Pub Date : 2025-12-10DOI: 10.1007/s11418-025-01974-8
Kamil Piska, Michał Zubek, Adam Bucki, Maria Świtalska, Paulina Koczurkiewicz-Adamczyk, Benedykt Władyka, Marcin Kołaczkowski, Elżbieta Pękala
Castration-resistant prostate cancer (CRPC) continues to represent a critical therapeutic hurdle owing to its resistance to both androgen deprivation and next-generation antiandrogens like abiraterone (ABI). One of the key mechanisms underlying this resistance involves overexpression of aldo-keto reductase 1C3 (AKR1C3), an enzyme contributing to intratumoral androgen biosynthesis. In this study, casticin (CAS), a flavonoid derived from Vitex agnus-castus, was identified as a potent inhibitor of AKR1C3. CAS showed potent inhibitory activity in enzymatic assays (IC₅₀ = 5.99 µM), significantly suppressed AKR1C3-mediated coumberone metabolism in 22Rv1 prostate cancer cells, and showed greater cytotoxicity in AKR1C3-expressing 22Rv1 cells relative to AKR1C3-deficient LNCaP cells. CAS significantly enhanced ABI’s cytotoxic efficacy in 22Rv1 cells, as evidenced by synergistic interactions (CI: 0.31–0.71); however, no such synergy was observed in LNCaP cells or with enzalutamide. CAS enhanced apoptosis in ABI-treated 22Rv1 cells, as well as combination showed only a limited effect against normal epithelial PNT-2 cell line. Docking and molecular dynamics simulations indicated a stable CAS–AKR1C3 interaction, characterized by crucial hydrogen bonding and aromatic stacking within the active site. These results suggest that CAS is a promising chemosensitizer targeting AKR1C3 to overcome ABI resistance in CRPC.
{"title":"Casticin inhibits AKR1C3 and enhances abiraterone efficacy in castration-resistant prostate cancer","authors":"Kamil Piska, Michał Zubek, Adam Bucki, Maria Świtalska, Paulina Koczurkiewicz-Adamczyk, Benedykt Władyka, Marcin Kołaczkowski, Elżbieta Pękala","doi":"10.1007/s11418-025-01974-8","DOIUrl":"10.1007/s11418-025-01974-8","url":null,"abstract":"<div><p>Castration-resistant prostate cancer (CRPC) continues to represent a critical therapeutic hurdle owing to its resistance to both androgen deprivation and next-generation antiandrogens like abiraterone (ABI). One of the key mechanisms underlying this resistance involves overexpression of aldo-keto reductase 1C3 (AKR1C3), an enzyme contributing to intratumoral androgen biosynthesis. In this study, casticin (CAS), a flavonoid derived from <i>Vitex agnus-castus</i>, was identified as a potent inhibitor of AKR1C3. CAS showed potent inhibitory activity in enzymatic assays (IC₅₀ = 5.99 µM), significantly suppressed AKR1C3-mediated coumberone metabolism in 22Rv1 prostate cancer cells, and showed greater cytotoxicity in AKR1C3-expressing 22Rv1 cells relative to AKR1C3-deficient LNCaP cells. CAS significantly enhanced ABI’s cytotoxic efficacy in 22Rv1 cells, as evidenced by synergistic interactions (CI: 0.31–0.71); however, no such synergy was observed in LNCaP cells or with enzalutamide. CAS enhanced apoptosis in ABI-treated 22Rv1 cells, as well as combination showed only a limited effect against normal epithelial PNT-2 cell line. Docking and molecular dynamics simulations indicated a stable CAS–AKR1C3 interaction, characterized by crucial hydrogen bonding and aromatic stacking within the active site. These results suggest that CAS is a promising chemosensitizer targeting AKR1C3 to overcome ABI resistance in CRPC.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"80 1","pages":"119 - 129"},"PeriodicalIF":2.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11418-025-01974-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145720364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-06DOI: 10.1007/s11418-025-01969-5
Haoran Wang, Jun Jiang, Wenjiao Kang, Baixiu Zhao, Yuwen Ma
Melanin is omnipresent across diverse taxa in the biosphere, spanning microorganisms to multicellular eukaryotes. This pervasive distribution reflects its multifaceted roles, encompassing pigmentation, radical quenching, photoprotective barriers and immunomodulatory activity. The process of melanin biosynthesis can be simply defined as the conversion of tyrosine into melanin through a complex series of steps in melanosomes within melanocytes. Skin pigmentation results from melanin production by melanocytes in the epidermis. With the development of society, people are becoming increasingly concerned about their skin appearance, particularly issues related to pigmentation and skin radiance. Elevated melanin levels may lead to skin disorders associated with excessive pigmentation, including age spots, freckles and even melanoma, which cause distress and lower the life quality. In recent years, the high demand for skin whitening and brightening has promoted the exploration of whitening active ingredients and melanin biosynthesis mechanisms. In this paper, the biosynthetic signaling pathways, generating factors, active natural compounds and advanced delivery system related to the deposition of melanin were systematically reviewed. Moreover, we were the first to introduce Chinese herbal formulas, TCM therapeutic techniques, and several advanced delivery systems designed to enhance the transdermal absorption of traditional Chinese medicines. The ideology, technologies and herbal drugs originated from Chinese medicine are expected to be an important development field for skin whitening and pigmentation prevention.
{"title":"Herbal medicine for melanin regulation: biological synthesis, effective formulas/compounds, and biopharmaceutical methods","authors":"Haoran Wang, Jun Jiang, Wenjiao Kang, Baixiu Zhao, Yuwen Ma","doi":"10.1007/s11418-025-01969-5","DOIUrl":"10.1007/s11418-025-01969-5","url":null,"abstract":"<div><p>Melanin is omnipresent across diverse taxa in the biosphere, spanning microorganisms to multicellular eukaryotes. This pervasive distribution reflects its multifaceted roles, encompassing pigmentation, radical quenching, photoprotective barriers and immunomodulatory activity. The process of melanin biosynthesis can be simply defined as the conversion of tyrosine into melanin through a complex series of steps in melanosomes within melanocytes. Skin pigmentation results from melanin production by melanocytes in the epidermis. With the development of society, people are becoming increasingly concerned about their skin appearance, particularly issues related to pigmentation and skin radiance. Elevated melanin levels may lead to skin disorders associated with excessive pigmentation, including age spots, freckles and even melanoma, which cause distress and lower the life quality. In recent years, the high demand for skin whitening and brightening has promoted the exploration of whitening active ingredients and melanin biosynthesis mechanisms. In this paper, the biosynthetic signaling pathways, generating factors, active natural compounds and advanced delivery system related to the deposition of melanin were systematically reviewed. Moreover, we were the first to introduce Chinese herbal formulas, TCM therapeutic techniques, and several advanced delivery systems designed to enhance the transdermal absorption of traditional Chinese medicines. The ideology, technologies and herbal drugs originated from Chinese medicine are expected to be an important development field for skin whitening and pigmentation prevention.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"80 1","pages":"1 - 25"},"PeriodicalIF":2.5,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gouty arthritis is a common metabolic disorder characterized by the deposition of monosodium urate (MSU) crystals in joints. Aberrant activation of the NLRP3 inflammasome is a key driver of MSU-induced joint inflammation, making it a promising therapeutic target for gouty arthritis. Gnetum montanum Markgr. has long been used in traditional medicine in parts of Asia to treat gout; however, its effects on gout-specific inflammatory responses have not been fully elucidated. In this study, we used two cell models, including MSU-stimulated mouse primary peritoneal and THP1 derived macrophages, in combination with western blot analysis, enzymatic activity assays, ELISA method, and flow cytometry analysis to evaluate the protective effect of G. montanum extract (GME) against MSU-driven inflammation. A mouse model of MSU-induced paw edema was then employed to validate the in vivo anti-inflammatory efficacy. We found that GME alleviated gouty inflammation by inhibiting NLRP3 inflammasome activation in mouse peritoneal and human THP-1 macrophages. GME also protected macrophages from MSU-induced pyroptosis, a pro-inflammatory form of programmed cell death. Mechanistically, GME suppressed xanthine oxidase (XO) activation triggered by MSU crystals, resulting in decreased reactive oxygen species (ROS) production. This reduction in ROS prevented the upregulation of thioredoxin-interacting protein (TXNIP), a key mediator that binds to and activates NLRP3. Furthermore, oral administration of GME in mice attenuated MSU-induced paw inflammation, likely through downregulation of XO-driven oxidative stress and NLRP3 inflammasome signaling. These findings suggest that GME effectively modulates gout-specific inflammatory pathways and warrants further investigation of GME as a potential therapeutic candidate for gouty arthritis.
{"title":"Gnetum Montanum Markgr. Extract mitigates gouty arthritis by targeting urate crystal-induced NLRP3 inflammasome activation","authors":"Duc-Vinh Pham, Hong-Linh Tran, Thu-Hang Nguyen, Thi-Hanh Do, Hoang-Anh Nguyen, Thuy-Duong Nguyen","doi":"10.1007/s11418-025-01977-5","DOIUrl":"10.1007/s11418-025-01977-5","url":null,"abstract":"<div><p>Gouty arthritis is a common metabolic disorder characterized by the deposition of monosodium urate (MSU) crystals in joints. Aberrant activation of the NLRP3 inflammasome is a key driver of MSU-induced joint inflammation, making it a promising therapeutic target for gouty arthritis. <i>Gnetum montanum</i> Markgr. has long been used in traditional medicine in parts of Asia to treat gout; however, its effects on gout-specific inflammatory responses have not been fully elucidated. In this study, we used two cell models, including MSU-stimulated mouse primary peritoneal and THP1 derived macrophages, in combination with western blot analysis, enzymatic activity assays, ELISA method, and flow cytometry analysis to evaluate the protective effect of <i>G. montanum</i> extract (GME) against MSU-driven inflammation. A mouse model of MSU-induced paw edema was then employed to validate the in vivo anti-inflammatory efficacy. We found that GME alleviated gouty inflammation by inhibiting NLRP3 inflammasome activation in mouse peritoneal and human THP-1 macrophages. GME also protected macrophages from MSU-induced pyroptosis, a pro-inflammatory form of programmed cell death. Mechanistically, GME suppressed xanthine oxidase (XO) activation triggered by MSU crystals, resulting in decreased reactive oxygen species (ROS) production. This reduction in ROS prevented the upregulation of thioredoxin-interacting protein (TXNIP), a key mediator that binds to and activates NLRP3. Furthermore, oral administration of GME in mice attenuated MSU-induced paw inflammation, likely through downregulation of XO-driven oxidative stress and NLRP3 inflammasome signaling. These findings suggest that GME effectively modulates gout-specific inflammatory pathways and warrants further investigation of GME as a potential therapeutic candidate for gouty arthritis.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"80 1","pages":"130 - 148"},"PeriodicalIF":2.5,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Citrus hassaku Yu. Tanaka is a relatively less-known species within the genus. In this study, we aimed to isolate novel compounds from this species, elucidate their chemical structures via spectroscopic and physicochemical analyses, and evaluate their antiproliferative effects using the WST-8 assay. Two new limonoids, 1-acetyl-sphaerocarpainic acid I (1) and 1-acetyl-sphaerocarpain I (2), and a new eremophilane-type nor-sesquiterpenoid enantiomer, 12-nor-11S-hydroxy-11-hydronootkatone (9), were isolated from the peels of C. hassaku, together with eleven known compounds: deacetylnomilin (3), nomilin (4), methyl nomilinate (5), obacunone (6), limonin (7), ichangin (8), nootkatone (10), (+)-(4R,5S,7R)-13-hydroxynootkatone (11), umbelliferone (12), auraptene (13), and marmin (14). Among them, compound (9) exhibited weak antiproliferative effects against human glioblastoma U-251 MG cells.
{"title":"Three new terpenoids from the fruit peels of Citrus Hassaku Yu.Tanaka","authors":"Daisuke Imahori, Takuya Muraoka, Tomoe Ohta, Tatsusada Yoshida, Hiroyuki Tanaka","doi":"10.1007/s11418-025-01983-7","DOIUrl":"10.1007/s11418-025-01983-7","url":null,"abstract":"<div><p><i>Citrus hassaku</i> Yu. Tanaka is a relatively less-known species within the genus. In this study, we aimed to isolate novel compounds from this species, elucidate their chemical structures via spectroscopic and physicochemical analyses, and evaluate their antiproliferative effects using the WST-8 assay. Two new limonoids, 1-acetyl-sphaerocarpainic acid I (<b>1</b>) and 1-acetyl-sphaerocarpain I (<b>2</b>), and a new eremophilane-type nor-sesquiterpenoid enantiomer, 12-nor-11<i>S</i>-hydroxy-11-hydronootkatone (<b>9</b>), were isolated from the peels of <i>C. hassaku</i>, together with eleven known compounds: deacetylnomilin (<b>3</b>), nomilin (<b>4</b>), methyl nomilinate (<b>5</b>), obacunone (<b>6</b>), limonin (<b>7</b>), ichangin (<b>8</b>), nootkatone (<b>10</b>), (+)-(4<i>R</i>,5<i>S</i>,7<i>R</i>)-13-hydroxynootkatone (<b>11</b>), umbelliferone (<b>12</b>), auraptene (<b>13</b>), and marmin (<b>14</b>). Among them, compound (<b>9</b>) exhibited weak antiproliferative effects against human glioblastoma U-251 MG cells.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"80 1","pages":"230 - 239"},"PeriodicalIF":2.5,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11418-025-01983-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Salvia castanea Diels f. tomentosa Stib. (SCD) is a traditional Tibetan herbal medicine that is frequently employed in the treatment of cardiovascular disease. However, the mechanism of its effect on plateau hypoxia-induced right ventricular hypertrophy remains unclear. In the present study, we evaluated the antihypoxic effect of the alcoholic extract of Salvia castanea Diels f. tomentosa Stib. (SCDA) through a normal pressure hypoxia tolerance experiment in mice, and investigated the effect and possible mechanism of SCDA on hypoxia-induced right ventricular hypertrophy in rats. 0.3 and 0.6 g/kg SCDA were used to treat Sugen5416 + hypoxia-induced right ventricular hypertrophy in SD rats for 3 weeks. The findings indicated that SCDA (0.6 g/kg) could inhibit right ventricular hypertrophy, as evidenced by a reduction in heart weight/body weight, Fulton’s index, mean pulmonary artery pressure and hypertrophic markers. Furthermore, through network pharmacology in conjunction with transcriptomics and molecular docking as well as experimental validation, it was demonstrated that SCDA reduced lipid peroxidation products, mainly through inhibiting hypoxia-induced activation of the tumour proteins p53 (P53), spermine/ spermine N1 acetyltransferase 1 (SAT1) and arachidonate 15-lipoxygenase (ALOX15). Similarly, SCDA also increased levels of the antioxidant glutathione (GSH), which is associated with inhibition of P53 and promotion of the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), resulting in an improved balance between antioxidant and oxidant systems. This provides new drugs and targets for the treatment of right ventricular hypertrophy.
{"title":"Alcoholic extract of Salvia castanea Diels f. tomentosa Stib. ameliorates hypobaric hypoxia-induced right ventricular hypertrophy by inhibiting the P53-SAT1-ALOX15 pathway and up-regulating the SLC7A11-GPX4 pathway","authors":"Jiajia Wu, Qi Si, Ruoxi Jia, Zheng Tang, Ruiping Li, Kunpeng Mao, Zihao Jia, Xiaoying Zhang","doi":"10.1007/s11418-025-01970-y","DOIUrl":"10.1007/s11418-025-01970-y","url":null,"abstract":"<div><p><i>Salvia castanea</i> Diels f. <i>tomentosa</i> Stib. (SCD) is a traditional Tibetan herbal medicine that is frequently employed in the treatment of cardiovascular disease. However, the mechanism of its effect on plateau hypoxia-induced right ventricular hypertrophy remains unclear. In the present study, we evaluated the antihypoxic effect of the alcoholic extract of <i>Salvia castanea</i> Diels f. <i>tomentosa</i> Stib. (SCDA) through a normal pressure hypoxia tolerance experiment in mice, and investigated the effect and possible mechanism of SCDA on hypoxia-induced right ventricular hypertrophy in rats. 0.3 and 0.6 g/kg SCDA were used to treat Sugen5416 + hypoxia-induced right ventricular hypertrophy in SD rats for 3 weeks. The findings indicated that SCDA (0.6 g/kg) could inhibit right ventricular hypertrophy, as evidenced by a reduction in heart weight/body weight, Fulton’s index, mean pulmonary artery pressure and hypertrophic markers. Furthermore, through network pharmacology in conjunction with transcriptomics and molecular docking as well as experimental validation, it was demonstrated that SCDA reduced lipid peroxidation products, mainly through inhibiting hypoxia-induced activation of the tumour proteins p53 (P53), spermine/ spermine N1 acetyltransferase 1 (SAT1) and arachidonate 15-lipoxygenase (ALOX15). Similarly, SCDA also increased levels of the antioxidant glutathione (GSH), which is associated with inhibition of P53 and promotion of the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), resulting in an improved balance between antioxidant and oxidant systems. This provides new drugs and targets for the treatment of right ventricular hypertrophy.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"80 1","pages":"76 - 90"},"PeriodicalIF":2.5,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145601597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Five guanacastane-type diterpenoids, including a novel compound, guanacastepene V (1), and four known compounds (2–5) along with a novel diterpenoid moniliforminol C (6), were isolated from a marine-derived fungus, Coprinellus xanthothrix. The structures of the isolated compounds were elucidated using NMR spectroscopy and computational chemistry. In antifungal assays against Candida auris, an emerging fungal pathogen, compounds 1 and 2 exhibited inhibitory activity, with minimum inhibitory concentration values of 6.25 and 3.12 µg/mL, respectively. This antifungal effect was specific to C. auris, with minimal activity observed against C. albicans. Moreover, compound 4 exhibited synergistic effects with amphotericin B.
{"title":"Guanacastane-type diterpenoids with antifungal activity against Candida auris isolated from a Marine-derived fungus Coprinellus xanthothrix","authors":"Kanako Usui, Hitoshi Kamauchi, Yuki Yatsui, Mikuru Kuroda, Yuka Kiba, Masashi Kitamura, Yoshiaki Sugita","doi":"10.1007/s11418-025-01975-7","DOIUrl":"10.1007/s11418-025-01975-7","url":null,"abstract":"<div><p>Five guanacastane-type diterpenoids, including a novel compound, guanacastepene V (<b>1</b>), and four known compounds (<b>2</b>–<b>5</b>) along with a novel diterpenoid moniliforminol C (<b>6</b>), were isolated from a marine-derived fungus, <i>Coprinellus xanthothrix</i>. The structures of the isolated compounds were elucidated using NMR spectroscopy and computational chemistry. In antifungal assays against <i>Candida auris</i>, an emerging fungal pathogen, compounds <b>1</b> and <b>2</b> exhibited inhibitory activity, with minimum inhibitory concentration values of 6.25 and 3.12 µg/mL, respectively. This antifungal effect was specific to <i>C. auris</i>, with minimal activity observed against <i>C. albicans</i>. Moreover, compound <b>4</b> exhibited synergistic effects with amphotericin B.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"80 1","pages":"207 - 214"},"PeriodicalIF":2.5,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In multicomponent drugs, such as Kampo (traditional Japanese medicine) medicines, compound–compound interactions, including synergistic effects, inhibitory effects, and complex formations, should be considered. Orengedokuto is a Kampo formula, which is used for the treatment of various diseases, including inflammation, hypertension, gastrointestinal disorders, and liver and cerebrovascular diseases. During the decoction process in the production of Orengedokuto, yellow precipitates are obtained from berberine–baicalin complexation; these precipitates enhance the in vivo coprecipitation and coabsorption of both compounds. Scutellaria root contains various baicalin analogs, such as wogonoside, oroxyloside, and scutellarin; however, the compound–compound interactions between berberine and flavonoid glycosides have not been investigated. Herein, we performed precipitation assays for berberine and the crude extract of Scutellaria root to detect and quantify compounds that interact with berberine by HPLC analysis. Furthermore, we performed precipitation assays and NMR experiments to identify chemical structures that affect the formation of precipitates; specifically, we analyzed all combinations of berberine and identified flavonoids to provide insights into associated compound–compound interactions. The NMR experiments indicated that C-8 modification affected the pi–pi interaction between berberine and flavonoids. This information enables the synthesis of more effective molecules and provides insights into their functions, such as drug delivery. The investigation of the interaction mechanisms of berberine and baicalin analogs in Kampo medicines can provide comprehensive insights regarding multicomponent drugs.
{"title":"Analysis of compound–compound interactions between berberine and baicalin derivatives","authors":"Takehiro Nishimura, Chihiro Iida, Haruhisa Kikuchi","doi":"10.1007/s11418-025-01979-3","DOIUrl":"10.1007/s11418-025-01979-3","url":null,"abstract":"<div><p>In multicomponent drugs, such as Kampo (traditional Japanese medicine) medicines, compound–compound interactions, including synergistic effects, inhibitory effects, and complex formations, should be considered. Orengedokuto is a Kampo formula, which is used for the treatment of various diseases, including inflammation, hypertension, gastrointestinal disorders, and liver and cerebrovascular diseases. During the decoction process in the production of Orengedokuto, yellow precipitates are obtained from berberine–baicalin complexation; these precipitates enhance the in vivo coprecipitation and coabsorption of both compounds. Scutellaria root contains various baicalin analogs, such as wogonoside, oroxyloside, and scutellarin; however, the compound–compound interactions between berberine and flavonoid glycosides have not been investigated. Herein, we performed precipitation assays for berberine and the crude extract of Scutellaria root to detect and quantify compounds that interact with berberine by HPLC analysis. Furthermore, we performed precipitation assays and NMR experiments to identify chemical structures that affect the formation of precipitates; specifically, we analyzed all combinations of berberine and identified flavonoids to provide insights into associated compound–compound interactions. The NMR experiments indicated that C-8 modification affected the pi–pi interaction between berberine and flavonoids. This information enables the synthesis of more effective molecules and provides insights into their functions, such as drug delivery. The investigation of the interaction mechanisms of berberine and baicalin analogs in Kampo medicines can provide comprehensive insights regarding multicomponent drugs.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"80 1","pages":"215 - 221"},"PeriodicalIF":2.5,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kampo medicines are widely co-prescribed with Western drugs, yet package inserts typically recommend preprandial dosing. This convention can complicate co-medication schedules and may reduce adherence, while human pharmacokinetic (PK) evidence on meal-timing effects remains limited. We compared pre- versus postprandial administration of maoto to quantify effects on absorption rate and extent for ephedrine and pseudoephedrine. In a two-period, two-sequence crossover, eight healthy adults received ethical maoto extract granules (2.5 g) 30 min before or after a standardized meal. Plasma ephedrine and pseudoephedrine were measured by LC–MS/MS through 24 h. PK was characterized by non-compartmental analysis (NCA) and a pre-specified one-compartment absorption model. The absorption rate constant (ka) was the mechanistic primary endpoint; AUC quantified extent. Sensitivity (male-only; leave-one-out) and crossover diagnostics (sequence/period) were conducted, and model adequacy was compared by modified Akaike’s Information Criterion (AICc). Preprandial dosing yielded higher Cmax, shorter Tmax, and larger ka for both analytes, indicating faster absorption. In contrast, AUC0–24 h and model-based AUC∞ were similar between conditions, and ke did not differ, indicating unchanged extent and disposition. Sensitivity analyses supported these findings; no sequence or period effects were detected. AICc distributions were comparable between conditions. Meal timing primarily alters the absorption rate of ephedrine/pseudoephedrine from maoto without materially changing overall exposure. Preprandial dosing may be preferred when rapid onset is desired, whereas postprandial dosing remains reasonable when adherence and co-medication scheduling are prioritized.
{"title":"Effect of pre- and postprandial administration of Maoto extract granules on the pharmacokinetics of ephedrine and pseudoephedrine in healthy adults","authors":"Toshiyuki Atsumi, Takumi Nakakubo, Miku Takakura, Tatsunori Toida, Kenji Ogata, Ikuo Yamamoto, Toshiaki Makino","doi":"10.1007/s11418-025-01980-w","DOIUrl":"10.1007/s11418-025-01980-w","url":null,"abstract":"<div><p>Kampo medicines are widely co-prescribed with Western drugs, yet package inserts typically recommend preprandial dosing. This convention can complicate co-medication schedules and may reduce adherence, while human pharmacokinetic (PK) evidence on meal-timing effects remains limited. We compared pre- versus postprandial administration of <i>maoto</i> to quantify effects on absorption rate and extent for ephedrine and pseudoephedrine. In a two-period, two-sequence crossover, eight healthy adults received ethical <i>maoto</i> extract granules (2.5 g) 30 min before or after a standardized meal. Plasma ephedrine and pseudoephedrine were measured by LC–MS/MS through 24 h. PK was characterized by non-compartmental analysis (NCA) and a pre-specified one-compartment absorption model. The absorption rate constant (<i>k</i><sub><i>a</i></sub>) was the mechanistic primary endpoint; <i>AUC</i> quantified extent. Sensitivity (male-only; leave-one-out) and crossover diagnostics (sequence/period) were conducted, and model adequacy was compared by modified Akaike’s Information Criterion (AICc). Preprandial dosing yielded higher <i>C</i><sub><i>max</i></sub>, shorter <i>T</i><sub><i>max</i></sub>, and larger <i>k</i><sub><i>a</i></sub> for both analytes, indicating faster absorption. In contrast, <i>AUC</i><sub><i>0–24 h</i></sub> and model-based <i>AUC</i><sub><i>∞</i></sub> were similar between conditions, and <i>k</i><sub><i>e</i></sub> did not differ, indicating unchanged extent and disposition. Sensitivity analyses supported these findings; no sequence or period effects were detected. AICc distributions were comparable between conditions. Meal timing primarily alters the absorption rate of ephedrine/pseudoephedrine from <i>maoto</i> without materially changing overall exposure. Preprandial dosing may be preferred when rapid onset is desired, whereas postprandial dosing remains reasonable when adherence and co-medication scheduling are prioritized.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"80 1","pages":"222 - 229"},"PeriodicalIF":2.5,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-23DOI: 10.1007/s11418-025-01960-0
Gehad Elshamy, Hany M El-Bassossy, Shimaa M Elshazly, Nesreen M I M Elkomy
Diabetic nephropathy (DN) is a multifactorial disease, so there is a global attitude to use natural products for DN management due to their polypharmacological effects. Anacardic acid (AA) is a natural product from Anacardium occidentale. We aimed to investigate the protective effect of AA on the kidney and pancreas through targeting hyperlipidemia, hyperglycemia, insulin resistance oxidative stress, TNF-α, TGFβR1, and α-SMA signaling. Network pharmacology, Molecular docking, experimental, and histopathological studies were established to evaluate the efficacy of AA on DN management. Biochemical analyses of glycated hemoglobin, fasting glucose, insulin, lipid profile, renal functions, MDA, GSH, TNF-α, and TGFβR1 parameters were measured. Additionally, immunohistopathological examination of α-SMA and histopathological examinations of pancreas and kidney tissues were performed to explore pancreatic and renal tissues changes. Network pharmacology suggested an association between AA and DN. In vivo results demonstrated that AA treatment had an effective improvement of insulin sensitivity as evidenced by low HOMA-IR, and suppression of DN progression as evidenced by high creatinine clearance, reduction of the bowman capsule space and reduction of collagen fiber deposition in kidney tissues. Molecular docking study showed a promising inhibitory effect of AA against TNF-α and TGFβR1 with binding energies of (-8and-7.1 kcal/mol, respectively), molecular dynamic simulation study for 200 ns assured the molecular docking results and the two complexes were structurally robust with binding free energy of (- 18.56 kcal/mol, - 30.39 kcal/mol, respectively). In conclusion, AA renoprotective effects in type 2 diabetic rats may be related to its inhibitory effect on TNF-α/ TGFβR1/ α-SMA signaling.
{"title":"Anacardic acid ameliorates insulin resistance and diabetic nephropathy: network pharmacology, in vivo and molecular docking studies targeting TNF- α / TGFβR1 signaling.","authors":"Gehad Elshamy, Hany M El-Bassossy, Shimaa M Elshazly, Nesreen M I M Elkomy","doi":"10.1007/s11418-025-01960-0","DOIUrl":"https://doi.org/10.1007/s11418-025-01960-0","url":null,"abstract":"<p><p>Diabetic nephropathy (DN) is a multifactorial disease, so there is a global attitude to use natural products for DN management due to their polypharmacological effects. Anacardic acid (AA) is a natural product from Anacardium occidentale. We aimed to investigate the protective effect of AA on the kidney and pancreas through targeting hyperlipidemia, hyperglycemia, insulin resistance oxidative stress, TNF-α, TGFβR1, and α-SMA signaling. Network pharmacology, Molecular docking, experimental, and histopathological studies were established to evaluate the efficacy of AA on DN management. Biochemical analyses of glycated hemoglobin, fasting glucose, insulin, lipid profile, renal functions, MDA, GSH, TNF-α, and TGFβR1 parameters were measured. Additionally, immunohistopathological examination of α-SMA and histopathological examinations of pancreas and kidney tissues were performed to explore pancreatic and renal tissues changes. Network pharmacology suggested an association between AA and DN. In vivo results demonstrated that AA treatment had an effective improvement of insulin sensitivity as evidenced by low HOMA-IR, and suppression of DN progression as evidenced by high creatinine clearance, reduction of the bowman capsule space and reduction of collagen fiber deposition in kidney tissues. Molecular docking study showed a promising inhibitory effect of AA against TNF-α and TGFβR1 with binding energies of (-8and-7.1 kcal/mol, respectively), molecular dynamic simulation study for 200 ns assured the molecular docking results and the two complexes were structurally robust with binding free energy of (- 18.56 kcal/mol, - 30.39 kcal/mol, respectively). In conclusion, AA renoprotective effects in type 2 diabetic rats may be related to its inhibitory effect on TNF-α/ TGFβR1/ α-SMA signaling.</p>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Naturally occurring compounds like Theobromine, found in tea, coffee, and cocoa, may have anticancer effects. This study explores how Theobromine induces cell death and apoptosis in bladder cancer cells and its impact on NRF2-related gene activity. Two human bladder cancer cell lines—RT112 (non-invasive) and HTB9 (invasive)—were employed. Cell viability was measured using the WST-1 assay, whereas apoptosis and caspase 3/7 activation were determined through flow cytometry. qPCR was performed to measure the expression of NRF2, KEAP1, and P62 genes. Theobromine exhibited a dose-dependent reduction in cell viability in both RT112 and HTB9 bladder cancer cells, while also significantly enhancing apoptosis and caspase 3/7 activity (p<0.0001). Flow cytometry analysis indicated G1-phase arrest in RT112 cells and S-phase accumulation in HTB9 cells following Theobromine treatment, while Cisplatin induced S-phase arrest in both cell lines. Theobromine suppressed NRF2 and P62 while increasing KEAP1 levels in HTB9 cells, suggesting NRF2 pathway inhibition. For RT112 cells, Theobromine upregulated NRF2 and P62 without altering KEAP1 expression, highlighting cell type-specific modulation of the NRF2 signaling pathway. This study shows that Theobromine differentially regulates the Nrf2-Keap1-p62 pathway in bladder cancer cells, inhibiting NRF2 and P62 expression in a cell-specific manner. These findings suggest its potential as a natural anticancer compound, warranting further in vivo studies to assess its therapeutic potential.
{"title":"Theobromine as a molecular switch: targeting Nrf2 pathway in invasive and non-invasive bladder cancer","authors":"Beyza Ecem Oz-Bedir, Elif Ercan, Emine Terzi, Tuba Ozdemir-Sanci","doi":"10.1007/s11418-025-01961-z","DOIUrl":"10.1007/s11418-025-01961-z","url":null,"abstract":"<div><p>Naturally occurring compounds like Theobromine, found in tea, coffee, and cocoa, may have anticancer effects. This study explores how Theobromine induces cell death and apoptosis in bladder cancer cells and its impact on NRF2-related gene activity. Two human bladder cancer cell lines—RT112 (non-invasive) and HTB9 (invasive)—were employed. Cell viability was measured using the WST-1 assay, whereas apoptosis and caspase 3/7 activation were determined through flow cytometry. qPCR was performed to measure the expression of <i>NRF2, KEAP1</i>, and <i>P62</i> genes. Theobromine exhibited a dose-dependent reduction in cell viability in both RT112 and HTB9 bladder cancer cells, while also significantly enhancing apoptosis and caspase 3/7 activity (<i>p</i><0.0001). Flow cytometry analysis indicated G1-phase arrest in RT112 cells and S-phase accumulation in HTB9 cells following Theobromine treatment, while Cisplatin induced S-phase arrest in both cell lines. Theobromine suppressed <i>NRF2</i> and <i>P62</i> while increasing <i>KEAP1</i> levels in HTB9 cells, suggesting <i>NRF2</i> pathway inhibition. For RT112 cells, Theobromine upregulated <i>NRF2</i> and <i>P62</i> without altering <i>KEAP1</i> expression, highlighting cell type-specific modulation of the <i>NRF2</i> signaling pathway. This study shows that Theobromine differentially regulates the Nrf2-Keap1-p62 pathway in bladder cancer cells, inhibiting <i>NRF2</i> and <i>P62</i> expression in a cell-specific manner. These findings suggest its potential as a natural anticancer compound, warranting further <i>in vivo</i> studies to assess its therapeutic potential.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"80 1","pages":"64 - 75"},"PeriodicalIF":2.5,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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