Search Results (243)

Pine needles are traditional herbal remedies used for centuries to treat various ailments, including rheumatism, bronchitis, burns, inflammation, and infections. This study aimed to evaluate the antioxidant, analgesic (peripheral and central), and wound-healing activities of Pinus pinaster (PPN) and Pinus halepensis (PAN) needles while identifying the bioactive compounds responsible for these effects. Phytochemical analysis revealed several phenolic compounds, including p-coumaroylquinic acid, quercetin, narcissin, and myricetin-3-O-glucoside. Both extracts showed strong antioxidant activity, with high total phenolic content (TPC: 384.84 ± 0.84 and 524.46 mg GAE/g DM for PPN and PAN, respectively) and flavonoid content (TFC: 109.44 ± 0.62 and 111.64 ± 0.62 mg QE/g DM, respectively). Peripheral analgesic activity, assessed using the acetic acid-induced writhing test, revealed that PAN (300 mg/kg) significantly reduced pain by 72.3%, while central analgesic effects, evaluated by the tail immersion test, were comparable to the reference drug for both extracts. In vivo wound-healing tests showed accelerated wound contraction and complete closure by day 21, indicating strong regenerative potential. Overall, this study demonstrates that PPN and PAN needle extracts possess significant antioxidant, analgesic, and wound-healing activities, supporting their traditional use and highlighting their potential as natural therapeutic agents for managing oxidative stress, pain, and skin injuries. Full article

Background/Objectives: Neuropathic pain remains a significant clinical challenge, with current treatments often providing inadequate relief and adverse effects. Sigma receptors (SRs) modulate nociception and have emerged as potential therapeutic targets for neuropathic pain. Although putative sigma-1 receptor (S1R) ligands have demonstrated analgesic efficacy in preclinical models, their in vivo efficacy and safety profiles require further clarification. Methods: Analogs of well-known selective S1R ligand UVM147 were synthesized using 3-component Ugi reactions and examined in vitro for receptor affinity in radioligand competition binding assays and in vivo with mouse models of neuropathic and inflammatory pain and adverse effects. Results: Three novel heterocyclic compounds (RO-4-3, RO-5-3, and RO-7-3) displayed in vitro nanomolar affinity with varying selectivity for both SR subtypes (S1R and S2R). When screened in vivo at a dose of 30 mg/kg s.c. in mice first subjected to chronic constriction injury (CCI), RO-5-3 and RO-7-3 possessed anti-allodynic potential, while UVM147 was inactive. Upon full characterization, RO-5-3 significantly attenuated mechanical allodynia in a dose-dependent manner, while RO-7-3 was ineffective at higher doses. Both compounds dose-dependently attenuated nociceptive behaviors in the mouse formalin assay. RO-5-3 induced mild respiratory depression without impairing locomotor activity, whereas RO-7-3 caused transient respiratory depression and locomotor impairment. Additionally, RO-5-3, but not RO-7-3, induced conditioned place aversion consistent with potential S2R involvement. Conclusions: RO-5-3 exerts antinociceptive and anti-allodynic effects with minimal adverse behavioral effects, supporting the role of SRs in pain modulation. These results add to growing evidence supporting the development of SR ligands as efficacious therapeutics for neuropathic pain with fewer clinical liabilities. Full article

The genus Plantago (Plantaginaceae) is widely distributed worldwide. The Plantago species are used in traditional medicine as wound healers, anti-inflammatory agents, antipyretics, and analgesics. This study aimed to investigate the phytochemical composition from the aerial parts of Plantago indica L. and to evaluate its biological activities. Isolation studies and in vitro investigations were conducted on an aqueous phase of 80% EtOH extract of Plantago indica. In addition, in vivo studies were carried out using the MeOH, 80% EtOH, and water extracts. Plantarenaloside (1), 3-oxo-α-ionol β-glucoside (2), martynoside (3), acteoside (4), feruloyl gardoside (5), and ursolic acid (6) were isolated from the extract. The structures of the compounds were elucidated using 1D- and 2D-NMR and ESI-MS analyses. The extract, fractions, and pure compounds were tested in vitro for cytotoxicity (MTT), anti-inflammatory activity (NO, IL-6, and TNF-α production), wound healing (scratch test), and antioxidant capacity (DPPH, ABTS, SO). Feruloyl gardoside (20.11–58.27%) significantly reduced NO levels at concentrations of 25–100 µM. It significantly reduced IL-6 levels (40.17%) at 100 µM. Additionally, the in vivo anti-inflammatory (acetic acid-induced vascular permeability) and wound healing (incision and excision models) effects of the extracts were investigated. The findings suggest that P. indica may be considered to be a potential therapeutic option for managing inflammation and for promoting wound healing. Full article

Background: Neuropathic pain is a complex condition often resistant to current therapies due to limited efficacy and adverse effects. Nutraceuticals offer promising alternatives, combining antioxidant and anti-inflammatory properties with good tolerability. This study aimed to compare the effects of a commercial nutraceutical formulation, SUPERALA CARNITINE^® (Pharma Suisse Laboratories SpA, Milan, Italy), containing Alpha-Lipoic Acid (ALA), with a novel formulation, called SUPERALA CARNITINE^® Forte, where ALA and vitamin B6 were replaced by N-acetylcysteine (NAC), Glutathione (GSH), and Uridine monophosphate (UMP). Methods: An indirect gut–peripheral nerve axis was employed to simulate oral absorption, metabolism, and effect on nervous tissues using 3D in vitro models. Both formulations and their individual components were assessed for cytotoxicity and permeability in the gut model (Caco-2 cells in Transwell^®) and, after gut metabolism, for antioxidant capacity, anti-inflammatory activity, and neuroprotective potential in the peripheral nerve model. Results: SUPERALA CARNITINE^® Forte improved cell viability and favoured the maintenance of intestinal integrity, showing enhanced permeability, and significantly reduced oxidative stress (OS) and pro-inflammatory cytokines (TNF-α, IL-2) at the peripheral nervous system. In addition, it increased levels of neuronal markers (p75, MPZ, NRG1, ERβ) and decreased NaV1.7 and NaV1.8 activity, indicating greater neuroprotection and analgesic modulation than the ALA-based formula. Conclusions: The replacement of ALA and vitamin B6 with NAC, GSH, and UMP produced favorable responses in vitro on neuronal cells, supporting a hypothetical potential interest in this nutraceutical combination and justifying further future in vivo investigations. Full article

Background: Chronic diseases are leading causes of morbidity and mortality worldwide and their prevalence is increasing due to aging and lifestyle factors. A central element in their pathophysiology is chronic low-grade inflammation, linking metabolic, cardiovascular, neurodegenerative, and proliferative disorders. In this context, Opuntia dillenii, a cactus species traditionally used in folk medicine, has attracted considerable scientific interest due to its promising nutraceutical potential. Methods: This systematic review was conducted through a PRISMA-guided literature search using PubMed, Scopus, and Web of Science, identifying 45 studies that analyze the phytochemical composition and biological activity of O. dillenii. Results: The compounds highlighted include betalains, polyphenols, flavonoids, and polysaccharides that exhibit potent anti-inflammatory and analgesic effects by modulating key inflammatory mediators. In addition, O. dillenii demonstrates antiproliferative activity, inducing apoptosis and inhibiting tumor growth in various in vivo models, suggesting a potential role in cancer prevention and as a complementary therapy. The cactus also exhibits antiatherogenic and hypotensive effects, as well as hypolipidemic and antidiabetic properties by improving lipid profiles, reducing serum cholesterol and triglycerides, and enhancing insulin sensitivity. Furthermore, its protective actions against tissue damage extend its therapeutic potential. Antimicrobial properties have also been reported, reinforcing its value as a functional food. Conclusions: Taken together, the evidence supports the use of O. dillenii as a versatile nutraceutical resource with a low toxicity profile, capable of contributing to the prevention and treatment of various chronic inflammatory and metabolic diseases. Nevertheless, human clinical trials are needed to validate these findings and explore their full therapeutic utility. Full article

The need for new medications to treat diabetes mellitus (DM) is a global health concern due to the cost and impact on patients and their families, health systems, and society. Recent approaches in drug development have focused on multitarget therapy for DM, considering its multifactorial and complex pathophysiology. The present work contributes to the review of the plant species Schinus molle L. (pirul), a tropical tree native to South America but now widespread worldwide, which has demonstrated anticancer, analgesic, antibacterial, and insecticidal properties. According to traditional uses, pirul has been employed as a food condiment, in the preparation of beverages and chewing gums, and in the treatment of DM. The antidiabetic effects of pirul appear to act through several mechanisms involved in DM. The methanolic extract of S. molle fruits collected in Tunisia exhibited a dose-dependent inhibition on both α-amylase and α-glucosidase enzymes (77.49% and 86.45%, respectively). A dose-dependent anti-inflammatory effect was also observed at 1, 2, 3, 4, and 5 h, in the carrageenan-induced rats’ paw edema model. Furthermore, in both the H₂O₂ and the superoxide radical assays, the pirul extract demonstrated moderate antioxidant activity (IC₅₀ = 0.22 mg/mL). Isomasticadienonic acid and Masazino-flavanone, the major components of active fractions and extracts of S. molle represent promising antidiabetic agents. Although pirul appears to be safe in in vivo acute and subchronic administrations, toxicological studies and clinical trials in individuals with DM are still pending. Full article

Background/Objectives: Lidocaine hydrochloride (LD-HCl) is the most commonly used local anesthetic in dentistry, often administered with epinephrine to extend its duration and reduce systemic absorption. However, its relatively short duration of action, the need for repeated injections, and the unpleasant taste may limit patient compliance and procedural efficiency. This study aimed to develop and evaluate a novel injectable nanoemulsion-based in situ gel depot system of LD to provide prolonged anesthetic activity. Methods: LD-loaded nanoemulsions were formulated by high-shear homogenization followed by probe sonication, employing Miglyol 812 N (oil phase), a combination of Tween 80 and soy lecithin (surfactant–co-surfactant), glycerin, and deionized water (aqueous phase). The selected nanoemulsion (S1) was dispersed in a thermoreversible poloxamer solution to form a nanoemulgel. The preparation was evaluated for globule diameter and uniformity, zeta potential, surface morphology, pH, drug content, stability, rheological behavior, injectability, and in vitro drug release. Analgesic efficacy was assessed via tail-flick and thermal paw withdrawal latency tests in Wistar rats. Cardiovascular safety was monitored using non-invasive electrocardiography and blood pressure measurements. Results: The developed nanoemulsions demonstrated a spherical shape, nanometer size (206 nm), high zeta-potential (−66.67 mV) and uniform size distribution, with a polydispersity index of approximately 0.40, while the nanoemulgel demonstrated appropriate thixotropic properties for parenteral administration. In vitro release profiles showed steady LD release (5 h), following the Higuchi model. In vivo studies showed significantly prolonged analgesic effects lasting up to 150 min (2.5 h) compared to standard LD-HCl injection (p < 0.001), with no adverse cardiovascular effects observed. Conclusions: The developed injectable LD in situ nanoemulgel offers a promising, patient-friendly alternative for prolonged anesthetic delivery in dental and operative procedures, potentially reducing the need for repeated injections and enhancing procedural comfort. Full article

In a continued search for novel plant-based therapeutics with multi-target pharmacological potential, the medicinal plant Dischidia bengalensis (Apocynaceae) was investigated for the first time for its anti-inflammatory, analgesic, and thrombolytic properties, addressing critical therapeutic areas such as rheumatoid arthritis, acute pain, and thrombosis. The methanolic extract and solvent fractions (dichloromethane, n-hexane, and ethyl acetate) were evaluated through integrated in vivo, in vitro, and in silico approaches. Phytochemical screening and GC–MS profiling revealed a diverse array of bioactive constituents, including fatty acids, terpenoids, and phenolic derivatives, many of which are reported to exhibit pharmacological activities. In vivo assays demonstrated that the methanolic extract (400 mg/kg) markedly suppressed carrageenan-induced paw edema (92.31% inhibition) from the 2nd to 4th hour (p  <  0.05, p  <  0.01), while the n-hexane fraction produced the most pronounced analgesic response in both writhing and tail-immersion models (p  <  0.001). Furthermore, the methanolic extract displayed significant thrombolytic activity (33.38  ±  4.27% at 20 mg/mL, p < 0.001) in human blood clot lysis, suggesting potential application in cardiovascular disorders. The scientific novelty of this study was further underscored by in silico molecular docking, ADME/T, and PASS prediction studies. Key bioactive compounds, identified by GC-MS, showed strong binding affinities and promising drug-like properties against pivotal human targets such as TNF-α (PDB: 2AZ5), COX-2 (PDB: 6COX), and tissue plasminogen activator. These findings conclusively establish D. Bengalensis as a promising and novel source of lead compounds for the development of novel therapeutics against inflammatory, pain-related, and cardiovascular disorders. Full article

The neuropeptide’s multifaceted involvement in various components of neural homeostasis impacts pain and behavioral regulation. One of the highly potent neuropeptides is dermorphin, extracted from the skin of the Amazon frog (Phyllomedusa sauvagei). The unique feature of dermorphin is the D-Ala residue in its sequence, which has inspired researchers to search for dermorphin analogs for use as pharmaceuticals. The primary objective of this study is to synthesize several new linear and cyclic dermorphin analogs and evaluate them as potential non-invasive analgesics. By exploring our method for converting linear peptides into 2,5-diketopiperazine(2,5-DKP) derivatives, which stabilize peptide structures, we synthesize several new dermorphin linear peptides and chimeric cyclopeptidomimetics. These compounds were tested in vitro and in vivo to determine their biological activities and potential applicability as pharmaceuticals. For the evaluation of in vitro opioid activity, the “Guinea Pig Ileum” (GPI) test was used. D2 showed the highest activity, and cyclopeptides D3 and D4 showed high activity. We can assume that dermorphin analogues D2, D3, and D4 are potent agonists of µ-type opioid receptors and have high opioid activity. However, this needs to be verified using molecular modeling methods in further research. The analgesic effects of dermorphins have been evaluated in the “Hot-Plate” and “Tail-Flick” tests. In rats, D2 dermorphin analogues demonstrated dose-dependent analgesic effect in the “Water Tail-Flick” test after intranasal administration. A smaller dose of 0.5 µg/kg resulted in 40% analgesia and a short-term state of stupor. The maximum long-lasting analgesia was observed at a dose of 1.0 µg/kg, which induced complete stupor. The analgesic effect of peptide D2 after intraperitoneal administration at a 5.0 mg/kg dose was over 50%. The “Open-Field” test demonstrated a dose-dependent (15, 50, 150 μg/kg) peptide D2 suppression effect on behavioural reactions in rats following intranasal administration. A new modification of linear peptides, combined with a 2,5-DKP scaffold (D3 and D4), proved promising for oral use based on the results of analgesic effect evaluation in mice following intragastric administration. Full article

Chronic, low-grade inflammation is a key contributor to the development of numerous non-communicable diseases (NCDs), including cardiovascular, metabolic, and neurodegenerative disorders. Conventional anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, often present safety concerns with prolonged use, highlighting the need for safer, multi-targeted therapeutic options. Iridoids, a class of monoterpenoid compounds abundant in several medicinal plants, have emerged as promising bioactive agents with diverse pharmacological properties. They exert anti-inflammatory and metabolic regulatory effects by modulating key signaling pathways, including nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), Janus kinase/signal transducer and activator of transcription (JAK/STAT), adenosine monophosphate-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor (PPAR) pathways. This review provides a comprehensive summary of the major iridoid metabolites derived from ten Bulgarian medicinal plant species, along with mechanistic insights from in vitro and in vivo studies. Documented biological activities include anti-inflammatory, antioxidant, immunomodulatory, antifibrotic, organoprotective, antibacterial, antiviral, analgesic, and metabolic effects. By exploring their phytochemical profiles and pharmacodynamics, we underscore the therapeutic potential of iridoid-rich Bulgarian flora in managing inflammation-related and metabolic diseases. These findings support the relevance of iridoids as complementary or alternative agents to conventional therapies and highlight the need for further translational and clinical research. Full article

Plant-derived pharmaceuticals represent a highly compelling area of research and continue to attract significant interest from countries, regions, scientific communities, and pharmaceutical companies worldwide. Among these, α- and β-amyrins have been identified as high-value triterpenoid compounds with a broad spectrum of potential therapeutic properties, including anti-inflammatory, antidiabetic, antiatherosclerotic, analgesic, antigout, neuroprotective, anti-Parkinsonian, anticancer, antibacterial, and anti-HIV activities. Relevant information and data were obtained through comprehensive searches of major scientific databases, including Web of Science, Elsevier, and the National Library of Medicine. This study highlighted the pharmaceutical potential of α- and β-amyrins, supported by specific evidence from in vivo, in vitro, and clinical trials. Various extraction methods for α- and β-amyrins are discussed, followed by recommendations for future directions in the development of these compounds as pharmaceutical agents and functional food ingredients. This review highlights the therapeutic of α- and β-amyrin compounds in the prevention and treatment of various serious diseases worldwide, potentially opening new opportunities and directions for the pharmaceutical industry. Full article

Background: Pain is a complex phenomenon characterized by unpleasant experiences with profound heterogeneity influenced by biological, psychological, and social factors. According to the National Health Interview Survey, 50.2 million U.S. adults (20.5%) experience pain on most days, with the annual cost of prescription medication for pain reaching approximately USD 17.8 billion. Theranostic pain nanomedicine therefore emerges as an attractive analgesic strategy with the potential for increased efficacy, reduced side-effects, and treatment personalization. Theranostic nanomedicine combines drug delivery and diagnostic features, allowing for real-time monitoring of analgesic efficacy in vivo using molecular imaging. However, clinical translation of these nanomedicines are challenging due to complex manufacturing methodologies, lack of standardized quality control, and potentially high costs. Quality by Design (QbD) can navigate these challenges and lead to the development of an optimal pain nanomedicine. Our lab previously reported a macrophage-targeted perfluorocarbon nanoemulsion (PFC NE) that demonstrated analgesic efficacy across multiple rodent pain models in both sexes. Here, we report PFC-free, biphasic nanoemulsions formulated with a biocompatible and non-immunogenic plant-based coconut oil loaded with a COX-2 inhibitor and a clinical-grade, indocyanine green (ICG) near-infrared fluorescent (NIRF) dye for parenteral theranostic analgesic nanomedicine. Methods: Critical process parameters and material attributes were identified through the FMECA (Failure, Modes, Effects, and Criticality Analysis) method and optimized using a 3 × 2 full-factorial design of experiments. We investigated the impact of the oil-to-surfactant ratio (w/w) with three different surfactant systems on the colloidal properties of NE. Small-scale (100 mL) batches were manufactured using sonication and microfluidization, and the final formulation was scaled up to 500 mL with microfluidization. The colloidal stability of NE was assessed using dynamic light scattering (DLS) and drug quantification was conducted through reverse-phase HPLC. An in vitro drug release study was conducted using the dialysis bag method, accompanied by HPLC quantification. The formulation was further evaluated for cell viability, cellular uptake, and COX-2 inhibition in the RAW 264.7 macrophage cell line. Results: Nanoemulsion droplet size increased with a higher oil-to-surfactant ratio (w/w) but was no significant impact by the type of surfactant system used. Thermal cycling and serum stability studies confirmed NE colloidal stability upon exposure to high and low temperatures and biological fluids. We also demonstrated the necessity of a solubilizer for long-term fluorescence stability of ICG. The nanoemulsion showed no cellular toxicity and effectively inhibited PGE2 in activated macrophages. Conclusions: To our knowledge, this is the first instance of a celecoxib-loaded theranostic platform developed using a plant-derived hydrocarbon oil, applying the QbD approach that demonstrated COX-2 inhibition. Full article

Background: Cardiovascular diseases, particularly hypertension, and gastrointestinal disorders represent major public health concerns in Mexico. Although a range of pharmacological treatments exists, their use is associated with adverse effects, highlighting the need for safer therapeutic alternatives. Species of the Ipomoea genus are widely employed in Mexican traditional medicine (MTM) for their purgative, anti-inflammatory, analgesic, and sedative properties. Particularly, Ipomoea purpurea is traditionally used as a diuretic and purgative; its leaves and stems are applied topically for their anti-inflammatory and soothing effects. This study aimed to determine their phytochemical composition and to evaluate the associated vasodilatory activity, modulatory effects on intestinal smooth-muscle motility, and toxicological effects of the methanolic (ME-Ip) and dichloromethane (DE-Ip) extracts obtained from the aerial parts of I. purpurea. Methods: The phytochemical composition of the ME-Ip and DE-Ip extracts of I. purpurea was assessed using UPLC-QTOF-MS and GC-MS, respectively. For both extracts, the vasodilatory activity and effects on intestinal smooth muscle were investigated using ex vivo models incorporating isolated rat aorta and ileum, respectively, whereas acute toxicity was evaluated in vivo. Results: Phytochemical analysis revealed, for the first time, the presence of two glycosylated flavonoids within the Ipomoea genus; likewise, constituents with potential anti-inflammatory activity were detected. The identified compounds in I. purpurea extracts may contribute to the vasodilatory, biphasic, and purgative effects observed in this species. The EC₅₀ values for the vasodilatory effects of the methanolic (ME-Ip) and dichloromethane (DE-Ip) extracts were 0.80 and 0.72 mg/mL, respectively. In the initial phase of the experiments on isolated ileal tissues, both extracts induced a spasmodic (contractile) effect on basal motility, with ME-Ip exhibiting higher potency (EC₅₀ = 27.11 μg/mL) compared to DE-Ip (EC₅₀ = 1765 μg/mL). In contrast, during the final phase of the experiments, both extracts demonstrated a spasmolytic effect, with EC₅₀ values of 0.43 mg/mL for ME-Ip and 0.34 mg/mL for DE-Ip. In addition, both extracts exhibited low levels of acute toxicity. Conclusions: The phytochemical profile and the vasodilatory and biphasic effects of the I. purpurea extracts explain, in part, the use of I. purpurea in MTM. The absence of acute toxic effects constitutes a preliminary step in the toxicological safety assessment of I. purpurea extracts and demonstrates their potential for the development of phytopharmaceutic agents as adjuvants for the treatment of cardiovascular and gastrointestinal disorders. Full article

Opioids are among the most effective drugs for treating moderate to severe pain. Unfortunately, opioid use, even short-term, can lead to addiction, tolerance, overdose, and respiratory depression. Therefore, efforts to design and develop novel compounds that would retain analgesic activity while reducing side effects continue unabated. The present study was designed to investigate the respiratory and cardiovascular effects of the hybrid peptide LENART01, which has evidenced potent antinociceptive and antimicrobial activity. This hybrid peptide, composed of N-terminally located dermorphin and C-terminal modified ranatensin pharmacophore, was tested in vivo in anesthetized rats. The main effect of LENART01 was apnea in 70% of examined animals, sighing, and a significant increase in blood pressure. Interestingly, the hybrid induced sighs less frequently than ranatensin, and apnea dependent on vagus nerve mu opioid receptor activation much less frequently and less intensely than dermorphin itself. This shows that LENART01 is a safer opioid system-related agent as compared to dermorphin for its prospective use in the treatment of pain. Full article

Background: Chronic pain poses a major global health burden, often inadequately managed by conventional analgesics due to limited efficacy and side effects. In this context, plant-based therapies offer a promising alternative. This study aimed to evaluate the antioxidant and analgesic potential of four medicinal plants traditionally used for pain relief: Morus alba, Angelica archangelica, Valeriana officinalis, and Passiflora incarnata. Methods: Phytochemical analyses quantified total phenolic acid, flavonoid, and polyphenolic acid contents in the extracts. Antioxidant activity was assessed using the ABTS radical scavenging assay. Analgesic effects were evaluated in vivo using the hot-plate and tail-flick tests in mice treated for 14 days with plant extracts or paracetamol. Results: Morus alba showed the highest polyphenolic content and strongest antioxidant activity (IC₅₀ = 0.0695 mg/mL). In analgesic tests, Angelica archangelica demonstrated the most significant effect in the hot-plate test (72.2% increase in latency), while Valeriana officinalis had the highest efficacy in the tail-flick test (41.81%), exceeding paracetamol’s performance in that model. Conclusions: While antioxidant activity correlated with polyphenol content, analgesic effects appeared to involve additional mechanisms. These findings support the potential of Angelica archangelica and Valeriana officinalis as effective natural alternatives for pain relief. Full article