Neem leaf glycoprotein regulates function of tumor associated M2 macrophages in hypoxic tumor core: Critical role of IL-10/STAT3 signaling

Goswami, Kuntal Kanti; Sarkar, Madhurima; Ghosh, Sarbari; Saha, Akata; Ghosh, Tithi; Guha, Ipsita; Barik, Subhasis; Banerjee, Saptak; Roy, Subhransu; Bose, Anamika; Dasgupta, Parthasarathi; Baral, Rathindranath

doi:10.1016/j.molimm.2016.10.008

Cited by 23 publications

(13 citation statements)

References 58 publications

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“… 29 Recent studies have demonstrated that TAMs can promote tumorigenesis through IL-6/STAT3 signaling or by regulating STAT3 through IL-10 signaling. 27 , 30 In our previous studies, we summarized that the main ZHENG s for pancreatic cancer were Shi-Re, Pi-Xu, and Xue-Yu. In addition, the Shi-Re ZHENG has been found to be correlated with inflammatory conditions.…”

Section: Discussionmentioning

confidence: 99%

TAM Infiltration Differences in “Tumor-First” and “ZHENG-First” Models and the Underlying Inflammatory Molecular Mechanism in Pancreatic Cancer

Wang

Chen

et al. 2018

Integr Cancer Ther

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Background: Syndrome (ZHENG in Chinese) in traditional Chinese medicine (TCM) refers to the intrinsic characteristics of a pathological process at a certain stage; these characteristics are influenced by internal and external environments and reveal the nature of a disease. Proper syndrome differentiation is the basic principle that guides clinical treatment. Objective: To have a good understanding of tumor progression and the different mechanisms related to ZHENG that have occurred before and after tumor development and to explore the valid evaluation criteria of different pancreatic cancer syndromes to improve the guiding role of TCM syndrome differentiation in pancreatic cancer treatment. Methods: In this study, we established mouse subcutaneous pancreatic cancer models, namely, Con (control), Pi-Xu (Spleen-Deficiency), Shi-Re (Dampness-Heat), and Xue-Yu (Blood-Stasis). Then, for the first time, we compared the different effects of “ZHENG-first” (referring to a different disease status that occurred before tumor occurrence) and “Tumor-first” (referring to the change in the tumor microenvironment and the resulting changes in the state of the body) conditions on tumor progression and evaluated the associated molecular mechanisms. Results: We found that tumor growth in the “ZHENG-first” and “Tumor-first” conditions was different. In the “Tumor-first” model, the tumor growth in the Pi-Xu group was faster than that in the other groups. However, in the “ZHENG-first” model, the tumor growth trend was most obvious in the Shi-Re group. There was a difference in tumor-associated macrophage infiltration between the 2 models. The expression levels of the inflammatory cytokines IL-6, IL-10, and P-STAT3 were also differentially altered. Conclusion: The emergence of ZHENG conditions before or after tumor occurrence had different impacts on pancreatic cancer development, and these impacts may be related to differences in tumor-associated macrophage infiltration and the involved inflammatory cytokines IL-6, IL-10, and P-STAT3. The study results uncovered the molecular basis of syndrome differentiation in pancreatic cancer progression, which might provide more specific guidance for TCM treatment of pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

TAM Infiltration Differences in “Tumor-First” and “ZHENG-First” Models and the Underlying Inflammatory Molecular Mechanism in Pancreatic Cancer

Wang

Chen

et al. 2018

Integr Cancer Ther

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“…Since, parallel to its efficacy as a bio-pesticide it also instills immunomodulatory (Goswami et al, 2016), anti-cancer (Sironmani, 2016), anti-microbial (Verma and Mehata, 2016), and wound healing (Bhagavathy and Kancharla, 2016) properties, which can pave way to an interdisciplinary approach by integrating the attributes of this plant to provide multiple benefits in agriculture as well as in biomedicine.…”

Section: Future Perspectivementioning

confidence: 99%

Progress on Azadirachta indica Based Biopesticides in Replacing Synthetic Toxic Pesticides

et al. 2017

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Over the years, extensive use of commercially available synthetic pesticides against phytophagous insects has led to their bioaccumulation in the environment causing increased resistance and reduction in soil biodiversity. Further, 90% of the applied pesticides enter the various environmental resources as a result of run-off, exposing the farmers as well as consumers of the agricultural produce to severe health issues. Therefore, growing attention has been given toward the development of alternate environmentally friendly pesticides/insecticides that would aid an efficient pest management system and also prevent chronic exposures leading to diseases. One such strategy is, the use of neem plant's (Binomial name: Azadirachta indica) active ingredients which exhibit agro-medicinal properties conferring insecticidal as well as immunomodulatory and anti-cancer properties. The most prominent constituent of neem is azadirachtin, which has been established as a pivotal insecticidal ingredient. It acts as an antifeedant, repellent, and repugnant agent and induces sterility in insects by preventing oviposition and interrupting sperm production in males. This review discusses, key neem pesticidal components, their active functional ingredients along with recent strategies on employing nanocarriers, to provide controlled release of the active ingredients and to improve their stability and sustainability.

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“…Immunoreactive proteins were detected by addition of the HRP color development reagent according to the manufacturer’s protocol. The membrane was immersed into the solution for 1 min, wrapped with a Saran wrap, exposed to X-ray film, and developed, as described [19].…”

Section: Methodsmentioning

confidence: 99%

NLGP counterbalances the immunosuppressive effect of tumor-associated mesenchymal stem cells to restore effector T cell functions

et al. 2019

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Background A dynamic interaction between tumor cells and its surrounding stroma promotes the initiation, progression, metastasis, and chemoresistance of solid tumors. Emerging evidences suggest that targeting the stromal events could improve the efficacies of current therapeutics. Within tumor microenvironment (TME), stromal progenitor cells, i.e., MSCs, interact and eventually modulate the biology and functions of cancer and immune cells. Our recent finding disclosed a novel mechanism stating that tumor-associated MSCs inhibit the T cell proliferation and effector functions by blocking cysteine transport to T cells by dendritic cells (DCs), which makes MSCs as a compelling candidate as a therapeutic target. Immunomodulation by nontoxic neem leaf glycoprotein (NLGP) on dysfunctional cancer immunity offers significant therapeutic benefits to murine tumor host; however, its modulation on MSCs and its impact on T cell functions need to be elucidated. Methods Bone marrow-derived primary MSCs or murine 10 T1/2 MSCs were tumor-conditioned (TC-MSCs) and co-cultured with B16 melanoma antigen-specific DCs and MACS purified CD4+ and CD8+ T cells. T cell proliferation of T cells was checked by Ki67-based flow-cytometric and thymidine-incorporation assays. Cytokine secretion was measured by ELISA. The expression of cystathionase in DCs was assessed by RT-PCR. The STAT3/pSTAT3 levels in DCs were assessed by western blot, and STAT3 function was confirmed using specific SiRNA. Solid B16 melanoma tumor growth was monitored following adoptive transfer of conditioned CD8+ T cells. Results NLGP possesses an ability to restore anti-tumor T cell functions by modulating TC-MSCs. Supplementation of NLGP in DC-T cell co-culture significantly restored the inhibition in T cell proliferation and IFNγ secretion almost towards normal in the presence of TC-MSCs. Adoptive transfer of NLGP-treated TC-MSC supernatant educated CD8+ T cells in solid B16 melanoma bearing mice resulted in better tumor growth restriction than TC-MSC conditioned CD8+ T cells. NLGP downregulates IL-10 secretion by TC-MSCs, and concomitantly, pSTAT3 expression was downregulated in DCs in the presence of NLGP-treated TC-MSC supernatant. As pSTAT3 negatively regulates cystathionase expression in DCs, NLGP indirectly helps to maintain an almost normal level of cystathionase gene expression in DCs making them able to export sufficient amount of cysteine required for optimum T cell proliferation and effector functions within TME. Conclusions NLGP could be a prospective immunotherapeutic agent to control the functions and behavior of highly immunosuppressive TC-MSCs providing optimum CD8+ T cell functions to showcase an important new approach that might be effective in overall cancer treatment.

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Neem leaf glycoprotein regulates function of tumor associated M2 macrophages in hypoxic tumor core: Critical role of IL-10/STAT3 signaling

Cited by 23 publications

References 58 publications

TAM Infiltration Differences in “Tumor-First” and “ZHENG-First” Models and the Underlying Inflammatory Molecular Mechanism in Pancreatic Cancer

TAM Infiltration Differences in “Tumor-First” and “ZHENG-First” Models and the Underlying Inflammatory Molecular Mechanism in Pancreatic Cancer

Progress on Azadirachta indica Based Biopesticides in Replacing Synthetic Toxic Pesticides

NLGP counterbalances the immunosuppressive effect of tumor-associated mesenchymal stem cells to restore effector T cell functions

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