Frontiers in Pharmacology最新文献

Introduction: Diabetes is a major health issue that has reached alarming levels worldwide. Although their effectiveness, the antidiabetic drugs have many side effects such as cardiovascular diseases, kidney failure, and hepatic complications. Many plant species of the genus Salvia L. such as "Arabian desert sage" (Salvia deserti) should began to be the focus of phytochemical and bioactivity studies.

Methods: The study aims to investigate, first-ever, the antidiabetic and antihyperlipidemic effects of the leaf hydroethanolic extract of S. deserti, an endemic and rare subshrub from Arabian desert. A single intraperitoneal injection of alloxan monohydrate (160 mg/kg) was used to induce type-2 diabetes. Development of diabetes was confirmed by measuring the blood glucose collected from the tail vein after 72 h of alloxan injection. Oral administration of hydroethanolic extracts of S. deserti at 200 and 400 mg/kg for 14 days were tested on the alloxan-induced diabetic mice and animals were divided into 6 groups of 6 mice each. The identity of phenolic compounds of the hydroethanolic extract of S. deserti was conducted through HPLC-Electrospray Ionization-Mass Spectrometry (LC-ESI-MS) analyses.

Results: Oral administration of hydroethanolic extract of S. deserti at 200 and 400 mg/kg for 14 days significantly decreased blood glucose and restored the hepatic and renal function by reducing the levels of ALT, AST, ALP, GGT, LDH, urea and creatinine. An improved lipid profile as revealed by the reduced levels of TC, TG and LDL coupled with increased level of HDL was also observed. Moreover, treatment with S. deserti hydroethanolic extract relieved oxidative stress (reduction of MDA and H₂O₂) and the activity of antioxidant enzymes SOD, CAT and GPx. The presence of several phenolic compounds (derivatives of ferulic, coumaric, and caffeic acids, among other derivatives) could at least in part explain the obtained data and empower the use of S. deserti as a source of bioactive ingredients with antioxidant, antidiabetic and antihyperlipidemic properties.

Discussion: Our research has unveiled S. deserti as a source of potential to effectively manage diabetes and its associated dyslipidemia by improving antioxidant status, recovery of the liver and kidney functions and presumably by increasing insulin secretion and sensitivity of peripheral tissues to insulin.

Ethnopharmacological studies revealed that the leaves and stems of Mimosa pudica L. (Fabaceae) are widely used for the treatment of epilepsy. This study sought to investigate the effects of the aqueous extract of Mimosa pudica leaves and stems against pilocarpine-picrotoxin kindling-induced temporal lobe epilepsy in mice and its implication on oxidative/nitrosative stress, GABAergic/cholinergic signalling, and brain-derived neurotrophic factor (BDNF) expression. The animals were treated for seven consecutive days as follows: one normal group and one negative control group that received orally distilled water; four test groups that received orally four doses of Mimosa pudica (20, 40, 80, and 160 mg/kg), respectively; and one positive control group that received 300 mg/kg sodium valproate intraperitoneally. One hour after the first treatment (first day), status epilepticus was induced by intraperitoneal injection of a single dose of pilocarpine (360 mg/kg). Then, 23 hours after the injection of pilocarpine to the mice, once again, they received their different treatments. Sixty minutes later, they were injected with a sub-convulsive dose of picrotoxin (1 mg/kg), and the anticonvulsant property of the extract was determined. On day 7, open-field, rotarod, and catalepsy tests were performed. Finally, the mice were sacrificed, and the hippocampi were isolated to quantify some biochemical markers of oxidative/nitrosative stress, GABAergic/cholinergic signalling, and BDNF levels in the hippocampus. Mimosa pudica extracts (160 mg/kg) significantly increased the latency time to status epilepticus by 70.91%. It significantly decreased the number of clonic and tonic seizures to 9.33 ± 1.03 and 5.00 ± 0.89, and their duration to 11.50 ± 2.07 and 6.83 ± 0.75 s, respectively. Exploratory behaviour, motor coordination, and catalepsy were significantly ameliorated, respectively, in the open-field, rotarod, and catalepsy tests. Pilocarpine-picrotoxin-induced alteration of oxidant-antioxidant balance, GABA-transaminase stability, acetylcholinesterase/butyrylcholinesterase activity, and neurogenesis were attenuated by the extract (80-160 mg/kg). This study showed that the aqueous extract of Mimosa pudica leaves and stems ameliorated epileptogenesis of temporal lobe epilepsy and could be used for the treatment of temporal lobe epilepsy.

Antibody-drug conjugates (ADCs) offer targeted cancer therapy by delivering cytotoxic agents directly to tumor cells. However, challenges such as relapse, resistance, and diverse patient needs drive ongoing innovation in ADC development. Exploration of new small-molecule toxins with unique antitumor and toxicity profiles is crucial. Tub114, a novel Tubulysin B analog with a hydrophilic ethylene glycol moiety, has been conjugated to the anti-HER2 antibody DX-CHO9, forming the ADC DX126-262. This study examines the efficacy, pharmacokinetics, and safety profile of DX126-262, with a focus on Tubulysin-associated liver toxicity. In vivo efficacy was assessed using three HER2-positive tumor models, with dose-dependent tumor growth inhibition compared to established treatments. Pharmacokinetic studies were conducted in cynomolgus monkeys across a dosing range (3-30 mg/kg) to compare clearance and stability with Kadcyla and Enhertu. Acute toxicity assays were conducted in mice (75 and 150 mg/kg doses), and repeated-dose toxicity was evaluated over five doses, administered every 3 weeks in rats and cynomolgus monkeys. DX126-262 demonstrated significant and dose-dependent tumor growth inhibition across HER2-positive models, with superior antitumor efficacy compared to Kadcyla and comparable efficacy to Enhertu in vivo studies. In pharmacokinetic studies, DX126-262 exhibited a clearance rate similar to Enhertu and enhanced stability compared to Kadcyla. Acute toxicity assays revealed reduced hepatotoxicity at doses of 75 and 150 mg/kg in mice, with improved tolerance. In repeated-dose toxicity studies, DX126-262 was well tolerated in rats at doses up to 200 mg/kg, with the highest non-severely toxic dose (HNSTD) established at 100 mg/kg. In cynomolgus monkeys, DX126-262 demonstrated superior hepatotoxic tolerability without significant bone marrow suppression, with an HNSTD of 30 mg/kg. DX126-262, incorporating Tub114, a novel Tubulysin B analog, effectively mitigates the inherent hepatotoxicity associated with Tubulysin compounds while maintaining strong antitumor efficacy. These findings suggest that DX126-262 could serve as a safer and more effective option for HER2-targeted cancer therapy, warranting further clinical studies to confirm its therapeutic potential.

As an active constituent in the extract of dried fruits of Schisandra chinensis, Schisandrin B exhibits diverse pharmacological effects, including liver protection, anti-inflammatory and anti-oxidant. Numerous studies have demonstrated that Schisandrin B exhibits significant antitumor activity against various malignant tumors in preclinical studies, which is achieved by inhibiting cell proliferation and metastasis and promoting apoptosis. As a potential antitumor agent, Schisandrin B holds broad application prospects. This review systematically elaborates on the antitumor effect of Schisandrin B and the related molecular mechanism, and preliminarily predicts its antitumor targets by network pharmacology, thereby pave the way for further research, development, and clinical application.

Background: Prostate cancer (PCa) is one of the prevalent malignant tumors among men. It can progress to castration-resistant prostate cancer (CRPC), which is significantly more challenging to treat. Saikosaponin A (SSA), a triterpenoid saponin extracted from the genus Bupleurum, exerts numerous pharmacological effects, including anti-inflammatory and anti-tumorigenic effects. However, the mechanism underlying the effects of SSA in prostate cancer treatment remains elusive.

Methods: In this study, a network pharmacology approach was applied to identify relevant targets from drug- and disease-related databases, and intersections were analyzed using Venny2.1 to construct a Protein-Protein interaction (PPI) interaction network. Next, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to elucidate associated biological functions and signaling pathways. Meanwhile, molecular docking between core targets and SSA was performed using Autodock software. Lastly, in vitro experiments were performed for validation.

Results: A least of four key targets, namely BCL2 apoptosis regulator (BCL2), estrogen receptor 1 (ESR1), hypoxia-inducible factor 1 subunit alpha (HIF1A), and signal transducer and activator of transcription 3 (STAT3) were identified in this study, and molecular docking analyses revealed that SSA stably binds to these targets. Moreover, the results of in vitro experiments revealed that SSA significantly inhibited the proliferative and migratory abilities of PC3 cells in a dose-dependent manner. Finally, SSA also induced G1-phase blockade and apoptosis in PC3 cells, further highlighting its potential role in prostate cancer treatment.

Conclusion: The present study revealed that SSA exerts anti-tumorigenic effects in prostate cancer by targeting multiple pathways, laying a theoretical reference for its use as a therapeutic candidate for prostate cancer.

Diabetes mellitus (DM) and its various complications, including diabetic nephropathy, retinopathy, neuropathy, cardiovascular disease, and ulcers, pose significant challenges to global health. This review investigates the potential of procyanidins (PCs), a natural polyphenolic compound, in preventing and managing diabetes and its complications. PCs, recognized for their strong antioxidant, anti-inflammatory, and anti-hyperglycemic properties, play a crucial role in reducing oxidative stress and enhancing endothelial function, which are essential for managing diabetic complications. This review elucidates the molecular mechanisms by which PCs improve insulin sensitivity and endothelial health, thereby providing protection against the various complications of diabetes. The comprehensive analysis underscores the promising therapeutic role of PCs in diabetes care, indicating the need for further clinical studies to confirm and leverage their potential in comprehensive diabetes management strategies.

Mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) are increasingly recognized for their therapeutic potential in regenerative medicine, driven by their capabilities in immunomodulation and tissue repair. However, MSCs present risks such as immunogenic responses, malignant transformation, and the potential to transmit infectious pathogens due to their intrinsic proliferative and differentiative abilities. In contrast, MSC-EVs, particularly exosomes (MSC-exosomes, 30-150 nm in diameter), offer a safer therapeutic profile. These acellular vesicles mitigate risks associated with immune rejection and tumorigenesis and are inherently incapable of forming ectopic tissues, thereby enhancing their clinical safety and applicability. This review highlights the therapeutic promise of MSC-exosomes especially focusing on the modulation of miRNA (one of bioactive molecules in MSC-EVs) profiles through various preconditioning strategies such as exposure to hypoxia, chemotherapeutic agents, inflammatory cytokines, and physical stimuli. Such conditioning is shown to optimize their therapeutic potential. Key miRNAs including miR-21, miR-146, miR-125a, miR-126, and miR-181a are particularly noted for their roles in facilitating tissue repair and modulating inflammatory responses. These functionalities position MSC-exosomes as a valuable tool in personalized medicine, particularly in the case of exosome-based interventions. Despite the potential of MSC-EVs, this review also acknowledged the limitations of traditional MSC therapies and advocates for a strategic pivot towards exosome-based modalities to enhance therapeutic outcomes. By discussing recent advances in detail and identifying remaining pitfalls, this review aims to guide future directions in improving the efficacy of MSC-exosome-based therapeutics. Additionally, miRNA variability in MSC-EVs presents challenges due to the diverse roles of miRNAs play in regulating gene expression and cell behavior. The miRNA content of MSC-EVs can be influenced by preconditioning strategies and differences in isolation and purification methods, which may alter the expression profiles of specific miRNAs, contributing to differences in their therapeutic effects.

Diabetic kidney disease is one of the common complications in diabetic patients and has gradually become an important pathogenic factor in chronic kidney disease. Therefore, studying the mechanisms of its occurrence and development is of great significance for the prevention and treatment of diabetic kidney disease. Some researchers have pointed out that there is a phenomenon of hypoxia in diabetic kidney tissue and believe that hypoxia-inducible factor-1α is closely related to the occurrence and progression of diabetic kidney disease. Additionally, the homeostasis of zinc plays a key role in the body's adaptation to hypoxic environments. However, the specific relationship among these three factors remains unclear. This article provides a detailed review of the multiple roles of hypoxia-inducible factor-1α in the pathogenesis of diabetic kidney disease, including: regulating angiogenesis, increasing the expression of erythropoietin, modulating oxidative stress through the PI3K/AKT and HIF-1α/HO-1 pathways, promoting inflammatory cell infiltration and the release of inflammatory factors to induce inflammatory responses, facilitating epithelial-mesenchymal transition, pathological angiogenesis, and promoting the release of fibrotic factors, ultimately leading to renal fibrosis. Furthermore, HIF-1α also participates in the occurrence and development of diabetic kidney disease through mechanisms such as regulating apoptosis, inducing mitochondrial autophagy, and vascular calcification. At the same time, this article clarifies the regulatory role of the trace element zinc on hypoxia-inducible factor-1α in diabetic kidney disease. This article provides references and insights for further research on the pathogenesis and progression of diabetic kidney disease.

Objective: This study aimed to evaluate the safety profile of sevoflurane in pediatric populations using real-world data.

Methods: Data were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS) from the first quarter of 2004 to the third quarter of 2024. We analyzed reports where sevoflurane was the primary suspect in individuals aged 0-18, employing disproportionality analysis to detect adverse events associated with sevoflurane. We also compared the adverse events related to sevoflurane between pediatric and adult populations.

Results: The FAERS database yielded 21,838,627 adverse event reports for children, with 474 involving sevoflurane as the primary suspect. Descriptive analysis revealed a majority of reports from male patients, primarily reported by physicians. Disproportionality analysis identified significant System Organ Classes (SOC) signals associated with sevoflurane, meeting four detection criteria, including "Cardiac disorders," "Respiratory, thoracic, and mediastinal disorders," and "Vascular disorders." The study also identified previously unreported adverse events, such as "Encephalopathy" and "Hypercapnia." Notable differences in signals were observed between children and adults for "Pulmonary alveolar hemorrhage," "Anaphylactic shock," and "Hypotension."

Conclusion: Our analysis of the FAERS database identified several significant adverse events associated with sevoflurane in pediatrics, affecting the cardiovascular, respiratory, and nervous systems. Differences in adverse event signals between children and adults were also observed. Furthermore, the new adverse events (such as encephalopathy and hypercapnia) indicated that anesthesiologists should be more vigilant in administering sevoflurane.