Sulfated Undaria pinnatifida polysaccharides inhibit kidney stone formation through crystalline modulation and relieving cellular oxidative damage and inflammation†

Background: Calcium oxalate (CaOx) crystal deposition and its resultant cellular oxidative damage and inflammation are important causes of renal stone formation. It is clinically important to conduct research on multifunctional anti-stone drugs targeting these predisposing factors. Methods: We modified natural Undaria pinnatifida polysaccharide (UPP0) by sulfation via the sulfur trioxide-pyridine method, resulting in four sulfated polysaccharides with varying sulfate group (–OSO₃⁻) contents: 1.59% (UPP0), 6.03% (UPP1), 20.83% (UPP2), and 36.39% (UPP3), and compared their differences in the inhibition of crystalline formation, renal injury, and inflammation in the process of renal stone formation at chemical and cellular levels. Results: The UPPS were able to inhibit the nucleation, growth and aggregation of CaOx crystals in vitro. Among them, UPP3 with the maximum sulfate group content showed the greatest crystallization inhibition ability. The nucleation inhibition and aggregation inhibition of UPP3 at a concentration of 0.5 mg mL⁻¹ were as high as 80.21% and 72.34%, respectively. The CaOx crystal size regulated by UPP3 was significantly reduced from 25.9 ± 2.8 μm to 5.9 ± 1.2 μm. Furthermore, UPPS were observed to up-regulate the expression of the antioxidant enzyme superoxide dismutase (SOD) in cells, reduce the levels of ROS and malonaldehyde (MDA), enhance lysosomal integrity, decrease intracellular Ca²⁺ levels, inhibit the decline in mitochondrial membrane potential, reduce the production of cellular inflammatory factors (TNF-α, MCP-1, IL-18, and IL-1β), and ultimately inhibit cell apoptosis. Conclusion: UPPS combine multiple biological functions of crystallization regulation, antioxidant and anti-inflammatory, and have important potential in the prevention of kidney stones. Sulfation modification can improve the biological activity of UPP0 and provide a reference for screening and optimization methods of stone drugs.