Breast cancer is one of the top-ranked malignant carcinomas associated with morbidity and mortality in women worldwide. Chemotherapy is one of the main approaches to breast cancer treatment. Breast cancer initially responds to traditional first- and second-line drugs (aromatase inhibitor, tamoxifen, and carboplatin), but eventually acquires resistance, and certain patients relapse within 5 years. Chemotherapeutic drugs also have obvious toxic effects. In recent years, natural products have been widely used in breast cancer research because of their low side effects, low toxicity, and good efficacy based on their multitarget therapy. Apoptosis, a programmed cell death, occurs as a normal and controlled process that promotes cell growth and death. Inducing apoptosis is an important strategy to control excessive breast cancer cell proliferation. Accumulating evidence has revealed that natural products become increasingly important in breast cancer treatment by suppressing cell apoptosis. In this study, we reviewed current studies on natural product–induced breast cancer cell apoptosis and summarized the proapoptosis mechanisms including mitochondrial, FasL/Fas, PI3K/AKT, reactive oxygen species, and mitogen-activated protein kinase–mediated pathway. We hope that our review can provide direction in the search for candidate drugs derived from natural products to treat breast cancer by promoting cell apoptosis.

To elucidate the molecular mechanisms involved in the therapeutic effects of proanthocyanidins from grape seeds (GSPE), we explore whether GSPE regulates the inflammatory response of TNBS-induced colitis in rats at the levels of NF-κB signal transduction pathway. Rats were intragastrically administered of different doses of GSPE (100, 200 and 400 mg·kg⁻¹) per day for seven days after ulcerative colitis (UC) was induced by intracolonic injection of 2,4,6-trinitrobenzenesulfonic acid (TNBS) dissolved in 50% ethanol. Sulfasalazine (SASP) at 400 mg/kg was used as a positive control drug. The expression of nuclear factor-kappa B (NF-κB), phospho-I kappaB-alpha (pIκBα), inhibitor kappa B kinase (IκK) in the colon tissues were all measured by enzyme-linked immunosorbent assay (ELISA) methods. Treatment with GSPE reduced the expression of NF-κB, pIκBα and IκK in the colon. The results of this study show that GSPE exerts beneficial effects in inflammatory bowel disease by inhibition of NF-κB signal transduction pathways.

Innate immunity is the first line of defense in human beings against pathogen infection; monocytes/macrophages are the primary cells of the innate immune system. Recently, macrophages/monocytes have been discovered to participate in LPS clearance, and the clearance efficiency determines the magnitude of the inflammatory response and subsequent organ injury. Previously, we reported that artesunate (AS) protected sepsis mice against heat-killed E. coli challenge. Herein, we further confirmed that AS protected cecal ligation/puncture (CLP) sepsis mice. Its protection on sepsis mice was related to not only reduction of pro-inflammatory cytokines and serum LPS levels but also improvement of liver function. Based on the fact that AS did not directly bind and neutralize LPS, we hypothesized that the reduction of serum LPS level might be related to enhancement of LPS internalization and subsequent detoxification. Our results showed that AS increased FITC-LPS internalization by peritoneal macrophage and liver Kupffer cell, but enhancement of LPS internalization by AS was not related to the clathrin-dependent pathway. However, AS induced mRNA expression of important scavenger receptors (SRs); SR-A and MARCO mRNA expression was upregulated, suggesting that AS enhancement of LPS internalization and inhibition of pro-inflammatory cytokines was related to changes in mRNA expression of SRs.

It is unclear whether membrane vitamin D receptor (mVDR) exists on the macrophage membrane or whether mVDR is associated with lipopolysaccharide (LPS) tolerance. Herein, we report that interfering with caveolae and caveolae-dependent lipid rafts inhibited the formation of LPS tolerance. VDR was detected as co-localized with membrane molecular markers. VDR was detected on the cell membrane and its level was higher in LPS-tolerant cells than that in only LPS treatment cells. Anti-VDR antibodies could abolish the effect of artesunate (AS) to reverse LPS tolerance, and the wild-type peptides (H397 and H305) of VDR, but not the mutant peptide (H397D and H305A), led to the loss of AS’s effect. AS decreased the mVDR level in LPS-tolerant cells. In vivo, AS significantly reduced VDR level in the lung tissue of LPS-tolerant mice. In summary, mVDR exists on the cell membrane of macrophages and is closely associated with the formation of LPS tolerance and the effects of AS.

Severe acute pancreatitis (SAP) is a severe clinical condition associated with high rates of morbidity and mortality. Multiple organ dysfunction syndrome that follows systemic inflammatory response syndrome is the leading cause of SAP‑related death. Since the inflammatory mechanism of SAP remains unclear, there is currently a lack of effective drugs available for its treatment. Therefore, it is important to study effective therapeutic drugs and their molecular mechanisms based on studying the inflammatory mechanism of SAP. In the present study, in vivo, a mouse model of AP induced by cerulein (CR) combined with lipopolysaccharide (LPS) was established to clarify the therapeutic effect of artesunate (AS) in AP mice by observing the gross morphological changes of the pancreas and surrounding tissues, calculating the pancreatic coefficient, and observing the histopathology of the pancreas. The serum amylase activity in AP mice was detected by iodine colorimetry and the superoxide dismutase activity in the pancreas was detected by WST‑1 assay. The levels of proinflammatory cytokines in the serum, the supernatant of pancreatic tissue homogenates and the peritoneal lavage fluid were detected by ELISA assay. The total number of peritoneal macrophages was assessed using the cellular automatic counter, and the expression of proteins related to autophagy, and the TLR4 pathway was detected by immunohistochemistry and western blotting. In vitro, the effect of trypsin (TP) combined with LPS was observed by detecting the release of proinflammatory cytokine levels from macrophages by ELISA assay, and detecting the expression of proteins related to autophagy and the TLR4 pathway by immunofluorescence and western blotting. The present study revealed that AS reduced pancreatic histopathological damage, decreased pancreatic TP and serum amylase activities, increased superoxide dismutase activity, and inhibited pro‑inflammatory cytokine levels in a mouse model of AP induced by cerulein combined with lipopolysaccharide. In vitro, TP combined with LPS was found to synergistically induce pro‑inflammatory cytokine release from mouse macrophages and RAW264.7 cells, while AS could inhibit cytokine release. Furthermore, CR combined with LPS synergistically increased amylase activity in acinar cells, whereas AS decreased amylase activity. Autophagy serves an important role in the release of pro‑inflammatory cytokines. In the present study, it was revealed that the autophagy inhibitor LY294002 suppressed the release of pro‑inflammatory cytokines from macrophages treated with TP combined with LPS, and pro‑inflammatory cytokine release was not further reduced by AS combined with LY294002. Furthermore, AS not only inhibited the expression of important molecules in the Toll‑like receptor 4 (TLR4) signaling pathway, but also inhibited autophagy proteins and reduced the number of autolysosomes in mice with AP and in macrophages. In conclusion, these results suggested that AS may protect against AP in mice via inhibition of TLR4‑dependent autophagy; therefore, AS may be considered a potential therapeutic agent against SAP.