Numerous natural products originated from Chinese herbal medicine exhibit anti-cancer activities, including anti-proliferative, pro-apoptotic, anti-metastatic, anti-angiogenic effects, as well as regulate autophagy, reverse multidrug resistance, balance immunity, and enhance chemotherapy in vitro and in vivo. To provide new insights into the critical path ahead, we systemically reviewed the most recent advances (reported since 2011) on the key compounds with anti-cancer effects derived from Chinese herbal medicine (curcumin, epigallocatechin gallate, berberine, artemisinin, ginsenoside Rg3, ursolic acid, silibinin, emodin, triptolide, cucurbitacin B, tanshinone I, oridonin, shikonin, gambogic acid, artesunate, wogonin, β-elemene, and cepharanthine) in scientific databases (PubMed, Web of Science, Medline, Scopus, and Clinical Trials). With a broader perspective, we focused on their recently discovered and/or investigated pharmacological effects, novel mechanism of action, relevant clinical studies, and their innovative applications in combined therapy and immunomodulation. In addition, the present review has extended to describe other promising compounds including dihydroartemisinin, ginsenoside Rh2, compound K, cucurbitacins D, E, I, tanshinone IIA and cryptotanshinone in view of their potentials in cancer therapy. Up to now, the evidence about the immunomodulatory effects and clinical trials of natural anti-cancer compounds from Chinese herbal medicine is very limited, and further research is needed to monitor their immunoregulatory effects and explore their mechanisms of action as modulators of immune checkpoints.

Inflammatory bowel disease (IBD) is a chronic intestinal disease with painful clinical manifestations and high risks of cancerization. With no curative therapy for IBD at present, the development of effective therapeutics is highly advocated. Drug delivery systems have been extensively studied to transmit therapeutics to inflamed colon sites through the enhanced permeability and retention (EPR) effect caused by the inflammation. However, the drug still could not achieve effective concentration value that merely utilized on EPR effect and display better therapeutic efficacy in the inflamed region because of nontargeted drug release. Substantial researches have shown that some specific receptors and cell adhesion molecules highly expresses on the surface of colonic endothelial and/or immune cells when IBD occurs, ligand-modified drug delivery systems targeting such receptors and cell adhesion molecules can specifically deliver drug into inflamed sites and obtain great curative effects. This review introduces the overexpressed receptors and cell adhesion molecules in inflamed colon sites and retrospects the drug delivery systems functionalized by related ligands. Finally, challenges and future directions in this field are presented to advance the development of the receptor-mediated targeted drug delivery systems for the therapy of IBD.

Low-grade inflammation in fat is associated with insulin resistance, although the mechanisms are unclear. We report that mice deficient in the immune cell transcription factor T-bet have lower energy expenditure and increased visceral fat compared with wild-type mice, yet paradoxically are more insulin sensitive. This striking phenotype, present in young T-bet(-/-) mice, persisted with high-fat diet and increasing host age and was associated with altered immune cell numbers and cytokine secretion specifically in visceral adipose tissue. However, the favorable metabolic phenotype observed in T-bet-deficient hosts was lost in T-bet(-/-) mice also lacking adaptive immunity (T-bet(-/-)xRag2(-/-)), demonstrating that T-bet expression in the adaptive rather than the innate immune system impacts host glucose homeostasis. Indeed, adoptive transfer of T-bet-deficient, but not wild-type, CD4(+) T cells to Rag2(-/-) mice improved insulin sensitivity. Our results reveal a role for T-bet in metabolic physiology and obesity-associated insulin resistance.

Excessive production of reactive oxygen species (ROS) induced by hyperglycemia increased the secretion of interleukin-1β (IL-1β), which contributes to the pathogenesis of diabetes and its complications. Although high glucose (HG)-induced oxidative stress and aberrant Ca²⁺ channels activity causes an increase in transmembrane Ca²⁺ influx, however the relative contribution of Transient receptor potential (TRP) channels is not well studied. Here, we identified that HG (30 mM glucose for 48 h) induced the activation of the NLRP3-ASC inflammasome, leading to caspase-1 activation, and IL-1β and IL-18 secretion in human monocytic cell lines. Moreover, we used a hyperglycemia model in U937 monocytes, showing that the activation of TRPM2 was augmented, and TRPM2-mediated Ca²⁺ influx was critical for NLRP3 inflammasome activation. This pathway involved NADPH oxidase-dependent ROS production and TXNIP-NLRP3 inflammasome pathway. Furthermore, the inhibition of TRPM2 reduced ROS production and lowered NADPH oxidase activity via cooperatively interaction with p47 phox in response to HG. These results provided a mechanistic linking between TRPM2-mediated Ca²⁺ influx and p47 phox signaling to induce excess ROS production and TXNIP-mediated NLRP3 inflammasome activation under HG, and suggested that TRPM2 represented a potential target for alleviating NLRP3 inflammasome activation related to hyperglycemia-induced oxidative stress in Type 2 diabetes Mellitus (T2DM).

The underlying mechanisms of itch are poorly understood. We have investigated a model involving the chemoattractant leukotriene B ₄ (LTB ₄ ) that is up‐regulated in common skin diseases. Intradermal injection of LTB ₄ (0.1 nmol/site) into female CD1 mice induced significant scratching movements (used as an itch index) compared with vehicle‐injected (0.1% bovine serum albumin‐saline) mice. Intraperitoneal transient receptor potential (TRP) channel antagonist treatment significantly inhibited itch as follows: TRP vanilloid 1 (TRPV1) antagonist SB366791 (0.5 mg/kg, by 97%) and the TRP ankyrin 1 (TRPA1) antagonists TCS 5861528 (10 mg/kg; 82%) and HC‐030031 (100 mg/kg; 76%). Leukotriene B ₄ receptor 2 antagonism by LY255283 (5 mg/kg i.p.; 62%) reduced itch. Neither TRPV1‐knockout (TRPV1‐KO) nor TRPA1‐knockout (TRPA1‐KO mice exhibited LTB ₄ ‐induced itch compared with their wild‐type counterparts. The reactive oxygen species scavengers N ‐acetylcysteine (NAC; 204 mg/kg i.p.; 86%) or superoxide dismutase (SOD; 10 mg/kg i.p.; 83%) also inhibited itch. LTB ₄ ‐induced superoxide release was attenuated by TCS 5861528 (56%) and HC‐030031 (66%), NAC (58%), SOD (50%), and LY255283 (59%) but not by the leukotriene B ₄ receptor 1 antagonist U‐75302 (9 nmol/site) or SB366791. Itch, superoxide, and myeloperoxidase generation were inhibited by the leukocyte migration inhibitor fucoidan (10 mg/kg i.v.) by 80, 61, and 34%, respectively. Myeloperoxidase activity was also reduced by SB366791 (35%) and SOD (28%). TRPV1‐KO mice showed impaired myeloperoxidase release, whereas TRPA1‐KO mice exhibited diminished production of superoxide. This result provides novel evidence that TRPA1 and TRPV1 contribute to itch via distinct mechanisms.—Fernandes, E. S., Vong, C. T., Quek, S., Cheong, J., Awal, S., Gentry, C., Aubdool, A. A., Liang, L., Bodkin, J.V., Bevan, S., Heads, R., Brain, S.D. Superoxide generation and leukocyte accumulation: key elements in the mediation of leukotriene B ₄ ‐induced itch by transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1. FASEB J. 27, 1664–1673 (2013). www.fasebj.org