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Low‐voltage‐gated calcium channels (LVGCCs; Cav3.1‐3.3) represent promising drug targets for epilepsy, pain, and essential tremor. At present, modulators with heightened selectivity for a subtype of LVGCCs are still highly desired. In this study we explored three classes of Buxus alkaloids and identified 9(10/19)abeo‐artanes Buxusemine H and Buxusemine L (BXSL) as an unprecedented type of Cav3.2 inhibitors. Particularly, BXSL exhibited Cav3.2 inhibition comparable to Z944, a non‐subtype‐selective LVGCCs inhibitor under clinical trial. While lacking specificity for Cav3.3, BXSL showed a 30‐fold selectivity of Cav3.2 over Cav3.1. As compared to several well‐known inhibitors, the experimental and computational studies suggested BXSL exhibits a distinct binding mode to Cav3.2, notably through the essential interaction with serine‐1543 in domain III. Furthermore, BXSL showed minimal impact on various recombinant and native nociceptive ion channels, while significantly reducing the excitability of isolated mouse dorsal root ganglion neurons. Animal studies in wild‐type and Cav3.2 knock‐out mice revealed that BXSL (5 mg/kg), by inhibiting Cav3.2, exhibits an analgesic effect equivalent to Z944 (10 mg/kg) or mibefradil (10 mg/kg). Moreover, we proposed a structural rationale for the high selectivity of 9(10/19)abeo‐artane‐type alkaloids towards Cav3.2 over Cav3.1. This study introduces a novel analgesic agent and valuable molecular insight for structure‐based innovative Cav3.2 drug development. [ABSTRACT FROM AUTHOR]

Microorganisms can produce a vast array of bioactive secondary metabolites, including DNA-intercalating agents like actinomycin D, doxorubicin, which hold great potential for cancer chemotherapy. However, discovering novel DNA-intercalating compounds remains challenging due to the limited sensitivity and specificity of conventional activity assays, which require large-scale fermentation and purification. Here, we introduced the single-molecule stretching assay (SMSA) directly to microbial cultures or extracts for discovering DNA-intercalating agents, even in trace amounts of microbial cultures (5 μl). We showed that the unique changes of dsDNA in contour length and overstretching transition enable the specific detection of intercalators from complex samples without the need for extensive purification. Applying force to dsDNA also enhanced the sensitivity by increasing both the binding affinity Ka and the quantity of ligands intercalation, thus allowing the detection of weak intercalators, which are often overlooked using traditional methods. We demonstrated the effectiveness of SMSA, identified two DNA intercalator-producing strains: Streptomyces tanashiensis and Talaromyces funiculosus, and isolated three DNA intercalators: medermycin, kalafungin and ligustrone B. Interestingly, both medermycin and kalafungin, classified as weak DNA intercalators (Ka ∼103 M-1), exhibited potent anti-cancer activity against HCT-116 cancer cells, with IC50 values of 52 ± 6 and 70 ± 7 nM, respectively., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Low-voltage-gated calcium channels (LVGCCs; Ca v 3.1-3.3) represent promising drug targets for epilepsy, pain, and essential tremor. At present, modulators with heightened selectivity for a subtype of LVGCCs are still highly desired. In this study we explored three classes of Buxus alkaloids and identified 9(10/19)abeo-artanes Buxusemine H and Buxusemine L (BXSL) as an unprecedented type of Ca v 3.2 inhibitors. Particularly, BXSL exhibited Ca v 3.2 inhibition comparable to Z944, a non-subtype-selective LVGCCs inhibitor under clinical trial. While lacking specificity for Ca v 3.3, BXSL showed a 30-fold selectivity of Ca v 3.2 over Ca v 3.1. As compared to several well-known inhibitors, the experimental and computational studies suggested BXSL exhibits a distinct binding mode to Ca v 3.2, notably through the essential interaction with serine-1543 in domain III. Furthermore, BXSL showed minimal impact on various recombinant and native nociceptive ion channels, while significantly reducing the excitability of isolated mouse dorsal root ganglion neurons. Animal studies in wild-type and Ca v 3.2 knock-out mice revealed that BXSL (5 mg/kg), by inhibiting Ca v 3.2, exhibits an analgesic effect equivalent to Z944 (10 mg/kg) or mibefradil (10 mg/kg). Moreover, we proposed a structural rationale for the high selectivity of 9(10/19)abeo-artane-type alkaloids towards Ca v 3.2 over Ca v 3.1. This study introduces a novel analgesic agent and valuable molecular insight for structure-based innovative Ca v 3.2 drug development., (© 2023 Wiley-VCH GmbH.)

Tuberous root of Liriope spicata var. prolifera has been widely used as a traditional Chinese medicine for the treatment of diabetes. The present study investigated the antidiabetic effect and the potential mechanisms of two new polysaccharides (LSP1, LSP2) and the total polysaccharides (TLSP), isolated from the tuberous roots. Upon the intragastric administration in obese insulin-resistant diabetic KKAy mice for 28 days, TLSP, LSP1, and LSP2 all caused a remarkable decrease of fasting blood glucose and significant improvement of insulin resistance and serum lipid metabolism in diabetic mice. In addition, liver histological analysis showed that TLSP, LSP1, and LSP2 significantly ameliorated the hepatocyte hypertrophy and decreased the lipid accumulation in the mice liver. Further experiments suggested that TLSP, LSP1, and LSP2 effectively inhibited hepatic gluconeogenesis and increased hepatic glycolysis and hepatic glycogen content. Furthermore, the mechanistic analysis showed the increased expression of insulin-receptor α subunit, insulin-receptor substrate-1, phosphatidylinositol 3-kinase, and peroxisome proliferators-activated receptors γ . These results suggested that TLSP, LSP1, and LSP2 manifest strong antidiabetic activity, therefore hold a great promise for therapeutic application in diabetic therapy and other related metabolic disorders.

The present study was to investigate the anti-diabetic activities of Swertia bimaculata. Based on the glucose consumption of S. bimaculata extractsand different fractions (petroleum, dichloromethane, ethyl acetate, n-butanol and water extracts) in 3T3-L1 adipocyte assay, ethanol (ETH) and dichloromethane (DTH) extracts had the most effective potency. Furthermore, ETH, DTH and corymbiferin (the most abundant component of DTH) were evaluated for anti-diabetic effects in high fat and sucrose fed combined with low dose streptozocin induced diabetic rats. DTH and corymbiferin displayed remarkable anti-diabetic activities. The fasting blood glucose levels were significantly decreased, while the serum insulin levels were obviously increased. The oral glucose tolerance was also improved. The lowed serum total cholesterol, low density lipoprotein (LDL) and triglyceride levels and increased ratio of HDL (high density lipoprotein)/LDL were observed. The insulin sensitivity was improved on the basis of increased expressions of insulin-receptor substrate-2, phosphatidylinositol 3-kinase and Ser/Thr kinase AKT2. And also DTH and corymbiferin improved antioxidant capacity and carbohydrate metabolism in diabetic rats, along with the improvement of histopathology of livers and pancreatic β cells. Corymbiferin was one of active constituents, responsible for anti-diabetic properties. Therefore, S. bimaculata could be considered as an alternative agent against diabetes mellitus.