Search Results (54)

Background: Gastrointestinal endoscopy is crucial for diagnosing colorectal cancer and inflammatory bowel diseases, but its effectiveness can be impacted by peristalsis, poor bowel preparation, and inadequate withdrawal time. Conventional antispasmodics, though effective, may not be suitable for elderly patients or those with comorbidities. L-menthol, derived from peppermint oil, has emerged as a safer alternative. Through calcium channel blockade, L-menthol promotes GI smooth muscle relaxation. This study evaluated L-menthol’s efficacy and safety as a potential alternative to antispasmodic agents in endoscopy. Methods: Following PRISMA2020 guidelines and the Cochrane Handbook, we conducted a systematic review and meta-analysis of randomized controlled trials involving adults undergoing endoscopy, comparing L-menthol to placebo. The primary outcome was the adenoma detection rate, with secondary outcomes, including severity of peristalsis, safety, withdrawal time, and ease of examination. We searched five databases on 31 May 2023, with updates on 20 October 2024. Results: Fourteen studies were included. L-menthol reduced peristalsis during colonoscopy and upper endoscopy, achieving a suppression rate of 55.9% (560/1002 patients; odds ratio (OR) = 3.88, 95% confidence interval (95% CI): 2.13–7.07), which improved mucosal visualization. It improved ease of examination (OR = 2.53, 95% CI: 1.35–4.73), allowing endoscopists to perform procedures with less technical difficulty. However, L-menthol had no significant impact on the adenoma detection rate (OR = 1.06, 95% CI: 0.69–1.64), indicating no added benefit for lesion detection, and did not prolong withdrawal time (MD = 3.24 s, 95% CI: −101.05–107.53). Adverse event rates remained low and comparable to placebo (OR = 0.97, 95% CI: 0.74–1.27). Conclusions: L-menthol reduces peristalsis and enhances ease of examination without adverse events. Although its effect on the adenoma detection rate remains inconclusive, its antispasmodic properties make it a promising alternative for patients who cannot tolerate conventional agents. Full article

Background: Mexico, one of the world’s most biodiverse countries, holds a rich tradition of using medicinal plants to manage chronic diseases such as type 2 diabetes and hypertension. Despite their historical significance, the scientific validation of these plants’ mechanisms and safety remains limited. Natural products have shown potential in improving insulin sensitivity, reducing insulin resistance, and promoting vasodilation. Prostachea livida (Lindl.) W.E.Higgins, a native orchid, is believed to possess therapeutic properties, yet its pharmacological effects are unexplored. Objective: The current investigation is aimed to bridge traditional knowledge and scientific evidence by investigating the antidiabetic, vasodilatory and antihypertensive activities of a 1:1 dichloromethane and methanol extract from Prosthechea livida bulbs, alongside an evaluation of its pharmacological safety. Methods: Antidiabetic effects of the extract were evaluated in a non-insulin-dependent mouse model using a 100 mg/kg dose. Vasodilatory activity was assessed ex vivo using rat aortic rings, exploring its mechanism through calcium channel blockade. Antihypertensive effects were evaluated in spontaneously hypertensive rats, while acute and subacute toxicity tests were conducted in a murine model. Results: The extract significantly reduced glycemia between 1, 3, 5, and 7 h compared to the positive control (* p = 0.04, *** p < 0.001) and induced vasorelaxation but showed no antihypertensive effects in vivo. Toxicity tests indicated no severe damage, though elevated transaminase activity and increased liver weight were observed. Histopathological analysis revealed minimal hepatocellular lesions with active regeneration. Conclusions: Prosthechea livida demonstrates potential in the discovery of active metabolites to treat diabetes, with significant hypoglycemic and vasorelaxant effects and promising pharmacological safety. Further research is needed to fully understand its therapeutic applications and ensure its safe integration. Full article

The search for novel compounds with anticonvulsant properties remains a key focus in neuropharmacology. Recently, the diazepine-benzimidazole derivative, DAB-19, has emerged as a promising candidate due to its demonstrated anxiolytic and analgesic effects. In this study, we investigate the mechanisms underlying DAB-19’s activity, focusing on its impact on glutamatergic transmission, a key target in the pathophysiology of various central nervous system disorders. Intriguingly, while DAB-19 suppressed evoked glutamatergic transmission in rat brain slices, it simultaneously enhanced spontaneous neurotransmission. Further experiments on glutamatergic neuromuscular synapses in fly larvae revealed two distinct mechanisms: calcium-dependent potentiation of glutamate release and inhibition of spike propagation via blockade of voltage-gated sodium channels. The latter effect was directly confirmed in rat brain neurons. Given its action on sodium channels, we tested DAB-19 in the pentylenetetrazole model, where it delayed seizure onset but did not prevent seizures. These findings position DAB-19 as a multifaceted compound with significant therapeutic potential. Full article

Metabolic stress on the heart can cause dilation of coronary arterioles for blood flow recruitment. Although potassium ions (K⁺) released from the myocardium are a major mediator for this response, the underlying signaling pathways for vasodilation are incompletely understood. Herein, the roles of smooth muscle inward-rectifier K⁺ channel subtype 2.1 (K_ir2.1) and Na⁺/K⁺-ATPase were examined. Porcine coronary arterioles were isolated, cannulated, and pressurized for vasomotor study. Vessels developed basal tone and dilated concentration-dependently to extraluminal K⁺ from 7 to 20 mM. Higher K⁺ concentrations (25–40 mM) caused graded vasoconstriction. Vasodilation to K⁺ (10 mM) was not altered by endothelial removal, and blockade of ATP-sensitive K⁺ channels, voltage-sensitive K⁺ channels, or calcium-activated K⁺ channels did not affect K⁺-induced vasodilation. However, sustained but not abrupt transient vasodilation to K⁺ was reduced by the nonspecific K_ir channel inhibitor Ba²⁺ or K_ir2.1 channel blocker chloroethylclonidine. The Na⁺/K⁺-ATPase inhibitor ouabain attenuated K⁺-elicited vasodilation, and ouabain with Ba²⁺ abolished the response. Transfection of arterioles with K_ir2.1 antisense oligonucleotides abolished sustained but not transient dilation. It is concluded that extraluminal K⁺ elevation within the physiological range induces initial transient dilation of porcine coronary arterioles by activating smooth muscle Na⁺/K⁺-ATPase and sustained dilation via smooth muscle K_ir2.1 channels. Full article

Scorpion venom peptides, particularly those derived from Asian species, have garnered significant attention, offering therapeutic potential in pain management, cancer, anticoagulation, and infectious diseases. This review provides a comprehensive analysis of scorpion venom peptides, focusing on their roles as voltage-gated sodium (Nav), potassium (Kv), and calcium (Cav) channel modulators. It analyzed Nav1.7 inhibition for analgesia, Kv1.3 blockade for anticancer activity, and membrane disruption for antimicrobial effects. While the low targeting specificity and high toxicity of some scorpion venom peptides pose challenges to their clinical application, recent research has made strides in overcoming these limitations. This review summarizes the latest progress in scorpion venom peptide research, discussing their mechanisms of action, therapeutic potential, and challenges in clinical translation. This work aims to provide new insights and directions for the development of novel therapeutic drugs. Full article

The healing process involves cell migration, which is sustained by an electrical potential difference that emerges between the edges of skin wounds and the center of the wound. The electrical potential in cells’ membranes is responsible for their migration in an electric field. The differences in the transmembrane electrochemical gradient generate this potential. The concomitant blockade of potassium and calcium channels by amiodarone at a medium dosage favored wound healing, but the effect was less intense than in the case of the selective blocking of potassium channels. According to this suggestion, blocking calcium channels might have a partial effect on blocking potassium channels. Given that nimodipine inhibits both L-type and T-type calcium channels, we aimed to investigate which of these calcium channels are involved in wound healing. Hence, we performed an experimental study in which nimodipine was used in three concentrations: 200 nM, which blocks only L-type calcium channels, 1000 nM, which blocks both L-type and T-type calcium channels, and 10,000 nM, which blocks calcium channels and activates CB1 cannabinoid receptors, respectively. The present research is a continuation of previous studies conducted by us, aimed to propose new perspectives on wound treatment. In conclusion, the blocking of calcium channels favored wound healing under our experimental conditions, but this happened only by simultaneously blocking the L-type and T-type calcium channels, because only the medium nimodipine concentration had a statistically significant effect. Full article

Arterial hypertension is a highly prevalent chronic disease worldwide, with several etiologies and treatments that may eventually have side effects or result in patients developing tolerance. There is growing interest in traditional medicine and functional foods to isolate biomolecules that could be useful as coadjuvants for treating several aliments. Pitaya, a desert fruit endemic in Mexico, is a rich source of bioactive molecules (betalains and phenolic compounds). In this work, the vasorelaxation properties of pitaya juice concentrate and fraction one were investigated using aortic and mesenteric rings from rats. The incubation of rings with pitaya juice concentrate or fraction one induced significant vasorelaxation, independent of the endothelium, and showed resistance to potassium channel blockers. This vasorelaxation was associated with the transmembrane influx of extracellular calcium through the vascular smooth muscle cells, with an inhibitory effect on the voltage-dependent calcium channel currents. Also, 400 mg/mL of pitaya juice concentrate in spontaneous hypertensive rats reduced their blood pressure for 48 h. Phytochemical analyses showed that the primary compounds in F1 were glycosidic in nature, and could be a complex mixture of disaccharides, dimeric disaccharides, or even tetrasaccharides. The glycosidic compounds found in F1 primarily contributed to vasodilatation, establishing a voltage-dependent calcium channel inhibition as a possible molecular target. Full article

5β-Dihydrosteroids are produced by the reduction of Δ⁴-3-ketosteroids catalyzed by steroid 5β-reductase (AKR1D1). By analogy with steroid 5α-reductase, genetic deficiency exists in AKR1D1 which leads to errors in newborn metabolism and in this case to bile acid deficiency. Also, like the 5α-dihydrosteroids (e.g., 5α-dihydrotestosterone), the 5β-dihydrosteroids produced by AKR1D1 are not inactive but regulate ligand access to nuclear receptors, can act as ligands for nuclear and membrane-bound receptors, and regulate ion-channel opening. For example, 5β-reduction of cortisol and cortisone yields the corresponding 5β-dihydroglucocorticoids which are inactive on the glucocorticoid receptor (GR) and provides an additional mechanism of pre-receptor regulation of ligands for the GR in liver cells. By contrast, 5β-pregnanes can act as neuroactive steroids at the GABA_A and NMDA receptors and at low-voltage-activated calcium channels, act as tocolytic agents, have analgesic activity and act as ligands for PXR, while bile acids act as ligands for FXR and thereby control cholesterol homeostasis. The 5β-androstanes also have potent vasodilatory properties and work through blockade of Ca²⁺ channels. Thus, a preference for 5β-dihydrosteroids to work at the membrane level exists via a variety of mechanisms. This article reviews the field and identifies gaps in knowledge to be addressed in future research. Full article

The incidence of cardiovascular diseases, such as high blood pressure, is increasing worldwide, owing to population aging and irregular lifestyle habits. Previous studies have reported the vasorelaxant effects of Prunus yedoensis bark methanol extract. However, various solvent extracts of P. yedoensis bark and their vascular relaxation mechanisms have not been sufficiently studied. We prepared extracts of P. yedoensis bark using various solvents (water, 30% ethanol, and 70% ethanol). P. yedoensis bark 30% ethanol extract (PYB-30E) decreased the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin in human umbilical vein endothelial cells (HUVECs) activated with 200 ng/mL TNF-α. Additionally, PYB-30E showed vasodilatory effects on isolated rat aortic rings. This was confirmed to be the result of the activation of the NO/cGMP pathway, regulation of non-selective calcium-activated K⁺ channels, and calcium channel blockade. Additionally, PYB-30E significantly reduced systolic and diastolic blood pressure in spontaneously hypertensive rats (SHR). Taken together, our results indicated that PYB-30E is a candidate functional material with preventive and therapeutic effects against hypertension. Full article

Natural compounds, known for diverse pharmacological properties, have attracted attention as potential sources for hypertension treatment. Previous studies have revealed the hypotensive effect and vascular relaxation of prunetin, a natural compound derived from Prunus yedoensis. However, the potential blood pressure-lowering and vasorelaxant effects of sakuranetin, another representative compound found in plants belonging to the genus Prunus, have remained unexplored. We aimed to fill this gap by investigating the hypotensive and vasorelaxant effects of sakuranetin in rats. Results indicated that sakuranetin, particularly in the sakuranetin 20 mg/kg group, led to significant reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) by −14.53 ± 5.64% and −19.83 ± 6.56% at 4 h after administration. In the sakuranetin 50 mg/kg group, the SBP and DBP decreased by −13.27 ± 6.86% and −16.62 ± 10.01% at 2 h and by −21.61 ± 4.49% and −30.45 ± 5.21% at 4 h after administration. In addition, we identified the vasorelaxant effects of sakuranetin, attributing its mechanisms to the inhibition of calcium influx and the modulation of angiotensin II. Considering its hypotensive and vasorelaxant effects, sakuranetin could potentially serve as an antihypertensive agent. However, further research is required to evaluate the safety and long-term efficacy. Full article

This work relates to the design and synthesis of a series of novel multi-target directed ligands (MTDLs), i.e., compounds 4a–l, via a convenient one-pot three-component Hantzsch reaction. This approach targeted calcium channel antagonism, antioxidant capacity, cathepsin S inhibition, and interference with Nrf2 transcriptional activation. Of these MTDLs, 4i emerged as a promising compound, demonstrating robust antioxidant activity, the ability to activate Nrf2-ARE pathways, as well as calcium channel blockade and cathepsin S inhibition. Dihydropyridine 4i represents the first example of an MTDL that combines these biological activities. Full article

Cocaine abuse is a serious public health problem as this drug exerts a plethora of functional and histopathological changes that potentially lead to death. Cocaine causes complex multiorgan toxicity, including in the heart where the blockade of the sodium channels causes increased catecholamine levels and alteration in calcium homeostasis, thus inducing an increased oxygen demand. Moreover, there is evidence to suggest that mitochondria alterations play a crucial role in the development of cocaine cardiotoxicity. We performed a systematic review according to the Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA) scheme to evaluate the mitochondrial mechanisms determining cocaine cardiotoxicity. Among the initial 106 articles from the Pubmed database and the 17 articles identified through citation searching, 14 final relevant studies were extensively reviewed. Thirteen articles included animal models and reported the alteration of specific mitochondria-dependent mechanisms such as reduced energy production, imbalance of membrane potential, increased oxidative stress, and promotion of apoptosis. However, only one study evaluated human cocaine overdose samples and observed the role of cocaine in oxidative stress and the induction of apoptosis though mitochondria. Understanding the complex processes mediated by mitochondria through forensic analysis and experimental models is crucial for identifying potential therapeutic targets to mitigate or reverse cocaine cardiotoxicity in humans. Full article

The aim of this work was to evaluate the vasorelaxant and antihypertensive effects of a standardized precipitate of the hydroalcoholic extract from Agastache mexicana (PPAm), comprising ursolic acid, oleanolic acid, acacetin, luteolin and tilianin, among others. In the ex vivo experiments, preincubation with L-NAME (nonspecific inhibitor of nitric oxide synthases) reduced the relaxation induced by PPAm; nevertheless, preincubation with indomethacin (nonspecific inhibitor of cyclooxygenases) did not generate any change in the vasorelaxation, and an opposed effect was observed to the contraction generated by CaCl₂ addition. Oral administration of 100 mg/kg of PPAm induced a significant acute decrease in diastolic (DBP) and systolic (SBP) blood pressure in spontaneously hypertensive rats, without changes in heart rate. Additionally, PPAm showed a sustained antihypertensive subacute effect on both DBP and SBP for 10 days compared to the control group. On the other hand, human umbilical vein cells treated with 10 µg/mL of PPAm showed a significant reduction (p < 0.05) in intracellular adhesion molecule-1, compared to the control, but not on vascular cell adhesion molecule-1. In conclusion, PPAm induces a significant antihypertensive effect in acute- and subacute-period treatments, due to its direct vasorelaxant action on rat aortic rings through NO production and Ca²⁺ channel blockade. Full article

The pharmacological treatment of postherpetic neuralgia (PHN) is unsatisfactory, and there is a clinical need for new approaches. Several drugs under advanced clinical development are addressed in this review. A systematic literature search was conducted in three electronic databases (Medline, Web of Science, Scopus) and in the ClinicalTrials.gov register from 1 January 2016 to 1 June 2023 to identify Phase II, III and IV clinical trials evaluating drugs for the treatment of PHN. A total of 18 clinical trials were selected evaluating 15 molecules with pharmacological actions on nine different molecular targets: Angiotensin Type 2 Receptor (AT2R) antagonism (olodanrigan), Voltage-Gated Calcium Channel (VGCC) α2δ subunit inhibition (crisugabalin, mirogabalin and pregabalin), Voltage-Gated Sodium Channel (VGSC) blockade (funapide and lidocaine), Cyclooxygenase-1 (COX-1) inhibition (TRK-700), Adaptor-Associated Kinase 1 (AAK1) inhibition (LX9211), Lanthionine Synthetase C-Like Protein (LANCL) activation (LAT8881), N-Methyl-D-Aspartate (NMDA) receptor antagonism (esketamine), mu opioid receptor agonism (tramadol, oxycodone and hydromorphone) and Nerve Growth Factor (NGF) inhibition (fulranumab). In brief, there are several drugs in advanced clinical development for treating PHN with some of them reporting promising results. AT2R antagonism, AAK1 inhibition, LANCL activation and NGF inhibition are considered first-in-class analgesics. Hopefully, these trials will result in a better clinical management of PHN. Full article

The apical dendrite of a cortical projection neuron (CPN) is generated from the leading process of the migrating neuron as the neuron completes migration. This transformation occurs in the cortical marginal zone (MZ), a layer that contains the Cajal-Retzius neurons and their axonal projections. Cajal-Retzius neurons (CRNs) are well known for their critical role in secreting Reelin, a glycoprotein that controls dendritogenesis and cell positioning in many regions of the developing brain. In this study, we examine the possibility that CRNs in the MZ may provide additional signals to arriving CPNs, that may promote the maturation of CPNs and thus shape the development of the cortex. We use whole embryonic hemisphere explants and multiphoton microscopy to confirm that CRNs display intracellular calcium transients of <1-min duration and high amplitude during early corticogenesis. In contrast, developing CPNs do not show high-amplitude calcium transients, but instead show a steady increase in intracellular calcium that begins at the time of dendritic initiation, when the leading process of the migrating CPN is encountering the MZ. The possible existence of CRN to CPN communication was revealed by the application of veratridine, a sodium channel activator, which has been shown to preferentially stimulate more mature cells in the MZ at an early developmental time. Surprisingly, veratridine application also triggers large calcium transients in CPNs, which can be partially blocked by a cocktail of antagonists that block glutamate and glycine receptor activation. These findings outline a model in which CRN spontaneous activity triggers the release of glutamate and glycine, neurotransmitters that can trigger intracellular calcium elevations in CPNs. These elevations begin as CPNs initiate dendritogenesis and continue as waves in the post-migratory cells. Moreover, we show that the pharmacological blockade of glutamatergic signaling disrupts migration, while forced expression of a bacterial voltage-gated calcium channel (CavMr) in the migrating neurons promotes dendritic growth and migration arrest. The identification of CRN to CPN signaling during early development provides insight into the observation that many autism-linked genes encode synaptic proteins that, paradoxically, are expressed in the developing cortex well before the appearance of synapses and the establishment of functional circuits. Full article