Berberine mediates tumor cell death by skewing tumor-associated immunosuppressive macrophages to inflammatory macrophages

Shah, Dhruvi; Challagundla, Naveen; Dave, Vaidehi; Patidar, Ashok; Saha, Bhaskar; Nivsarkar, Manish; Trivedi, Varsha B; Agrawal-Rajput, Reena

doi:10.1016/j.phymed.2021.153904

Cited by 21 publications

(20 citation statements)

References 34 publications

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“…Berberine has been shown to inhibit the activation of regulatory T cells (Tregs) and attenuate the activity of immunosuppressive myeloid-derived suppressor cells (MDSCs) as well as enhance tumor-infiltrating T-cell immunity resulting in antitumor effects ( 134 ). Besides, berberine inhibits tumor antigen-mediated IL-6 and TGF-β expression as well as IL-10 proliferation but restores anti-tumor cytotoxicity of T cells in the tumor microenvironment ( 135 ). Th1 immune responses were intensified and CD8+ T cell activity was significantly enhanced after resveratrol treatment of mouse lung tumors, which may be due to the downregulation of PD-1 expression on CD4 + T cells and CD8 + T cells in lungs of tested mice ( 136 ).…”

Section: Mechanisms Underlying Natural Products Remodeling Tumor Micr...mentioning

confidence: 99%

Remodeling tumor microenvironment with natural products to overcome drug resistance

Zhang

et al. 2022

Front. Immunol.

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With cancer incidence rates continuing to increase and occurrence of resistance in drug treatment, there is a pressing demand to find safer and more effective anticancer strategy for cancer patients. Natural products, have the advantage of low toxicity and multiple action targets, are always used in the treatment of cancer prevention in early stage and cancer supplement in late stage. Tumor microenvironment is necessary for cancer cells to survive and progression, and immune activation is a vital means for the tumor microenvironment to eliminate cancer cells. A number of studies have found that various natural products could target and regulate immune cells such as T cells, macrophages, mast cells as well as inflammatory cytokines in the tumor microenvironment. Natural products tuning the tumor microenvironment via various mechanisms to activate the immune response have immeasurable potential for cancer immunotherapy. In this review, it highlights the research findings related to natural products regulating immune responses against cancer, especially reveals the possibility of utilizing natural products to remodel the tumor microenvironment to overcome drug resistance.

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Section: Mechanisms Underlying Natural Products Remodeling Tumor Micr...mentioning

confidence: 99%

Remodeling tumor microenvironment with natural products to overcome drug resistance

Zhang

et al. 2022

Front. Immunol.

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“…However, the relationship is greatly complex between tumors and immune cells. Previous studies have reported that M2 macrophage promote tumor invasion, progression and immune escape through increasing the expression of MHC class I molecules and secreting anti-inflammatory cytokines ( 29 – 31 ). Moreover, Tregs also inhibit the immune response, which led to immunosuppressive functions and accelerated the malignant tumors progression ( 32 , 33 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

et al. 2022

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Copper (Cu) is an essential element of organisms, which can affect the survival of cells. However, the role of copper metabolism and cuproptosis on hepatic carcinoma is still unclear. In this study, the TCGA database was used as the test set, and the ICGC database and self-built database were used as the validation set. We screened out a class of copper metabolism and cuproptosis-related genes (CMCRGs) that could influence hepatic carcinoma prognosis by survival analysis and differential comparison. Based on CMCRGs, patients were divided into two subtypes by cluster analysis. The C2 subtype was defined as the high copper related subtype, while the C1 subtype was defied as the low copper related subtype. At the clinical level, compared with the C1 subtype, the C2 subtype had higher grade pathological features, risk scores, and worse survival. In addition, the immune response and metabolic status also differed between C1 and C2. Specifically, C2 subtype had a higher proportion of immune cell composition and highly expressed immune checkpoint genes. C2 subtype had a higher TIDE score with a higher proportion of tumor immune dysfunction and exclusion. At the molecular level, the C2 subtype had a higher frequency of driver gene mutations (TP53 and OBSCN). Mechanistically, the single nucleotide polymorphisms of C2 subtype had a very strong transcriptional strand bias for C>A mutations. Copy number variations in the C2 subtype were characterized by LOXL3 CNV gain, which also showed high association with PDCD1/CTLA4. Finally, drug sensitivity responsiveness was assessed in both subtypes. C2 subtype had lower IC50 values for targeted and chemotherapeutic agents (sorafenib, imatinib and methotrexate, etc.). Thus, CMCRGs related subtypes showed poor response to immunotherapy and better responsiveness to targeted agents, and the results might provide a reference for precision treatment of hepatic carcinoma.

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“…Arginase activity was measured protein extract as mentioned earlier [34]. Enzyme activity was analysed by measuring the conversion of arginine to urea.…”

Section: Methodsmentioning

confidence: 99%

“…Mouse Bone marrow derived macrophages (BMDMs) were generated as described elsewhere (Shah D et al, 2021). Briefly, bone marrow cells were collected from femurs of BALB/c mice and cultured in RMPI-1650 supplemented with 10% FBS.…”

Section: Cells and Cell Culture Mediummentioning

confidence: 99%

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IFNγ insufficiency during mouse intravaginal Chlamydia trachomatis infection exacerbates alternative activation in macrophages with compromised CD40 functions

Challagundla

Shah

Dalai

et al. 2022

Preprint

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Chlamydia trachomatis (C.tr), an obligate intracellular pathogen, causes asymptomatic genital infections in women and is also a leading cause of preventable blindness. Limited mouse model of chronic C.tr infection are available to study the host immune response. We have developed in vivo mice models of acute and chronic infections for C. trachomatis to explore the significance of macrophage-directed response in mediating immune activation/suppression. During chronic and repeated infections, IFNγ secretion from T cells is abated while TGFβ and IL-10 secretion is enhanced. An increase in exhaustion (PD1, CTLA4) and anergic (Klrg3, Tim3) T cell markers is also observed during chronic infection. It was observed that alternatively-activated macrophages with low CD40 expression promote Th2 and Treg differentiation and lead to sustained C. trachomatis genital infection. Macrophages infected with C. trachomatis or treated with supernatant of infected epithelial cells drive them to alternately-activated phenotype. C. trachomatis infection prevents increase in CD40 expression. Low IFNγ, as observed in chronic infection leads to incomplete clearance of bacteria and poor immune activation. C. trachomatis decapacitates IFNγ responsiveness in macrophages via hampering IFNγRI and IFNγRII expression which can be correlated with poor expression of MHC-II, CD40, iNOS and NO release even following IFNγ supplementation. Alternatively-activated macrophages during C. trachomatis infection express low CD40 rendering immunosuppressive, Th2 and Treg differentiation which could not be reverted even after IFNγ supplementation. The alternative macrophages also harbour high bacterial load and are poor responders to IFNγ, thus promoting immunosupression. Thus, C. trachomatis modulate the innate immune cells attenuating the anti-chlamydial functions of T cells in a manner that involves decreased CD40 expression on macrophages.

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Berberine mediates tumor cell death by skewing tumor-associated immunosuppressive macrophages to inflammatory macrophages

Cited by 21 publications

References 34 publications

Remodeling tumor microenvironment with natural products to overcome drug resistance

Remodeling tumor microenvironment with natural products to overcome drug resistance

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

IFNγ insufficiency during mouse intravaginal Chlamydia trachomatis infection exacerbates alternative activation in macrophages with compromised CD40 functions

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