Traditional Chinese herbal medicine(TCM)has been shown to enhance the efficacy of standard anticancer agents.However,there are only a limited number of well-controlled preclinical and clinical studies documenting the ...Traditional Chinese herbal medicine(TCM)has been shown to enhance the efficacy of standard anticancer agents.However,there are only a limited number of well-controlled preclinical and clinical studies documenting the potential benefit of TCM.OBJECTIVE To identify biologically active formulas that were effective against colorectal cancer(CRC)by screening TCM formulas in in vitro and in vivo animal models.METHODS Cell growth assays,cell cycle analysis,immunoblot analysis and qRT-PCR were performed to investigate the mechanism(s)of action of the formulason human CRC cells.In vivo animal models were used to evaluate the antitumor activity of formulasalone and in combination with 5-FU.RESULTS We identified Huangqin Gegen Tang(HQGGT)which suppressed the in vivo growth of human CRC HT-29 xenografts.HQGGT significantly inhibited the growth of CRC cell lines.HQGGT enhanced the cytotoxicity of 5-FU against human 5-FU-resistant cells(H630R1)and mouse colon cancer cells(MC38).This synergy was the result of suppression of thymidylate synthase expression by HQGGT.HQGGT significantly enhanced the antitumor effect of 5-FU in mice bearing MC38 xenografts.Ongoing studies have identified Huangqin as the herb responsible for TS inhibi⁃tion.CONCLUSION These findings provide support for the potential role of HQGGT as a novel modulator of fluoropyrim⁃idine chemotherapy for CRC treatment.展开更多
Regulatory T cells(Treg cells)are a specialized subset of CD4+T cells defined by expression of the lineage-specifying transcription factor FOXP3 and a potent capacity to maintain peripheral immune tolerance.The modern...Regulatory T cells(Treg cells)are a specialized subset of CD4+T cells defined by expression of the lineage-specifying transcription factor FOXP3 and a potent capacity to maintain peripheral immune tolerance.The modern concept of Tregs was catalyzed by Shimon Sakaguchi's identification of CD4+CD25+suppressive T cells and subsequent work establishing FOXP3 as a central determinant of Treg cell development and function;together with landmark FOXP3 genetic discoveries by Mary E.Brunkow and Fred Ramsdell,these advances transformed understanding of immune homeostasis and were recognized by the 2025 Nobel Prize in Physiology or Medicine.Under normal physiological conditions,FOXP3+Treg cells restrain autoreactive lymphocytes,prevent excessive inflammation,and shape antigen-presenting cell activity through contact-dependent pathways and suppressive cytokines,thereby protecting tissues from immune-mediated damage.Disruption of Treg abundance,stability,or suppressive capacity can therefore lead to immune dysregulation and disease.Over the past two decades,Treg cells have become a major focus of immunology because their roles are highly context-dependent.In autoimmune and chronic inflammatory diseases,impaired Treg cell function or insufficient Treg activity contributes to loss of tolerance and persistent tissue injury,supporting therapeutic approaches designed to enhance Treg cell number,stability,and suppressive potency.In contrast,many cancers exploit Treg cells by promoting their expansion,activation,and recruitment into the tumor microenvironment(TME),where they blunt antitumor immunity by suppressing cytotoxic T-cell priming and effector function,limiting dendritic cell activation,and fostering immune escape.In both settings,immune checkpoint pathways critically influence Treg cell biology.Beyond PD-1/PD-L1 and CTLA-4,emerging checkpoints and costimulatory receptors,including TIGIT,TIM-3,LAG-3,and OX40,modulate Treg cell generation,stability,and suppressive functions,thereby shaping the balance between tolerance and immunity.Meanwhile,immunometabolic adaptations further tune Treg cell fitness and function in inflamed tissues and tumors;lipid utilization and mitochondrial programs,among other metabolic axes,enable Treg cells to persist in nutrient-and oxygen-restricted microenvironments,while microenvironmental stress can drive functional remodeling or fragility in a subset-dependent manner.In this review,we summarize the discovery and defining biological features of Treg cells,highlight core suppressive mechanisms and regulatory circuits,and synthesize evidence for the dual roles of Treg cells in preventing autoimmunity yet enabling tumor immune evasion.We further outline current and emerging therapeutic strategies aimed at augmenting Treg cell activity to restore tolerance in autoimmune disease,or selectively depleting,functionally inhibiting,and reprogramming tumor-resident Treg cells to enhance cancer immunotherapy.Overall we discuss how deeper insight into Treg heterogeneity,checkpoint control,and immunometabolic regulation may enable more precise Treg celldirected interventions and inform next-generation immunotherapeutic combinations across immune-mediated and malignant diseases.展开更多
文摘Traditional Chinese herbal medicine(TCM)has been shown to enhance the efficacy of standard anticancer agents.However,there are only a limited number of well-controlled preclinical and clinical studies documenting the potential benefit of TCM.OBJECTIVE To identify biologically active formulas that were effective against colorectal cancer(CRC)by screening TCM formulas in in vitro and in vivo animal models.METHODS Cell growth assays,cell cycle analysis,immunoblot analysis and qRT-PCR were performed to investigate the mechanism(s)of action of the formulason human CRC cells.In vivo animal models were used to evaluate the antitumor activity of formulasalone and in combination with 5-FU.RESULTS We identified Huangqin Gegen Tang(HQGGT)which suppressed the in vivo growth of human CRC HT-29 xenografts.HQGGT significantly inhibited the growth of CRC cell lines.HQGGT enhanced the cytotoxicity of 5-FU against human 5-FU-resistant cells(H630R1)and mouse colon cancer cells(MC38).This synergy was the result of suppression of thymidylate synthase expression by HQGGT.HQGGT significantly enhanced the antitumor effect of 5-FU in mice bearing MC38 xenografts.Ongoing studies have identified Huangqin as the herb responsible for TS inhibi⁃tion.CONCLUSION These findings provide support for the potential role of HQGGT as a novel modulator of fluoropyrim⁃idine chemotherapy for CRC treatment.
文摘Regulatory T cells(Treg cells)are a specialized subset of CD4+T cells defined by expression of the lineage-specifying transcription factor FOXP3 and a potent capacity to maintain peripheral immune tolerance.The modern concept of Tregs was catalyzed by Shimon Sakaguchi's identification of CD4+CD25+suppressive T cells and subsequent work establishing FOXP3 as a central determinant of Treg cell development and function;together with landmark FOXP3 genetic discoveries by Mary E.Brunkow and Fred Ramsdell,these advances transformed understanding of immune homeostasis and were recognized by the 2025 Nobel Prize in Physiology or Medicine.Under normal physiological conditions,FOXP3+Treg cells restrain autoreactive lymphocytes,prevent excessive inflammation,and shape antigen-presenting cell activity through contact-dependent pathways and suppressive cytokines,thereby protecting tissues from immune-mediated damage.Disruption of Treg abundance,stability,or suppressive capacity can therefore lead to immune dysregulation and disease.Over the past two decades,Treg cells have become a major focus of immunology because their roles are highly context-dependent.In autoimmune and chronic inflammatory diseases,impaired Treg cell function or insufficient Treg activity contributes to loss of tolerance and persistent tissue injury,supporting therapeutic approaches designed to enhance Treg cell number,stability,and suppressive potency.In contrast,many cancers exploit Treg cells by promoting their expansion,activation,and recruitment into the tumor microenvironment(TME),where they blunt antitumor immunity by suppressing cytotoxic T-cell priming and effector function,limiting dendritic cell activation,and fostering immune escape.In both settings,immune checkpoint pathways critically influence Treg cell biology.Beyond PD-1/PD-L1 and CTLA-4,emerging checkpoints and costimulatory receptors,including TIGIT,TIM-3,LAG-3,and OX40,modulate Treg cell generation,stability,and suppressive functions,thereby shaping the balance between tolerance and immunity.Meanwhile,immunometabolic adaptations further tune Treg cell fitness and function in inflamed tissues and tumors;lipid utilization and mitochondrial programs,among other metabolic axes,enable Treg cells to persist in nutrient-and oxygen-restricted microenvironments,while microenvironmental stress can drive functional remodeling or fragility in a subset-dependent manner.In this review,we summarize the discovery and defining biological features of Treg cells,highlight core suppressive mechanisms and regulatory circuits,and synthesize evidence for the dual roles of Treg cells in preventing autoimmunity yet enabling tumor immune evasion.We further outline current and emerging therapeutic strategies aimed at augmenting Treg cell activity to restore tolerance in autoimmune disease,or selectively depleting,functionally inhibiting,and reprogramming tumor-resident Treg cells to enhance cancer immunotherapy.Overall we discuss how deeper insight into Treg heterogeneity,checkpoint control,and immunometabolic regulation may enable more precise Treg celldirected interventions and inform next-generation immunotherapeutic combinations across immune-mediated and malignant diseases.
