Chronic pain represents a significant global health challenge, and the limitations of conventional analgesics have urged a search for alternative therapeutic strategies. Cannabinoids derived from Cannabis sativa have emerged as prominent candidates. While psychotropic cannabinoids are known for their analgesic effects, their psychoactive properties often limit their clinical utility. Consequently, interest has shifted towards non-psychotropic cannabinoids that offer potential pain relief without inducing cognitive or euphoric effects. This comprehensive review investigates the pain-modulating mechanisms of cannabinoids, encompassing interactions with the endocannabinoid system and other non-traditional pathways, and summarizes the existing preclinical and clinical evidence supporting their use in various pain states. Furthermore, it discusses the therapeutic potential, clinical considerations, significant challenges, and the need for product standardization. This review also aims to evaluate the role and prospects of non-psychotropic cannabinoids as a therapeutic option for pain management.
Objective: To evaluate the hepatoprotective effects of skate-derived bioactives—collagen peptides (CPs) and chondroitin—against ethanol (EtOH)-induced liver injury and to elucidate their underlying mechanisms.
Methods: The protective effects of CPs and chondroitin were assessed in different in vitro and in vivo EtOH-induced injury models. Oxidative stress was evaluated by measuring reactive oxygen species production and antioxidant markers (NRF2 and GCLC). EtOH metabolism was examined by measuring alchohol-metabolizing enzymes (alcohol dehydrogenase and aldehyde dehydrogenase) and cytochrome P450 enzymes. Furthermore, lipid dysregulation was assessed by Oil Red O staining and determination of lipogenic markers (SREBP-1 and FAS). Liver injury was also evaluated by measuring serum glutamate oxaloacetate transaminase and glutamate pyruvate transaminase, and performing histological analysis.
Results: In hepatocytes and zebrafish, both CPs and chondroitin reduced oxidative stress, downregulated cytochrome P450 enzymes and lipogenic markers, and enhanced antioxidant defenses, with chondroitin showing the strongest hepatoprotection. In EtOH-fed mice, chondroitin significantly improved liver enzyme profiles, reduced hepatic lipid accumulation and inflammation, and restored antioxidant and metabolic homeostasis.
Conclusions: Skate-derived chondroitin significantly attenuates EtOH-induced liver injury by modulating oxidative stress, EtOH metabolism, and lipid regulation. These findings demonstrate the hepatoprotective potential of chondroitin in different preclinical models of alcohol-induced liver damage.
Objective: To investigate the effect of pectic polysaccharides isolated from Rauvolfia verticillata on ulcerative colitis and its underlying mechanisms.
Methods: Pectic polysaccharides were characterized using high-performance liquid chromatography with 1-phenyl-3-methyl-5-pyrazolone pre-column derivatization, phenol-sulfuric acid assay, and gel permeation chromatography. HT-29 cells were stimulated with lipopolysaccharide and then treated with pectic polysaccharides; conditioned medium was applied to THP-1-derived macrophages to assess cell viability and polarization, while tight junction protein expression was analyzed in HT-29 cells. Furthermore, a mouse model of dextran sulfate sodium-induced colitis was treated with oral pectic polysaccharides or NOS2 overexpression. Body weight, disease activity index, colon length, histopathology, and the protein expression related to the JAK2/STAT3-NOS2 signaling were evaluated.
Results: The pectic polysaccharide was characterized as an acidic pectic polysaccharide, primarily composed of galacturonic acid and various neutral sugars, with a narrow molecular weight distribution and high purity. Pectic polysaccharides significantly enhanced THP-1 macrophage viability, promoted M1 to M2 polarization, and upregulated the expression of epithelial tight junction proteins. In addition, pectic polysaccharide treatment attenuated body weight loss, lowered disease activity index scores and improved colon histology in mice with dextran sulfate sodium-induced colitis. It also reduced JAK2/STAT3 phosphorylation and NOS2 expression, and increased the expression of tight junction proteins (ZO-1, occludin, and claudin-1).
Conclusions: Pectic polysaccharides attenuate ulcerative colitis by increasing M2-related macrophage markers, inhibiting the JAK2/ STAT3-NOS2 signaling, and enhancing epithelial barrier-related protein expression. These findings support pectic polysaccharides as a natural candidate for the treatment of ulcerative colitis.
Objective: To investigate the effect of a water-soluble nacre extract derived from Pinctada fucata on skeletal muscle aging.
Methods: Naturally aged C57BL/6J mice received nacre extract mixed in chow for 12 weeks. Forelimb grip strength, hanging performance, and locomotor activity were assessed. Skeletal muscle remodeling and signaling were evaluated by histology and immunostaining for fibrosis, contractile-marker features, senescence- and DNA damage-associated markers, inflammatory signaling, and mitochondrial proteins. Oxidative status was assessed by determining antioxidant capacity, lipid peroxidation, and oxidative DNA damage. Transcriptomic profiling was also performed, and selected targets were validated by quantitative RT-PCR and immunostaining. In addition, differentiated C2C12 myotubes were exposed to doxorubicin and treated with nacre extract; senescence-associated β-galactosidase, DNA damage signaling, and cell viability were measured.
Results: Nacre extract increased forelimb grip strength and showed a positive trend in hanging performance without altering spontaneous locomotion. It also reduced collagen deposition, preserved contractile-marker immunoreactivity, attenuated senescence- and inflammation-associated signals, and increased mitochondrial protein immunoreactivity. Oxidative DNA damage was notably reduced by nacre extract. Transcriptomics indicated modulation of stress/redox programs and increased neurotrophic tyrosine kinase receptor type 2 expression, which were supported by tissue-level validation. In C2C12 myotubes, nacre extract suppressed doxorubicin-induced senescence-associated phenotypes without loss of cell viability.
Conclusions: Water-soluble nacre extract mitigates skeletal muscle aging through coordinated modulation of oxidative stress, inflammation, mitochondrial features, and cellular senescence.