Garcinia lucida is used in Cameroonian folk medicine to handle a variety of ailments, including arterial hypertension. This study aimed at determining the phytochemical profile and the antihypertensive effect of the stem bark aqueous extract of G. lucida (AEGL). AEGL was subjected to LC-MS analysis, and its effect (75, 150, and 300 mg/kg/day; by gavage) was evaluated against Nω-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg)-induced hypertension in adult male Wistar rats for four consecutive weeks. Blood pressure and heart rate were monitored weekly using tail-cuff plethysmography. The vasorelaxant effect of cumulative concentrations (3-10-30-100-300 μg/mL) of AEGL was examined on endothelium-intact and denuded thoracic aorta rings which were precontracted with KCl (90 mM) or norepinephrine (NE; 10^-5 M), and in the absence or presence of L-NAME (10^-4 M), indomethacin (10^-5 M), methylene blue (10^-6 M), tetraethylammonium (TEA, 5 × 10^-6 M), glibenclamide (10 × 10^-6 M) or propranolol (5 × 10^-6 M). The influence of AEGL on the response to NE, KCl, and CaCl₂ was also investigated. Six compounds, including Garcinia biflavonoids GB1 and GB2, were identified. AEGL prevented the development of hypertension (p < 0.01 and p < 0.001) without affecting the heart rate. AEGL induced a concentration-dependent relaxation of aortic rings precontracted with NE (EC₅₀ = 7.915 μg/mL) that was significantly inhibited by the removal of the endothelium, L-NAME, or methylene blue (p < 0.05-0.001). Indomethacin, propranolol, TEA, and glibenclamide did not affect AEGL-evoked vasorelaxation. Preincubation of aortic rings with AEGL reduced the magnitude of contraction elicited by CaCl₂ but did not alter that of KCl or NE. AEGL possesses an antihypertensive effect that is mediated by both endothelium-dependent and endothelium-independent mechanisms. The activation of the NO/sGC/cGMP pathway accounts for the endothelium-dependent vasorelaxation. These pharmacological effects of AEGL could be attributed to the presence of the Garcinia biflavonoids GB1 and GB2.

The antidiabetic effects of the methanol extract of the stem bark of Ceiba pentandra (Cp) have been demonstrated in various experimental models. Besides, this extract is rich in 8-formyl-7-hydroxy-5-isopropyl-2-methoxy-3-methyl-1,4-naphthaquinone, 2,4,6-Trimethoxyphenol and vavain. However, it remains unknown whether Cp can mitigate cardiometabolic syndrome (CMS). The present study assessed the curative properties of Cp against Monosodium Glutamate (MSG)-induced CMS in rats. Male neonate Wistar rats were intraperitoneally administered with MSG (4 mg/g/day) during the first 5 days of life (postnatal days 2-6). They were kept under standard breeding conditions up to 5 months of age for the development of CMS. Diseased animals were then orally treated with atorvastatin (80 mg/kg/d) or Cp (75 and 150 mg/kg/day) for 28 days during which food intake, body mass, blood pressure, heart rate, glucose, and insulin tolerance were monitored. Plasma and tissues were collected on day 29th to assess the lipid profile, oxidative stress, and inflammatory parameters. The histomorphology of the adipose tissue was also evaluated. Cp significantly (p < 0.001) reduced the obesogenic and lipid profiles, adipocyte size, blood pressure, and oxidative and inflammatory status in MSG-treated rats. Cp also ameliorated glucose (p < 0.05) and insulin sensitivities (p < 0.001) hence, reducing animals' cardiometabolic risk score (p < 0.001). The curative effect of Cp on cardiometabolic syndrome is related to its capacity to reduce oxidative stress, inflammation, dyslipidemia, and increase insulin sensitivity. These results demonstrate the potential of Cp as a good candidate for alternative treatment of CMS.

Marine cyanobacteria have gained momentum in recent years as a source of novel bioactive small molecules. This paper describes the structure elucidation and pharmacological evaluation of two new, veraguamide O ( 1 ) and veraguamide P ( 2 ), and one known, veraguamide C( 3 ), analogs isolated from a cyanobacterial collection made in the Las Perlas Archipelago of Panama. We hypothesized that these compounds would be cytotoxic in cancer cell lines. The compounds were screened against HEK-293, estrogen receptor positive (MCF-7), and triple-negative breast cancer (MDA-MB-231) cells as well as against a broad panel of membrane bound receptors. The planar structures were determined based on NMR and MS data along with comparison to previously isolated veraguamide analogs. Phylogenetic analysis of the collection suggests it to be an Okeania sp., a similar species to the cyanobacterium reported to produce other veraguamides. Veraguamide O shows no cytotoxicity (greater than 100 M) against ER positive cells (MCF-7) with 13 M IC ₅₀ against MDA-MB-231 TNBC cells. Interestingly, these compounds show affinity for the sigma2/TMEM-97 receptor making them potential leads for development of non-toxic sigma 2 targeting ligands.

Chronic pain is a major global health issue, yet effective treatments are limited by poor translation from preclinical studies to humans. To address this, we developed a high-content screening (HCS) platform for analgesic discovery using hiPSC-derived nociceptors. These cells were cultured on multi-well micro-electrode arrays to monitor activity, achieving nearly 100% active electrodes by week two, maintaining stable activity for at least two weeks. After maturation (28 days), we exposed the nociceptors to various drugs, assessing their effects on neuronal activity, with excellent assay performance (Z’ values >0.5). Pharmacological tests showed responses to analgesic targets, including ion channels (Nav, Cav, Kv, TRPV1), neurotransmitter receptors (AMPAR, GABA-R), and kinase inhibitors (tyrosine, JAK1/2). Transcriptomic analysis confirmed the presence of these drug targets, although expression levels varied compared to primary human dorsal root ganglion cells. This HCS platform facilitates the rapid discovery of novel analgesics, reducing the risk of preclinical-to-human translation failure. Motivation: Chronic pain affects approximately 1.5 billion people worldwide, yet effective treatments remain elusive. A significant barrier to progress in analgesic drug discovery is the limited translation of preclinical findings to human clinical outcomes. Traditional rodent models, although widely used, often fail to accurately predict human responses, while human primary tissues are limited by scarcity, technical difficulties, and ethical concerns. Recent advancements have identified human induced pluripotent stem cell (hiPSC)-derived nociceptors as promising alternatives; however, current differentiation protocols produce cells with inconsistent and physiologically questionable phenotypes. To address these challenges, our study introduces a novel high-content screening (HCS) platform using hiPSC-derived nociceptors cultured on multi-well micro-electrode arrays (MEAs). The “Anatomic” protocol, used to generate these nociceptors, ensures cells with transcriptomic profiles closely matching human primary sensory neurons. Our platform achieves nearly 100% active electrode yield within two weeks and demonstrates sustained, stable activity over time. Additionally, robust Z’ factor analysis (exceeding 0.5) confirms the platform’s reliability, while pharmacological validation establishes the functional expression of critical analgesic targets. This innovative approach improves both the efficiency and clinical relevance of analgesic drug screening, potentially bridging the translational gap between preclinical studies and human clinical trials, and offering new hope for effective pain management.

This study reveals that locomotion speed is encoded in mouse primary motor cortex through a sigmoidal state-transition mechanism carried by two functionally distinct spiking populations with a shared speed threshold. Using high-density laminar recordings and markerless motion tracking, we show that this framework extends to local field potentials and enables accurate, generalizable decoding. These findings establish a push-pull sigmoidal architecture and highlight implications for stable, calibration-light brain-machine interface design.

Ver E’s structure was validated by ¹H NMR, HRMS, and molecular networking analyses. Computational docking and NMR titration confirmed direct, saturable, and tight binding of Ver E to the human Sigma-2 receptor/transmembrane protein 97 (σ₂R/TMEM97). Functional calcium imaging in primary mouse sensory neurons revealed that Ver E increases intracellular Ca²⁺ levels without modulating store-operated calcium entry (SOCE). Multi-well microelectrode array experiments using human induced pluripotent stem cell (hiPSC) derived nociceptors showed that Ver E significantly reduced neuronal activity at physiological temperatures, but not under heat-stress conditions. Ver E exhibited no cytotoxicity at concentrations up to 30 µM in HEK293 cells, and immunocytochemistry confirmed that it does not alter phosphorylated eIF2α (p-eIF2α) expression, indicating a mechanism distinct from integrated stress response modulators. Collectively, these findings position Ver E as a non-toxic compound capable of selectively modulating neuronal excitability, thereby advancing the development of novel therapeutics for pain management. Significance Natural products have long been recognized as a rich source of therapeutics, accounting for over 60% of currently approved small-molecule drugs and underscoring their pivotal role in drug discovery. Marine cyanobacteria produce structurally diverse secondary metabolites with a wide array of biological activities. Among these are the veraguamides, a family of depsipeptides that have shown promise as future therapeutics in our recent studies. This work presents a detailed biological and chemical characterization of veraguamide E (Ver E), isolated from a Panamanian marine cyanobacterial collection. The σ₂R/TMEM97 system has been identified as a promising target to address unmet need for non-opioid therapeutics which can modulate neuronal excitability in the context of chronic pain. Discovery and identification of novel compounds which modulate this system can help us better understand its function as well as allow us to develop future therapeutics targeting this pathway. Highlights Veraguamide E specifically binds σ₂R/TMEM97 receptor with high affinity. Computational docking and NMR confirm a distinct binding mechanism. Ver E modulates calcium signaling in mouse DRG neurons and human iPSC-derived nociceptors. Ver E demonstrates no detectable cytotoxicity in human cell lines.