Macrophages exist in various tissues, several body cavities, and around mucosal surfaces and are a vital part of the innate immune system for host defense against many pathogens and cancers. Macrophages possess binary M1/M2 macrophage polarization settings, which perform a central role in an array of immune tasks via intrinsic signal cascades and, therefore, must be precisely regulated. Many crucial questions about macrophage signaling and immune modulation are yet to be uncovered. In addition, the clinical importance of tumor-associated macrophages is becoming more widely recognized as significant progress has been made in understanding their biology. Moreover, they are an integral part of the tumor microenvironment, playing a part in the regulation of a wide variety of processes including angiogenesis, extracellular matrix transformation, cancer cell proliferation, metastasis, immunosuppression, and resistance to chemotherapeutic and checkpoint blockade immunotherapies. Herein, we discuss immune regulation in macrophage polarization and signaling, mechanical stresses and modulation, metabolic signaling pathways, mitochondrial and transcriptional, and epigenetic regulation. Furthermore, we have broadly extended the understanding of macrophages in extracellular traps and the essential roles of autophagy and aging in regulating macrophage functions. Moreover, we discussed recent advances in macrophages-mediated immune regulation of autoimmune diseases and tumorigenesis. Lastly, we discussed targeted macrophage therapy to portray prospective targets for therapeutic strategies in health and diseases.

Purpose: Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP–P2RY2 axis could be a potential therapeutic approach for PDAC treatment. Experimental Design: Expression of P2RY2 was determined in 264 human PDAC samples and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity, and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression. Results: P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT–mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevated expression of c-Myc and HIF1α, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacologic inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. In addition, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice. Conclusions: These findings reveal the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.

Curcumin has been proven to have a weight-loss effect in a menopausal rat model induced by ovariectomy. However, the effects of curcumin on gut microfloral communities of ovariectomized (OVX) rats remains unclear. Here, we used high-throughput 16S rDNA sequencing to explore the effects of curcumin on microbial diversity in the gut of OVX rats. Female Wistar rats were subjected to either ovariectomy or a sham operation (SHAM group). The OVX rats were treated with vehicle (OVX group) or curcumin (CUR group) by oral gavage. After 12-week treatments, the weights of the bodies and uteri of rats were recorded, the levels of estradiol in the serum were assayed by electrochemiluminescence immunoassay (ECLIA). Then, the fragments encompassing V3–V4 16S rDNA hypervariable regions were PCR amplified from fecal samples, and the PCR products of V3–V4 were sequenced on an Illumina MiSeq for characterization of the gut microbiota. Our results showed that, compared to rats in the SHAM group, rats in the OVX group had more weight gain and lower levels of estradiol in the serum, and curcumin could cause significant weight loss in OVX rats but did not increase the levels of estradiol. Sequencing results revealed the presence of 1120, 1114, and 1119 operational taxonomic units (OTUs) found in the SHAM, OVX, and CUR groups, respectively. The percentage of shared OTUs was 86.1603%. Gut microbiota of rats from the SHAM or CUR group had higher levels of biodiversity and unevenness estimations than those from the OVX group. At the phyla level, compared to rats in SHAM group, rats in the OVX group had a higher ratio of phyla Firmicutes and Bacteroidetes in the gut; at the genus level, four differential gut microbiota (Incertae_Sedis, Anaerovorax, Anaerotruncus, and Helicobacter) between SHAM and OVX groups were found, whereas seven differential gut microbiota (Serratia, Anaerotruncus, Shewanella, Pseudomonas, Papillibacter, Exiguobacterium, and Helicobacter) between OVX and CUR groups were found. In conclusion, estrogen deficiency induced by ovariectomy caused changes in the distribution and structure of intestinal microflora in rats, and curcumin could partially reverse changes in the diversity of gut microbiota.

Background: Although metformin, a first-line drug for treating diabetes, may play an important role in inhibition of epithelial ovarian cancer cell growth and cancer stem cells (CSCs), metformin at low dose showed less effect on the proliferation of ovarian cancer cells. In this study, we evaluated the effect of metformin at low dose on ovarian CSCs in order to understand the molecular mechanisms underlying.Methods: The inhibitory effects of metformin at los dose on proliferation and population of ovarian cancer cells including SKOV3 and A2780 were assessed by cell proliferation assay and flow cytometry. Quantitative real-time PCR assay on expression of Bcl-2, Survivin and Bax was performed to determine the effect of metformin at low dose on epithelial-mesenchymal transition (EMT) of cancer cells and CSCs. Tumor sphere formation assay was also performed to evaluate the effect of metformin on spheres forming ability of CSCs. The therapeutic efficacy and the anti-CSC effects of metformin at low dose were investigated by using both SKOV3 cells and primary tumor xenografts. In addition, the CSC frequency and EMT in tumor xenograft models were also assessed by flow cytometry and quantitative real-time PCR.Results: Metformin at low dose did not affect the proliferation of ovarian cancer cells. However, it inhibited population of CD44⁺CD117⁺selectively, neither CD133⁺nor ALDH⁺cells. It suppressed expression of snail2, twist and vimentin significantly in cancer cells and CD44⁺CD117⁺CSCsin vitro. Low dose of metformin reduced survivin expression in CSCs. Low concentrations of metformin inhibited the secondary and the tertiary tumor sphere formation, decreased SKOV3 and primary ovarian tumor xenograft growth, enhanced the anticancer effect of cisplatin, and lowered the proportion of CD44⁺CD117⁺CSCs in the xenograft tissue. Metformin was also associated with a reduction of snail2, twist, and vimentin in CD44⁺CD117⁺ovarian CSCsin vivo.Conclusions: Our results implicate that metformin at low dose inhibits selectively CD44⁺CD117⁺ovarian CSCs through inhibition of EMT and potentiates the effect of cisplatin.

Dysregulation of the miR-34a-SIRT1 axis inhibits breast cancer stemness Dysregulation of the miR-34a-SIRT1 axis inhibits breast cancer stemness

The underlying molecular mechanisms of chronic pancreatitis (CP) developing into pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. Here we show that the level of serotonin in mouse pancreatic tissues is upregulated in caerulein-induced CP mice. In vitro study demonstrates that serotonin promotes the formation of acinar-to-ductal metaplasia (ADM) and the activation of pancreatic stellate cells (PSCs), which results from the activation of RhoA/ROCK signaling cascade. Activation of this signaling cascade increases NF-κB nuclear translocation and α-SMA expression, which further enhance the inflammatory responses and fibrosis in pancreatic tissues. Intriguingly, quercetin inhibits both ADM lesion and PSCs activation in vitro and in vivo via its inhibitory effect on serotonin release. Our findings underscore the instrumental role of serotonin-mediated activation of RhoA/ROCK signaling pathway in development of PDAC from CP and highlight a potential to impede PDAC development by disrupting tumor-promoting functions of serotonin.