursor for bioactive compounds like serotonin and melatonin, which impact various physiological functions. Methods: Experimental studies have been conducted to reveal the interaction mechanisms of these endogenous indole derivatives with calf thymus DNA (ct-DNA). These investigations involve viscosity measurements and analysis of double-stranded DNA behavior in the presence of indole molecules, using spectrophotometric UV absorption techniques to assess their impact on DNA stability. Additionally, the influence of calcium and magnesium ions on the resulting complexes of these indole derivatives with ct-DNA has been evaluated. Molecular docking validated our findings, offering additional insights into potential DNA–ligand interactions. Utilizing a crystallographic oligomer with an intercalation gap improved docking accuracy, distinguishing intercalation from groove recognition and enhancing assessment precision. Results: Our study offers detailed insights into the interaction patterns of the indole derivatives with DNA and is highly supported by molecular docking analyses: the indole derivatives were predominantly localized between C and G, interacting via π-π interactions and hydrogen bonds and aligning with known data on conventional intercalators. These findings underscore the importance of small compounds’ planar structure and appropriate size, facilitating tight insertion between adjacent base pairs and disrupting regular DNA stacking. Conclusions: Indoles’ physiological roles and potential as drug candidates targeting specific pathways are highlighted, emphasizing their significance as ubiquitous molecules with the ability to modulate biological effects on DNA structure. Full article

The increasing incidence of diabetes has prompted the need for new treatment strategies, including natural products that reduce glycemia values. This work examined the in vitro and in vivo antihyperglycemic effects of new metabiotics derived from Boletus edulis extracts. The metabiotics were obtained from 100% B. edulis, and two other products, CARDIO and GLYCEMIC, from Anoom Laboratories SRL, which contain other microbial species related to B. edulis. Our in vitro investigations (simulations of the microbiota of patients with type 2 diabetes (T2D)) demonstrated that B. edulis extracts modulate the microbiota, normalizing its pattern. The effects were further tested in vivo, employing a mouse model of T2D. The tested extracts decreased glycemia values compared to the control and modulated the microbiota. The metabiotics had positive effects on T2D in vitro and in vivo, suggesting their potential to alleviate diabetes-associated microbiota dysbiosis. Full article

Phosphodiesterase type 5 (PDE5) is pivotal in cellular signalling, regulating cyclic guanosine monophosphate (cGMP) levels crucial for smooth muscle relaxation and vasodilation. By targeting cGMP for degradation, PDE5 inhibits sustained vasodilation. PDE5 operates in diverse anatomical regions, with its upregulation linked to various pathologies, including cancer and neurodegenerative diseases. Sildenafil, a selective PDE5 inhibitor, is prescribed for erectile dysfunction and pulmonary arterial hypertension. However, considering the extensive roles of PDE5, sildenafil might be useful in other pathologies. This review aims to comprehensively explore sildenafil’s therapeutic potential across medicine, addressing a gap in the current literature. Recognising sildenafil’s broader potential may unveil new treatment avenues, optimising existing approaches and broadening its clinical application. Full article

Osteoarthritis is characterized by progressive articular cartilage degradation, subchondral bone changes, and synovial inflammation, and affects various joints, causing pain and disability. Current osteoarthritis therapies, primarily focused on pain management, face limitations due to limited effectiveness and high risks of adverse effects. Safer and more effective treatments are urgently needed. Considering that the endocannabinoid 2-arachidonoyl glycerol is involved in pain processing, increasing its concentration through monoacylglycerol lipase (MAGL) inhibition reduces pain in various animal models. Furthermore, drug repurposing approaches leverage established drug safety profiles, presenting a cost-effective route to accelerate clinical application. To this end, cetirizine and levetiracetam were examined for their MAGL inhibitory effects. In vitro studies revealed that cetirizine and levetiracetam inhibited MAGL with IC₅₀ values of 9.3931 µM and 3.0095 µM, respectively. In vivo experiments demonstrated that cetirizine, and to a lesser extent levetiracetam, reduced mechanical and thermal nociception in complete Freund adjuvant (CFA)-induced osteoarthritis in rats. Cetirizine exhibited a notable anti-inflammatory effect, reducing CFA-induced inflammation, as well as the inflammatory infiltrate and granuloma formation in the affected paw. These findings suggest that cetirizine may serve as a promising starting point for the development of novel compounds for osteoarthritis treatment, addressing both pain and inflammation. Full article

The regular administration of antibiotics is a public concern due to the prejudices of large population groups and the high frequency with which antimicrobial products are prescribed. The current study aimed to evaluate the in vitro effect of a new extract from Boletus edulis (BEE) on the human microbiota. One of the disadvantages of this extensive use is the disruption of the human microbiota, leading to potential negative health consequences. The in vitro evaluation of BEE consisted in determining its cytotoxicity, influence on the concentration of four types of cytokines (IL-6, IL-10, IL-1β, TNFα), and capacity to modulate the human microbiota after administering antibiotics. The latter was assessed by microbiome analysis and the evaluation of short-chain fatty acid synthesis (SCFAs). Simultaneously, the content of total polyphenols, the antioxidant capacity, and the compositional analysis of the extract (individual polyphenols composition) were determined. The results showed that BEE modulates the microbial pattern and reduces inflammatory progression. The data demonstrated antioxidant properties correlated with the increase in synthesizing some biomarkers, such as SCFAs, which mitigated antibiotic-induced dysbiosis without using probiotic products. Full article