<div><h3>Background</h3><div>Mitochondria are central regulators of cellular energy metabolism and its dysfunction drives cellular senescence. CISD2, a mitochondrial outer membrane protein and longevity gene, declines with age, highlighting its role in cellular senescence; however, how its post-translational modifications (PTMs) regulate cellular senescence remains poorly understood.</div></div><div><h3>Purpose</h3><div>This study aimed to elucidate the molecular mechanisms by which ginsenoside Rg5, as a regulator of histone acetyltransferase KAT8 activity, modulates CISD2 PTMs and thereby exerts anti-aging effects.</div></div><div><h3>Methods</h3><div>Using SILAC-based acetyl-proteomics, CISD2 was identified as a substrate of the KAT8/MSL acetyltransferase complex. The interaction between KAT8 and CISD2 was examined by Co-immunoprecipitation, GST pull-down, cycloheximide chase, and protein stability assays. KAT8-mediated acetylation of CISD2 was evaluated using in vitro lysine acetyltransferase assays, modification-specific antibodies, and site-directed mutagenesis. The functional impact of CISD2 acetylation on mitochondrial homeostasis was assessed by comparing CISD2 wild-type and K74 mutant cell lines using a series of assays, including ROS production, JC-1 staining, ATP measurement, SA-β-Gal staining, and analyses of mitochondrial morphology. The interaction between Rg5 and KAT8 was investigated using cellular thermal shift assays (CETSA), Rg5-PEGA pull-down, competitive binding assays, and UV-absorption spectroscopy. Evolutionary conservation was evaluated in C. elegans through genetic depletion of mys-2 (the KAT8 homolog) and cisd-1 (the CISD2 homolog). Mitochondrial function (JC-1, DCFH-DA, mtDNA content, and ATP levels) and cellular senescence (SA-β-Gal staining, EdU incorporation, and CCK-8 assays) were assessed in senescent cells and in C. elegans following CISD-1 and/or MYS-2 RNAi.</div></div><div><h3>Results</h3><div>We demonstrate for the first time that the KAT8/MSL complex acetylates CISD2 at K74, thereby preventing STUB1-mediated ubiquitination and degradation at K105. Importantly, acetylation of CISD2 at K74 preserves mitochondrial homeostasis and enhances cellular resistance to oxidative stress and aging. In <em>C. elegans</em>, simultaneous knockdown of MYS-2 and CISD-1 exacerbates mitochondrial dysfunction and shortens lifespan. Moreover, ginsenoside Rg5 directly binds to KAT8, promotes CISD2 acetylation at the K74 site, maintaining mitochondrial homeostasis, and alleviates aging-associated phenotypes in both cells and nematodes.</div></div><div><h3>Conclusion</h3><div>This study reveals that KAT8-mediated acetylation of CISD2 at K74 preserves mitochondrial homeostasis by inhibiting ubiquitin-mediated degradation, representing a critical mechanism for counteracting cellular senescence. Ginsenoside Rg5 acts as a KAT8 agonist to target and activate this pathway, thereby providing a novel strategy for anti-aging intervention.</di
{"title":"Ginsenoside Rg5 targets the KAT8-CISD2 axis to maintain mitochondrial homeostasis and antagonize senescence","authors":"Jinmeng Chu, Qingzhi Zhao, Yizhen Wang, Chengyu Cai, Xueli Cui, Na Zhang, Tiantian Xu, Haoqing Dou, Fei Wang, Feiran Yu, Yong Cai, Jingji Jin","doi":"10.1016/j.phymed.2026.157923","DOIUrl":"10.1016/j.phymed.2026.157923","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondria are central regulators of cellular energy metabolism and its dysfunction drives cellular senescence. CISD2, a mitochondrial outer membrane protein and longevity gene, declines with age, highlighting its role in cellular senescence; however, how its post-translational modifications (PTMs) regulate cellular senescence remains poorly understood.</div></div><div><h3>Purpose</h3><div>This study aimed to elucidate the molecular mechanisms by which ginsenoside Rg5, as a regulator of histone acetyltransferase KAT8 activity, modulates CISD2 PTMs and thereby exerts anti-aging effects.</div></div><div><h3>Methods</h3><div>Using SILAC-based acetyl-proteomics, CISD2 was identified as a substrate of the KAT8/MSL acetyltransferase complex. The interaction between KAT8 and CISD2 was examined by Co-immunoprecipitation, GST pull-down, cycloheximide chase, and protein stability assays. KAT8-mediated acetylation of CISD2 was evaluated using in vitro lysine acetyltransferase assays, modification-specific antibodies, and site-directed mutagenesis. The functional impact of CISD2 acetylation on mitochondrial homeostasis was assessed by comparing CISD2 wild-type and K74 mutant cell lines using a series of assays, including ROS production, JC-1 staining, ATP measurement, SA-β-Gal staining, and analyses of mitochondrial morphology. The interaction between Rg5 and KAT8 was investigated using cellular thermal shift assays (CETSA), Rg5-PEGA pull-down, competitive binding assays, and UV-absorption spectroscopy. Evolutionary conservation was evaluated in C. elegans through genetic depletion of mys-2 (the KAT8 homolog) and cisd-1 (the CISD2 homolog). Mitochondrial function (JC-1, DCFH-DA, mtDNA content, and ATP levels) and cellular senescence (SA-β-Gal staining, EdU incorporation, and CCK-8 assays) were assessed in senescent cells and in C. elegans following CISD-1 and/or MYS-2 RNAi.</div></div><div><h3>Results</h3><div>We demonstrate for the first time that the KAT8/MSL complex acetylates CISD2 at K74, thereby preventing STUB1-mediated ubiquitination and degradation at K105. Importantly, acetylation of CISD2 at K74 preserves mitochondrial homeostasis and enhances cellular resistance to oxidative stress and aging. In <em>C. elegans</em>, simultaneous knockdown of MYS-2 and CISD-1 exacerbates mitochondrial dysfunction and shortens lifespan. Moreover, ginsenoside Rg5 directly binds to KAT8, promotes CISD2 acetylation at the K74 site, maintaining mitochondrial homeostasis, and alleviates aging-associated phenotypes in both cells and nematodes.</div></div><div><h3>Conclusion</h3><div>This study reveals that KAT8-mediated acetylation of CISD2 at K74 preserves mitochondrial homeostasis by inhibiting ubiquitin-mediated degradation, representing a critical mechanism for counteracting cellular senescence. Ginsenoside Rg5 acts as a KAT8 agonist to target and activate this pathway, thereby providing a novel strategy for anti-aging intervention.</di","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157923"},"PeriodicalIF":8.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-05DOI: 10.1016/j.phymed.2026.157925
Saduddin , Mohd Aleemuddin Quamri , Monalisha Samal , Md Anzar Alam
Background and objectives
Subclinical hypothyroidism (SCH) is a thyroid disorder characterized by the absence of prominent symptoms of thyroid deficiency. It is more prevalent in women (11.4%) than in men (6.2%). While levothyroxine is commonly used to treat SCH, its use remains a topic of debate. Therefore, this study aimed to assess the efficacy of Jadwar in managing subclinical hypothyroidism.
Methods and materials
A randomized, single-blind, single-center, placebo-controlled study was conducted at the National Institute of Unani Medicine, Bengaluru, between August 2022 and January 2023. A total of 30 subjects, aged 20–60 years, with elevated serum thyroid-stimulating hormone (TSH) levels (4.5-15 mIU/L), were enrolled and randomly assigned to either the test group (n=15) or the placebo group (n=15). Participants in the test group received 500 mg of Jadwar, while those in the placebo group were administered placebo capsules (starch powder), with both groups taking 1 g twice a day (4 × 500 mg) for 56 days. Serum TSH and free thyroxine (FT4) levels, along with safety parameters (serum blood urea, serum creatinine, aspartate aminotransferase, and alanine aminotransferase), were measured at baseline and at the end of the trial . Additionally, subjective symptoms (fatigue, constipation, weight gain, cold intolerance, and dry skin) were evaluated every two weeks throughout the trial period.
Results
The test group demonstrated significant improvement compared to the control group in subjective parameters, including fatigue and constipation, with p-values of <0.001 and 0.028, respectively. However, no significant change was observed in weight gain (p=0.159). Additionally, a significant reduction in TSH levels was noted in the test group (p<0.001) compared to the control group. Statistical analysis was performed using Student's t-test for hypothyroidism.
Conclusion
Treatment with Jadwar is effective for managing subclinical hypothyroidism (SCH) and demonstrates a good safety profile, with no adverse events reported.
{"title":"Efficacy of Jadwar (Delphinium denudatum Wall. ex Hook.f. & Thomson) in subclinical hypothyroid patients: A single-blind, randomized placebo controlled trial","authors":"Saduddin , Mohd Aleemuddin Quamri , Monalisha Samal , Md Anzar Alam","doi":"10.1016/j.phymed.2026.157925","DOIUrl":"10.1016/j.phymed.2026.157925","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Subclinical hypothyroidism (SCH) is a thyroid disorder characterized by the absence of prominent symptoms of thyroid deficiency. It is more prevalent in women (11.4%) than in men (6.2%). While levothyroxine is commonly used to treat SCH, its use remains a topic of debate. Therefore, this study aimed to assess the efficacy of <em>Jadwar</em> in managing subclinical hypothyroidism.</div></div><div><h3>Methods and materials</h3><div>A randomized, single-blind, single-center, placebo-controlled study was conducted at the National Institute of Unani Medicine, Bengaluru, between August 2022 and January 2023. A total of 30 subjects, aged 20–60 years, with elevated serum thyroid-stimulating hormone (TSH) levels (4.5-15 mIU/L), were enrolled and randomly assigned to either the test group (n=15) or the placebo group (n=15). Participants in the test group received 500 mg of <em>Jadwar</em>, while those in the placebo group were administered placebo capsules (starch powder), with both groups taking 1 g twice a day (4 × 500 mg) for 56 days. Serum TSH and free thyroxine (FT4) levels, along with safety parameters (serum blood urea, serum creatinine, aspartate aminotransferase, and alanine aminotransferase), were measured at baseline and at the end of the trial . Additionally, subjective symptoms (fatigue, constipation, weight gain, cold intolerance, and dry skin) were evaluated every two weeks throughout the trial period.</div></div><div><h3>Results</h3><div>The test group demonstrated significant improvement compared to the control group in subjective parameters, including fatigue and constipation, with p-values of <0.001 and 0.028, respectively. However, no significant change was observed in weight gain (p=0.159). Additionally, a significant reduction in TSH levels was noted in the test group (p<0.001) compared to the control group. Statistical analysis was performed using Student's t-test for hypothyroidism.</div></div><div><h3>Conclusion</h3><div>Treatment with <em>Jadwar</em> is effective for managing subclinical hypothyroidism (SCH) and demonstrates a good safety profile, with no adverse events reported.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157925"},"PeriodicalIF":8.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-05DOI: 10.1016/j.phymed.2026.157926
Yu-jie Xi , Rui Cai , Shao-wei Hu , Bo Zhang , He Xu , Hong-yan Zhao , Hong-jun Yang , Fei-fei Guo
Background
Clinical evidence suggests a strong association between bone and muscle; however, the underlying mechanisms beyond the physiological relationship remain unclear.
Objective
To explore the pathological changes between bone and muscle using a bilateral ovariectomy (OVX) model and to evaluate the therapeutic potential of Rengong hugu power (RGHGP) as a peptide-derived intervention in regulating muscle–bone health.
Methods
Dual-tissue transcriptomics, network construction, and therapeutic intervention experiments were performed. Tissue-specific ligand–receptor and signaling pathway interaction networks were constructed based on dual-tissue transcriptomics sequencing data. Crucial ligands and receptors were identified to provide a foundation for interorgan communication. RGHGP was administered to regulate muscle–bone health, and its role as a ligand-like molecule binding to major receptors and pathways was verified. Potential peptides coordinating muscle–bone health were predicted. Weight, mass, imaging, and histopathological changes were assessed. TRAP staining, protein–peptide docking, and in vitro assays were used to evaluate the role of RGHGP and Laminin subunit beta 1 (LAMB1) on bone metabolism and osteoclastogenesis.
Results
OVX induced osteoporosis and muscle atrophy, whereas RGHGP reversed these pathological changes. Six myokines, represented by LAMB1 and connective tissue growth factor (CTGF), mediated bone metabolism through the mitogen-activated protein kinases(MAPK) pathway. In the OVX model, muscle-secreted LAMB1 and CTGF were upregulated in bone, activating MAPK signaling (phosphorylation of p38 and JNK) and increasing osteoclasts, as detected by TRAP staining. RGHGP treatment repressed LAMB1/CTGF expression, MAPK pathway activation, and osteoclast number. In vitro studies showed that the recombinant protein LAMB1 (rLAMB1) promotes osteoclast formation by activating the MAPK pathway. In contrast, the therapeutic peptide RGHGP effectively blocks this process. This therapeutic effect is structurally supported by protein–peptide docking, which confirmed the ability of RGHGP to bind key receptors in MAPK receptor signaling.
Conclusion
This study establishes a ligand (LAMB1)–receptor–pathway (MAPK) model for muscle–bone crosstalk, highlighting the role of muscle-derived ligands in counteracting muscle atrophy and regulating osteoclasts and osteoporosis. RGHGP-derived peptides act as muscle-mimetic ligands, reconfiguring muscle–bone crosstalk, and modulating skeletal remodeling. Furthermore, this reconfigured crosstalk influences energy metabolism, a process intrinsically linked to bone remodeling and overall musculoskeletal homeostasis. LAMB1 is identified as a pivotal mediator of integrated bone–muscle homeostasis.
{"title":"Targeting muscle-bone crosstalk with hormone-like peptides: Systems approach reveals RGHGP-mediated suppression of LAMB1-MAPK osteoclastogenesis","authors":"Yu-jie Xi , Rui Cai , Shao-wei Hu , Bo Zhang , He Xu , Hong-yan Zhao , Hong-jun Yang , Fei-fei Guo","doi":"10.1016/j.phymed.2026.157926","DOIUrl":"10.1016/j.phymed.2026.157926","url":null,"abstract":"<div><h3>Background</h3><div>Clinical evidence suggests a strong association between bone and muscle; however, the underlying mechanisms beyond the physiological relationship remain unclear.</div></div><div><h3>Objective</h3><div>To explore the pathological changes between bone and muscle using a bilateral ovariectomy (OVX) model and to evaluate the therapeutic potential of Rengong hugu power (RGHGP) as a peptide-derived intervention in regulating muscle–bone health.</div></div><div><h3>Methods</h3><div>Dual-tissue transcriptomics, network construction, and therapeutic intervention experiments were performed. Tissue-specific ligand–receptor and signaling pathway interaction networks were constructed based on dual-tissue transcriptomics sequencing data. Crucial ligands and receptors were identified to provide a foundation for interorgan communication. RGHGP was administered to regulate muscle–bone health, and its role as a ligand-like molecule binding to major receptors and pathways was verified. Potential peptides coordinating muscle–bone health were predicted. Weight, mass, imaging, and histopathological changes were assessed. TRAP staining, protein–peptide docking, and in vitro assays were used to evaluate the role of RGHGP and Laminin subunit beta 1 (LAMB1) on bone metabolism and osteoclastogenesis.</div></div><div><h3>Results</h3><div>OVX induced osteoporosis and muscle atrophy, whereas RGHGP reversed these pathological changes. Six myokines, represented by LAMB1 and connective tissue growth factor (CTGF), mediated bone metabolism through the mitogen-activated protein kinases(MAPK) pathway. In the OVX model, muscle-secreted LAMB1 and CTGF were upregulated in bone, activating MAPK signaling (phosphorylation of p38 and JNK) and increasing osteoclasts, as detected by TRAP staining. RGHGP treatment repressed LAMB1/CTGF expression, MAPK pathway activation, and osteoclast number. In vitro studies showed that the recombinant protein LAMB1 (rLAMB1) promotes osteoclast formation by activating the MAPK pathway. In contrast, the therapeutic peptide RGHGP effectively blocks this process. This therapeutic effect is structurally supported by protein–peptide docking, which confirmed the ability of RGHGP to bind key receptors in MAPK receptor signaling.</div></div><div><h3>Conclusion</h3><div>This study establishes a ligand (LAMB1)–receptor–pathway (MAPK) model for muscle–bone crosstalk, highlighting the role of muscle-derived ligands in counteracting muscle atrophy and regulating osteoclasts and osteoporosis. RGHGP-derived peptides act as muscle-mimetic ligands, reconfiguring muscle–bone crosstalk, and modulating skeletal remodeling. Furthermore, this reconfigured crosstalk influences energy metabolism, a process intrinsically linked to bone remodeling and overall musculoskeletal homeostasis. LAMB1 is identified as a pivotal mediator of integrated bone–muscle homeostasis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157926"},"PeriodicalIF":8.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-05DOI: 10.1016/j.phymed.2026.157921
Max Kam-Kwan Chan , Philip Chiu-Tsun Tang , Zoey Zeyuan Ji , Jeff Yat-Fai Chung , Aaron Qi Zhang , Yan-Fang Xian , Qing Zhang , Chun-Kwok Wong , Ka-Fai To , Chunjie Li , Dongmei Zhang , Patrick Ming-Kuen Tang
Cancer-associated fibroblasts (CAFs) are major components of the tumor microenvironment (TME). They are highly heterogeneous containing both anti-cancer and pro-tumor populations, which largely limits their translational development. Recently, we have identified macrophage‐myofibroblast transition (MMT) as a novel and key origin of pro-tumoral CAF in non-small-cell lung cancer (NSCLC), targeting it with Traditional Chinese Medicine (TCM) may represent a safe and effective strategy for solid tumors. Here, by spatial single-cell bioinformatics, we revealed that not only Smad3 activation but also Smad7 reduction occurs in the macrophages undergoing MMT in clinical NSCLC. Therefore, we optimized our well-established TCM-derived natural product formulation AANG, which remodulated TGF-β1/Smad3/Smad7 signaling and synergistically blocked MMT on the bone marrow derived macrophages (BMDM) in vitro. More encouragingly, this optimized AANG can effectively block MMT-derived cancer progression on mouse cancer models with syngeneic lung cancer LLC and human NSCLC xenograft A549 without side-effect in vivo. Thus, AANG may represent the first natural compound formulation for blocking MMT-derived pro-tumoral CAF formation in the clinical NSCLC.
{"title":"AANG: A natural compound formulation for targeting macrophage-myofibroblast transition in non-small-cell lung carcinoma","authors":"Max Kam-Kwan Chan , Philip Chiu-Tsun Tang , Zoey Zeyuan Ji , Jeff Yat-Fai Chung , Aaron Qi Zhang , Yan-Fang Xian , Qing Zhang , Chun-Kwok Wong , Ka-Fai To , Chunjie Li , Dongmei Zhang , Patrick Ming-Kuen Tang","doi":"10.1016/j.phymed.2026.157921","DOIUrl":"10.1016/j.phymed.2026.157921","url":null,"abstract":"<div><div>Cancer-associated fibroblasts (CAFs) are major components of the tumor microenvironment (TME). They are highly heterogeneous containing both anti-cancer and pro-tumor populations, which largely limits their translational development. Recently, we have identified macrophage‐myofibroblast transition (MMT) as a novel and key origin of pro-tumoral CAF in non-small-cell lung cancer (NSCLC), targeting it with Traditional Chinese Medicine (TCM) may represent a safe and effective strategy for solid tumors. Here, by spatial single-cell bioinformatics, we revealed that not only Smad3 activation but also Smad7 reduction occurs in the macrophages undergoing MMT in clinical NSCLC. Therefore, we optimized our well-established TCM-derived natural product formulation AANG, which remodulated TGF-β1/Smad3/Smad7 signaling and synergistically blocked MMT on the bone marrow derived macrophages (BMDM) in vitro. More encouragingly, this optimized AANG can effectively block MMT-derived cancer progression on mouse cancer models with syngeneic lung cancer LLC and human NSCLC xenograft A549 without side-effect in vivo. Thus, AANG may represent the first natural compound formulation for blocking MMT-derived pro-tumoral CAF formation in the clinical NSCLC.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157921"},"PeriodicalIF":8.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-05DOI: 10.1016/j.phymed.2026.157928
Feiyue Sun , Ruining She , Tong Yang , Bei Chen , Zi Liao , Jun Liao , Zhigang Mei
Background
Cerebral ischemia-reperfusion injury (CIRI) leads to severe mitochondrial dysfunction, which is a critical trigger of widespread neuronal apoptosis. Therefore, restoring mitochondrial homeostasis represents a key strategy for neuroprotection. Clinical observations suggest that the herbal pair Geum japonicum Thunb. var. chinense-P. decorata H. Andres (GJ-PD) shows therapeutic advantages in alleviating CIRI. However, its precise neuroprotective effects and underlying molecular mechanisms remain unclear.
Purpose
This study aimed to elucidate the protective mechanisms of combined GJ-PD against CIRI, with particular emphasis on mitochondrial transfer and neuronal PANoptosis.
Methods
Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to identify the chemical constituents of GJ-PD in brain. The mechanisms of GJ-PD in CIRI were investigated using transmission electron microscopy, Western blotting, immunofluorescence, immunohistochemistry, and pathological staining. In addition, an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R)-induced co-culture injury model was established using HT22 neurons and C8-D1A astrocytes. Scanning electron microscopy and laser confocal microscopy combined with MitoTracker staining were applied to explore the effects of GJ-PD on mitochondrial transfer and neuronal PANoptosis. Furthermore, the involvement of CD38 and Miro1 was examined using CD38- and Miro1-overexpression plasmids, both alone and in combination with GJ-PD treatment.
Results
GJ-PD exhibited significant neuroprotective effects following CIRI. It reduced cerebral infarct volume, alleviated neuronal oxidative stress and mitochondrial dysfunction, and increased CD38 and Miro1 expression, thereby attenuating programmed cell death. These effects contributed to its anti-CIRI efficacy. In vitro results were consistent with in vivo findings. Treatment with GJ-PD-containing plasma alone in the co-culture system enhanced mitochondrial transfer from C8-D1A astrocytes to neurons via tunneling nanotubes (TNTs). This was accompanied by increased neuronal proliferation and ATP production, along with reduced neuronal PANoptosis. Co-treatment with CD38- or Miro1-overexpressing C8-D1A cells further improved cell viability and ATP levels, decreased the expression of programmed cell death-related proteins, and elevated CD38 and Miro1 protein expression. Notably, Miro1 overexpression did not significantly affect CD38 expression.
Conclusions
GJ-PD promotes the transfer of astrocytic mitochondria to neurons via TNTs through the CD38/Miro1 pathway. This process alleviates neuronal PANoptosis and improves neurological function, thereby exerting protective effects against CIRI.
背景：脑缺血再灌注损伤（CIRI）导致严重的线粒体功能障碍，这是广泛的神经元凋亡的关键触发因素。因此，恢复线粒体稳态是神经保护的关键策略。临床观察表明，中药对金菊有一定的治疗作用。var. chinense-P。decorata H. Andres （GJ-PD）在缓解CIRI方面显示出治疗优势。然而，其确切的神经保护作用和潜在的分子机制尚不清楚。目的：本研究旨在阐明GJ-PD联合对CIRI的保护机制，重点研究线粒体转移和神经元PANoptosis。方法：采用超高效液相色谱联用四极杆飞行时间质谱法（UPLC-Q-TOF/MS）对脑用GJ-PD进行化学成分鉴定。采用透射电镜、Western blotting、免疫荧光、免疫组织化学、病理染色等方法研究GJ-PD在CIRI中的作用机制。此外，以HT22神经元和C8-D1A星形胶质细胞建立体外氧葡萄糖剥夺/再氧化（OGD/R）诱导的共培养损伤模型。采用扫描电镜、激光共聚焦显微镜联合MitoTracker染色观察GJ-PD对线粒体转移和神经元PANoptosis的影响。此外，使用CD38和Miro1过表达质粒，单独或联合GJ-PD治疗，检测CD38和Miro1的参与情况。结果：GJ-PD在CIRI后表现出明显的神经保护作用。减少脑梗死体积，减轻神经元氧化应激和线粒体功能障碍，增加CD38和Miro1表达，从而减轻程序性细胞死亡。这些作用有助于其抗ciri的作用。体外实验结果与体内实验结果一致。在共培养系统中单独使用含gj - pd的血浆，可增强线粒体通过隧道纳米管（TNTs）从C8-D1A星形胶质细胞向神经元的转移。这伴随着神经元增殖和ATP生成的增加，以及神经元PANoptosis的减少。与过表达CD38或Miro1的C8-D1A细胞共处理进一步提高了细胞活力和ATP水平，降低了程序性细胞死亡相关蛋白的表达，并提高了CD38和Miro1蛋白的表达。值得注意的是，Miro1过表达并未显著影响CD38的表达。结论：GJ-PD通过CD38/Miro1通路促进星形细胞线粒体通过tnt向神经元转移。这一过程减轻了神经元PANoptosis，改善了神经功能，从而对CIRI发挥保护作用。
{"title":"Geum japonicum Thunb. var. Chinese-P.decorata H.Andres herbal pair ameliorates CIRI-induced neuronal injury by facilitating mitochondrial transfer via the CD38/Miro1 signaling pathway","authors":"Feiyue Sun , Ruining She , Tong Yang , Bei Chen , Zi Liao , Jun Liao , Zhigang Mei","doi":"10.1016/j.phymed.2026.157928","DOIUrl":"10.1016/j.phymed.2026.157928","url":null,"abstract":"<div><h3>Background</h3><div>Cerebral ischemia-reperfusion injury (CIRI) leads to severe mitochondrial dysfunction, which is a critical trigger of widespread neuronal apoptosis. Therefore, restoring mitochondrial homeostasis represents a key strategy for neuroprotection. Clinical observations suggest that the herbal pair <em>Geum japonicum</em> Thunb. var. <em>chinense</em>-<em>P. decorata</em> H. Andres (GJ-PD) shows therapeutic advantages in alleviating CIRI. However, its precise neuroprotective effects and underlying molecular mechanisms remain unclear.</div></div><div><h3>Purpose</h3><div>This study aimed to elucidate the protective mechanisms of combined GJ-PD against CIRI, with particular emphasis on mitochondrial transfer and neuronal PANoptosis.</div></div><div><h3>Methods</h3><div>Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to identify the chemical constituents of GJ-PD in brain. The mechanisms of GJ-PD in CIRI were investigated using transmission electron microscopy, Western blotting, immunofluorescence, immunohistochemistry, and pathological staining. In addition, an <em>in vitro</em> oxygen-glucose deprivation/reoxygenation (OGD/R)-induced co-culture injury model was established using HT22 neurons and C8-D1A astrocytes. Scanning electron microscopy and laser confocal microscopy combined with MitoTracker staining were applied to explore the effects of GJ-PD on mitochondrial transfer and neuronal PANoptosis. Furthermore, the involvement of CD38 and Miro1 was examined using CD38- and Miro1-overexpression plasmids, both alone and in combination with GJ-PD treatment.</div></div><div><h3>Results</h3><div>GJ-PD exhibited significant neuroprotective effects following CIRI. It reduced cerebral infarct volume, alleviated neuronal oxidative stress and mitochondrial dysfunction, and increased CD38 and Miro1 expression, thereby attenuating programmed cell death. These effects contributed to its anti-CIRI efficacy. <em>In vitro</em> results were consistent with <em>in vivo</em> findings. Treatment with GJ-PD-containing plasma alone in the co-culture system enhanced mitochondrial transfer from C8-D1A astrocytes to neurons via tunneling nanotubes (TNTs). This was accompanied by increased neuronal proliferation and ATP production, along with reduced neuronal PANoptosis. Co-treatment with CD38- or Miro1-overexpressing C8-D1A cells further improved cell viability and ATP levels, decreased the expression of programmed cell death-related proteins, and elevated CD38 and Miro1 protein expression. Notably, Miro1 overexpression did not significantly affect CD38 expression.</div></div><div><h3>Conclusions</h3><div>GJ-PD promotes the transfer of astrocytic mitochondria to neurons via TNTs through the CD38/Miro1 pathway. This process alleviates neuronal PANoptosis and improves neurological function, thereby exerting protective effects against CIRI.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157928"},"PeriodicalIF":8.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-05DOI: 10.1016/j.phymed.2026.157922
Jianfeng Wu , Siqi Liu , Zhen Ma , Badrakh Munkhbayar , Qichao Liao , Menglong Hou , Yutian Wei , Yang Xiao , Yang Wang , Ruxue Chen , Batbold Batsaikhan , Khongorzul Batchuluun , Lei Zhou , Yixing Li
Background
Metabolic associated fatty liver disease (MAFLD) is a chronic liver condition with a high global prevalence. Obesity and its associated insulin resistance are among the main risk factors for MAFLD, for which no effective clinical treatments are currently available. Aloesin, a natural chromone compound derived from Aloe vera, has anti-inflammatory, antioxidant, anticancer, and antidiabetes activity. However, its involvement in MAFLD has not been systematically studied.
Purpose
This study investigated the effectiveness of aloesin against MAFLD and obesity and elucidated its potential molecular mechanism.
Methods
Aloesin was added to the high-fat diet-of an induced mouse model and to oleic acid/palmitic acid-induced HepG2 cells to explore its effect on lipid metabolism. Molecular targets were identified by reverse docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS).
Results
Aloesin significantly reduced lipid accumulation in hepatocytes in both the high-fat diet-induced MAFLD mouse model and the oleic acid/palmitic acid-induced HepG2 cells. It also alleviated oxidative stress and energy metabolism disorders and decreased the body fat mass in mice fed the high-fat diet, which ameliorated the pathological features of MAFLD and obesity. Target prediction and validation identified TGFBR1 as a direct target of aloesin, which was confirmed by CETSA and DARTS. Functional experiments demonstrated that overexpression of TGFBR1 increased lipid accumulation and metabolic disturbances, which were reversed by aloesin.
Conclusion
Aloesin improved lipid deposition and slowed the progression of MAFLD by targeting TGFBR1. The results support its potential application for the prevention and treatment of MAFLD.
{"title":"Aloesin improves metabolic associated fatty liver disease and obesity by targeting TGFBR1","authors":"Jianfeng Wu , Siqi Liu , Zhen Ma , Badrakh Munkhbayar , Qichao Liao , Menglong Hou , Yutian Wei , Yang Xiao , Yang Wang , Ruxue Chen , Batbold Batsaikhan , Khongorzul Batchuluun , Lei Zhou , Yixing Li","doi":"10.1016/j.phymed.2026.157922","DOIUrl":"10.1016/j.phymed.2026.157922","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic associated fatty liver disease (MAFLD) is a chronic liver condition with a high global prevalence. Obesity and its associated insulin resistance are among the main risk factors for MAFLD, for which no effective clinical treatments are currently available. Aloesin, a natural chromone compound derived from <em>Aloe vera,</em> has anti-inflammatory, antioxidant, anticancer, and antidiabetes activity. However, its involvement in MAFLD has not been systematically studied.</div></div><div><h3>Purpose</h3><div>This study investigated the effectiveness of aloesin against MAFLD and obesity and elucidated its potential molecular mechanism.</div></div><div><h3>Methods</h3><div>Aloesin was added to the high-fat diet-of an induced mouse model and to oleic acid/palmitic acid-induced HepG2 cells to explore its effect on lipid metabolism. Molecular targets were identified by reverse docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS).</div></div><div><h3>Results</h3><div>Aloesin significantly reduced lipid accumulation in hepatocytes in both the high-fat diet-induced MAFLD mouse model and the oleic acid/palmitic acid-induced HepG2 cells. It also alleviated oxidative stress and energy metabolism disorders and decreased the body fat mass in mice fed the high-fat diet, which ameliorated the pathological features of MAFLD and obesity. Target prediction and validation identified TGFBR1 as a direct target of aloesin, which was confirmed by CETSA and DARTS. Functional experiments demonstrated that overexpression of TGFBR1 increased lipid accumulation and metabolic disturbances, which were reversed by aloesin.</div></div><div><h3>Conclusion</h3><div>Aloesin improved lipid deposition and slowed the progression of MAFLD by targeting TGFBR1. The results support its potential application for the prevention and treatment of MAFLD.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157922"},"PeriodicalIF":8.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-03DOI: 10.1016/j.phymed.2026.157834
Libin Xu , Siyu Li , Jiaxin Qi , Yan Mi , Ying Zhang , Yuxin Yang , Yingjie Wang , Di Zhou , Ning Li , Yue Hou
{"title":"Corrigendum to “Effusol ameliorates ischemic stroke by targeting NLRP3 protein to regulate NLRP3 inflammasome-mediated pyroptosis” [Phytomedicine, 136 (2025) 156253/PMID: 39615210]","authors":"Libin Xu , Siyu Li , Jiaxin Qi , Yan Mi , Ying Zhang , Yuxin Yang , Yingjie Wang , Di Zhou , Ning Li , Yue Hou","doi":"10.1016/j.phymed.2026.157834","DOIUrl":"10.1016/j.phymed.2026.157834","url":null,"abstract":"","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"152 ","pages":"Article 157834"},"PeriodicalIF":8.3,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146114025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-03DOI: 10.1016/j.phymed.2026.157918
Sina Tamaddonfard , Amir Abbas Farshid , Esmaeal Tamaddonfard , Seyedeh Soraya Mahmoudi , Amir Erfanparast , Mehdi Imani
Background
Crocetin (CRT), one of the active ingredients in saffron, exerts health-promoting effects on body systems such as neuroprotective, cardioprotective and hepatoprotective properties.
Purpose
In the present study, the effects of CRT and lansoprazole (LAP), as a reference drug, were investigated on indomethacin (IND)-induced gastric ulcer and related anxiety.
Methods
Thirty rats were divided into five groups of six. Groups 1 and 2 received vehicle and groups 3, 4 and 5 received CRT (5 and 20 mg/kg) and LAP (30 mg/kg) for seven consecutive days. All groups were deprived of food on day 6. On day 7, group 1 was treated with vehicle and groups 2, 3, 4 and 5 received 50 mg/kg IND. Anxiety and locomotor activity were recorded, and then the animals were euthanized and stomach and hippocampus samples were taken. The effects of the aforementioned treatments were studied in 24 intact rats in four equal groups.
Results
CRT (20 mg/kg) and LAP restored IND-induced alterations in the gastric content volume and pH and ulcer index and protection and cyclooxygenases 1 and 2 and prostaglandin E2 and gastric mucosal and hippocampal superoxide dismutase, malondialdehyde, tumor necrosis factor-alpha, interleukin-1β and caspase-3 and hippocampal brain derived neurotrophic factor. Histopathological alterations in the gastric mucosa and hippocampus were improved, and anxiety was suppressed. Intact rats were not influenced.
Conclusions
CRT and LAP caused protective effects against IND-induced gastric ulcer and by antioxidative, anti-inflammatory, anti-apoptotic and PGE2-increasing activities. Anxiolytic effects of CRT and LAP were also observed.
{"title":"Effects of crocetin, a constituent of saffron, on indomethacin-induced gastric ulcer and related anxiety-like behavior in rats","authors":"Sina Tamaddonfard , Amir Abbas Farshid , Esmaeal Tamaddonfard , Seyedeh Soraya Mahmoudi , Amir Erfanparast , Mehdi Imani","doi":"10.1016/j.phymed.2026.157918","DOIUrl":"10.1016/j.phymed.2026.157918","url":null,"abstract":"<div><h3>Background</h3><div>Crocetin (CRT), one of the active ingredients in saffron, exerts health-promoting effects on body systems such as neuroprotective, cardioprotective and hepatoprotective properties.</div></div><div><h3>Purpose</h3><div>In the present study, the effects of CRT and lansoprazole (LAP), as a reference drug, were investigated on indomethacin (IND)-induced gastric ulcer and related anxiety.</div></div><div><h3>Methods</h3><div>Thirty rats were divided into five groups of six. Groups 1 and 2 received vehicle and groups 3, 4 and 5 received CRT (5 and 20 mg/kg) and LAP (30 mg/kg) for seven consecutive days. All groups were deprived of food on day 6. On day 7, group 1 was treated with vehicle and groups 2, 3, 4 and 5 received 50 mg/kg IND. Anxiety and locomotor activity were recorded, and then the animals were euthanized and stomach and hippocampus samples were taken. The effects of the aforementioned treatments were studied in 24 intact rats in four equal groups.</div></div><div><h3>Results</h3><div>CRT (20 mg/kg) and LAP restored IND-induced alterations in the gastric content volume and pH and ulcer index and protection and cyclooxygenases 1 and 2 and prostaglandin E2 and gastric mucosal and hippocampal superoxide dismutase, malondialdehyde, tumor necrosis factor-alpha, interleukin-1β and caspase-3 and hippocampal brain derived neurotrophic factor. Histopathological alterations in the gastric mucosa and hippocampus were improved, and anxiety was suppressed. Intact rats were not influenced.</div></div><div><h3>Conclusions</h3><div>CRT and LAP caused protective effects against IND-induced gastric ulcer and by antioxidative, anti-inflammatory, anti-apoptotic and PGE<sub>2</sub>-increasing activities. Anxiolytic effects of CRT and LAP were also observed.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157918"},"PeriodicalIF":8.3,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-03DOI: 10.1016/j.phymed.2026.157920
Yuan Chen , Guang Yue , Yanjun Liu , Wei Wang , Ge Jiang , Jinhua Zhang , Zhuo Ga , Yanfei Zhang , Xiaoya Liu , Qingjia Ren , Caolong Li
<div><h3>Background</h3><div>Chronic atrophic gastritis (CAG) is a pivotal premalignant stage in the Correa cascade, characterized by progressive and largely irreversible loss of gastric glands and an elevated risk of gastric cancer. Renqingchangjue (RQCJ), a classical Tibetan multi-herb formula, has demonstrated clinical and pharmacological benefits in gastritis, yet its mechanisms of action in CAG remain inadequately defined.</div></div><div><h3>Purpose</h3><div>This study aims to clarify the therapeutic efficacy and mechanistic basis of RQCJ in CAG.</div></div><div><h3>Methods</h3><div>We established a network pharmacology–bioinformatics workflow to predict potential RQCJ targets in CAG, integrating targets obtained from TCMSP/SwissTargetPrediction with CAG-related genes to construct a STRING protein–protein interaction (PPI) network and perform GO/KEGG enrichment analyses. Constituents were characterized by UHPLC–HRMS/MS. An MNNG-induced CAG mouse model (control group, model group, Weifuchun positive control group, RQCJ low-dose group and RQCJ high-dose group) was validated by histopathology (H&E), immunohistochemistry (IHC), immunofluorescence (IF), TUNEL, ELISA, and Western blot (WB). In vitro, MNNG-injured GES-1 cells were evaluated using CCK-8, scratch wound-healing, and Annexin V–FITC/PI flow cytometry. Mechanistically, RT-qPCR, WB, and reference-based transcriptome sequencing of gastric tissue were employed, and compound druggability was assessed by AutoDock Vina docking.</div></div><div><h3>Results</h3><div>RQCJ markedly ameliorated MNNG-induced chronic atrophic gastritis in vivo and in vitro. UHPLC–HRMS/MS profiling identified 43 constituents, of which 31 were detected as circulating prototypes. Network pharmacology first predicted 154 putative RQCJ–CAG targets enriched in TNF/NF-κB signaling; integrating serum-absorbed component targets with CAG-related genes refined this to 140 high-confidence targets with consistent TNF/NF-κB enrichment. Functionally, RQCJ (20–40 μg/mL) improved GES-1 cell viability and migration while suppressing apoptosis, and in mice dose-dependently repaired gastric mucosal architecture, lowered TNF-α, IL-1β and IL-6, and normalized gastrin and pepsinogen. RQCJ also reduced IL-8, CCL2 and CXCL1 mRNA and increased IL-10 in both models. Mechanistically, it inhibited phosphorylation of IKKβ, IκBα and NF-κB p65 in a dose- and time-dependent manner, decreased cleaved caspase-8/3, restored the Bax/Bcl-2 ratio. Transcriptomics confirmed enrichment of NF-κB and apoptosis pathways, and intersecting differentially expressed genes with the 140 serum-based targets yielded 99 core genes converging on TNF/NF-κB-mediated apoptosis. Molecular docking further supported target engagement, with a chromen-7-ol derivative showing strong predicted affinity for MMP9.</div></div><div><h3>Conclusions</h3><div>Together, these multi-level data indicate that RQCJ exerts clinically relevant protection against CAG via multi-component su
背景：慢性萎缩性胃炎（CAG）是Correa级联中一个关键的癌前阶段，其特征是胃腺的进行性和大部分不可逆的丧失以及胃癌的风险升高。仁青肠觉是一种经典的藏药复方，其治疗胃炎的临床和药理作用已得到证实，但其治疗CAG的作用机制尚不明确。目的：本研究旨在阐明RQCJ治疗CAG的疗效及机制基础。方法：建立网络药理学-生物信息学工作流程预测CAG中潜在的RQCJ靶点，将TCMSP/SwissTargetPrediction获得的靶点与CAG相关基因整合，构建STRING蛋白-蛋白相互作用（STRING protein-protein interaction， PPI）网络，并进行GO/KEGG富集分析。采用UHPLC-HRMS/MS对成分进行表征。采用组织病理学（H&E）、免疫组化（IHC）、免疫荧光（IF）、TUNEL、ELISA、Western blot等方法对mnng诱导的CAG小鼠模型（对照组、模型组、维复春阳性对照组、RQCJ低剂量组和RQCJ高剂量组）进行验证。体外，采用CCK-8、划伤创面愈合和Annexin V-FITC/PI流式细胞术评估mnng损伤的GES-1细胞。在机制上，采用RT-qPCR、WB和基于参考的胃组织转录组测序，并通过AutoDock Vina对接评估复方药物的可药物性。结果：RQCJ在体内外均能显著改善mnng诱导的慢性萎缩性胃炎。UHPLC-HRMS/MS分析鉴定出43种成分，其中31种为循环原型。网络药理学首次预测了154个富含TNF/NF-κB信号的RQCJ-CAG靶点；将血清吸收成分靶点与cag相关基因整合，将其细化为140个高可信度靶点，具有一致的TNF/NF-κB富集。在功能上，RQCJ （20 ~ 40 μg/mL）可提高GES-1细胞活力和迁移能力，抑制细胞凋亡，并在小鼠胃粘膜结构中呈剂量依赖性修复，降低TNF-α、IL-1β和IL-6，并使胃泌素和胃蛋白酶原正常化。RQCJ还降低了两种模型中IL-8、CCL2和CXCL1 mRNA的表达，增加了IL-10的表达。机制上，其抑制IKKβ、i -κ b α和NF-κ b p65磷酸化呈剂量依赖性和时间依赖性，降低裂解caspase-8/3，恢复Bax/Bcl-2比值。转录组学证实了NF-κB和凋亡通路的富集，并将差异表达基因与140个基于血清的靶点相交，获得了99个核心基因，这些基因聚集在TNF/NF-κB介导的凋亡中。分子对接进一步支持了靶标结合，铬-7-醇衍生物显示出对MMP9的强亲和性。结论：这些多层面数据表明，RQCJ通过多组分抑制TNF-NF-κ b /Caspase-3轴、促/抗炎细胞因子的广泛再平衡以及恢复胃功能，对CAG具有临床相关的保护作用。
{"title":"Renqingchangjue ameliorates MNNG-induced chronic atrophic gastritis by inhibiting the TNF/NF-κB/Caspase-3 axis","authors":"Yuan Chen , Guang Yue , Yanjun Liu , Wei Wang , Ge Jiang , Jinhua Zhang , Zhuo Ga , Yanfei Zhang , Xiaoya Liu , Qingjia Ren , Caolong Li","doi":"10.1016/j.phymed.2026.157920","DOIUrl":"10.1016/j.phymed.2026.157920","url":null,"abstract":"<div><h3>Background</h3><div>Chronic atrophic gastritis (CAG) is a pivotal premalignant stage in the Correa cascade, characterized by progressive and largely irreversible loss of gastric glands and an elevated risk of gastric cancer. Renqingchangjue (RQCJ), a classical Tibetan multi-herb formula, has demonstrated clinical and pharmacological benefits in gastritis, yet its mechanisms of action in CAG remain inadequately defined.</div></div><div><h3>Purpose</h3><div>This study aims to clarify the therapeutic efficacy and mechanistic basis of RQCJ in CAG.</div></div><div><h3>Methods</h3><div>We established a network pharmacology–bioinformatics workflow to predict potential RQCJ targets in CAG, integrating targets obtained from TCMSP/SwissTargetPrediction with CAG-related genes to construct a STRING protein–protein interaction (PPI) network and perform GO/KEGG enrichment analyses. Constituents were characterized by UHPLC–HRMS/MS. An MNNG-induced CAG mouse model (control group, model group, Weifuchun positive control group, RQCJ low-dose group and RQCJ high-dose group) was validated by histopathology (H&E), immunohistochemistry (IHC), immunofluorescence (IF), TUNEL, ELISA, and Western blot (WB). In vitro, MNNG-injured GES-1 cells were evaluated using CCK-8, scratch wound-healing, and Annexin V–FITC/PI flow cytometry. Mechanistically, RT-qPCR, WB, and reference-based transcriptome sequencing of gastric tissue were employed, and compound druggability was assessed by AutoDock Vina docking.</div></div><div><h3>Results</h3><div>RQCJ markedly ameliorated MNNG-induced chronic atrophic gastritis in vivo and in vitro. UHPLC–HRMS/MS profiling identified 43 constituents, of which 31 were detected as circulating prototypes. Network pharmacology first predicted 154 putative RQCJ–CAG targets enriched in TNF/NF-κB signaling; integrating serum-absorbed component targets with CAG-related genes refined this to 140 high-confidence targets with consistent TNF/NF-κB enrichment. Functionally, RQCJ (20–40 μg/mL) improved GES-1 cell viability and migration while suppressing apoptosis, and in mice dose-dependently repaired gastric mucosal architecture, lowered TNF-α, IL-1β and IL-6, and normalized gastrin and pepsinogen. RQCJ also reduced IL-8, CCL2 and CXCL1 mRNA and increased IL-10 in both models. Mechanistically, it inhibited phosphorylation of IKKβ, IκBα and NF-κB p65 in a dose- and time-dependent manner, decreased cleaved caspase-8/3, restored the Bax/Bcl-2 ratio. Transcriptomics confirmed enrichment of NF-κB and apoptosis pathways, and intersecting differentially expressed genes with the 140 serum-based targets yielded 99 core genes converging on TNF/NF-κB-mediated apoptosis. Molecular docking further supported target engagement, with a chromen-7-ol derivative showing strong predicted affinity for MMP9.</div></div><div><h3>Conclusions</h3><div>Together, these multi-level data indicate that RQCJ exerts clinically relevant protection against CAG via multi-component su","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157920"},"PeriodicalIF":8.3,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-03DOI: 10.1016/j.phymed.2026.157919
Dong Xue , Xixi Hu , Ranchang Li , Tongyu Sun , Siying Qian , Fuxin Chu , Huawu Gao , Feng Li , Biao Cai
Background
Alzheimer’s disease (AD) is increasingly recognized as a multisystem disorder shaped not only by central neurodegeneration but also by peripheral metabolic and immune dysregulation. Growing evidence highlights the gut microbiota and its metabolites as key modulators of amyloid accumulation, tau phosphorylation, neuroinflammation, and microglial dysfunction.
Purpose
This review aims to synthesize current advances on how plant-derived bioactive compounds modulate AD pathophysiology through microbiota-dependent metabolic and neuroimmune mechanisms, and to establish a systems-level framework linking botanical interventions to gut microbiota remodeling and metabolite signaling.
Methods
A comprehensive literature survey was conducted using PubMed, Web of Science, ScienceDirect, and Google Scholar, covering publications from 2010 to 2026. Studies investigating gut microbiota, microbial metabolites, and plant-derived bioactive compounds in AD-related metabolic, immune, and neurodegenerative pathways were systematically reviewed and integrated.
Results
Plant-derived bioactive compounds, including phytochemicals, polysaccharides, and multi-herb formulations, interact extensively with the gut microbiota, undergoing microbial biotransformation to yield more active metabolites while simultaneously reshaping microbial community structure and metabolite profiles. These bidirectional interactions position the microbiota as a central mediator of plant-derived therapeutic activity. We summarize current evidence on how plant-derived compounds influence AD pathophysiology through microbiota-dependent metabolic and neuroimmune pathways. Major microbial metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), bile acids (BAs), and indole derivatives, are discussed, together with their regulatory roles in signaling networks such as nuclear factor κB (NF-κB), phosphatidylinositol 3-kinase/Akt (PI3K/Akt), cAMP response element-binding protein/brain-derived neurotrophic factor (CREB/BDNF), and triggering receptor expressed on myeloid cells 2 (TREM2)-associated microglial states. We further summarize evidence for synergistic strategies combining plant bioactives with probiotics and highlight advances in microbial biotransformation, precision metabolite modulation, and engineered microbial systems. Finally, future directions integrating multi-omics, personalized microbiota-guided interventions, and synthetic biology are outlined to support the development of targeted, mechanism-based therapies.
Conclusion
By framing AD through a gut microbiota-centered perspective, this review provides a unified mechanistic foundation for the development of next-generation interventions based on plant-derived compounds and microbiota regulation.
背景：阿尔茨海默病（AD）越来越被认为是一种多系统疾病，不仅由中枢神经退行性变引起，还由外周代谢和免疫失调引起。越来越多的证据表明，肠道微生物群及其代谢物是淀粉样蛋白积累、tau磷酸化、神经炎症和小胶质细胞功能障碍的关键调节剂。目的：本文旨在综述植物源性生物活性化合物如何通过微生物依赖的代谢和神经免疫机制调节阿尔茨海默病病理生理的最新进展，并建立植物干预与肠道微生物群重塑和代谢物信号传导之间的系统水平框架。方法：采用PubMed、Web of Science、ScienceDirect、谷歌Scholar等数据库，对2010 - 2026年发表的文献进行综合调查。对肠道微生物群、微生物代谢物和植物源性生物活性化合物在ad相关代谢、免疫和神经退行性途径中的研究进行了系统的回顾和整合。结果：植物衍生的生物活性化合物，包括植物化学物质、多糖和多种草药配方，与肠道微生物群广泛相互作用，经历微生物生物转化，产生更活跃的代谢物，同时重塑微生物群落结构和代谢物谱。这些双向相互作用将微生物群定位为植物源性治疗活性的中心介质。我们总结了目前关于植物源性化合物如何通过微生物依赖的代谢和神经免疫途径影响AD病理生理的证据。主要的微生物代谢物，包括短链脂肪酸（SCFAs）、三甲胺n-氧化物（TMAO）、胆胆酸（BAs）和吲哚衍生物，以及它们在信号网络中的调节作用，如核因子κB （NF-κB）、磷脂酰肌醇3-激酶/Akt （PI3K/Akt）、cAMP反应元件结合蛋白/脑源性神经营养因子（CREB/BDNF）和髓样细胞2 （TREM2）相关小胶质状态的触发受体表达。我们进一步总结了将植物生物活性与益生菌相结合的协同策略的证据，并重点介绍了微生物生物转化、精确代谢物调节和工程微生物系统的进展。最后，展望了整合多组学、个性化微生物引导干预和合成生物学的未来方向，以支持靶向、基于机制的治疗方法的发展。结论：通过以肠道微生物群为中心的视角来构建AD，本综述为基于植物源性化合物和微生物群调节的下一代干预措施的开发提供了统一的机制基础。
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