Chemotherapy is the treatment of choice for gastric cancer; however, the currently available therapeutic drugs for treatment have limited efficacy. Cancer stemness and the tumor microenvironment may play crucial roles in tumor growth and chemoresistance. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum chaperone facilitating protein folding and cell homeostasis during stress and may participate in chemoresistance. Isoliquiritigenin (ISL) is a bioactive flavonoid found in licorice. In this study, we demonstrated the role of GRP78 in gastric cancer stemness and evaluated GRP78-mediated stemness inhibition, tumor microenvironment regulation, and chemosensitivity promotion by ISL. ISL not only suppressed GRP78-mediated gastric cancer stem cell–like characteristics, stemness-related protein expression, and cancer-associated fibroblast activation but also gastric tumor growth in xenograft animal studies. The findings indicated that ISL is a promising candidate for clinical use in combination chemotherapy.

Cancer stemness is the process by which cancer cells acquire chemoresistance and self-renewal in the tumor microenvironment. Glucose-regulated protein 78 (GRP78) is a biomarker for gastric cancer and is involved in cancer stemness. By inducing cancer stemness in various types of cancer, the polarization of macrophages into tumor-associated macrophages (TAMs) controls tumor progression. Betulinic acid (BA) is a bioactive natural compound with anticancer properties. However, whether GRP78 regulates TAM-mediated cancer stemness in the tumor microenvironment and whether BA inhibits GRP78-mediated cancer stemness in gastric cancer remain unknown. In this study, we investigated the role of GRP78 in gastric cancer stemness in a tumor microenvironment regulated by BA. The results indicated that BA inhibited not only GRP78-mediated stemness-related protein expression and GRP78-TGF-β-mediated macrophage polarization into TAMs, but also TAM-mediated cancer stemness. Therefore, BA is a promising candidate for clinical application in combination-chemotherapy targeting cancer stemness.

Background: A long-acting κreceptor agonist parenteral analgesic may theoretically improve acute pain and reduce incidence of chronic postsurgical pain (CPSP) after laparoscopic cholecystectomy with minimal drug-related side effects of the traditional μreceptor opioids. Methods: Eighty adult patients undergoing elective laparoscopic cholecystectomy were randomly assigned to receive single intramuscular injection of an extended-release sebacoyl dinalbuphine ester (SDE, Naldebain 150 mg; n = 40) or placebo ( n = 40) after anesthesia induction. Standard multimodal analgesia (MMA) was administered for postoperative pain control. The primary endpoint was pain intensity within 7 days after surgery. The secondary endpoints were incidence CPSP at 3 months and adverse reactions up to 7 days after surgery. Results: The highest visual analogue scale (VAS) and area under the curve of VAS 0 to 48 hours after operation were not different between the two groups and a similar proportion of patients requested rescue parenteral analgesics. Average pain intensities were also not different at 72 hours and 7 days after surgery. Incidence of CPSP was 22.5% and 13.1% in patients who received placebo and SDE treatment, respectively ( P = .379). Significantly higher incidence of drug-related adverse events, including dizziness, nausea and injection site reactions, were recorded in the SDE group. Conclusion: A single dose of extended-release analgesic SDE given intraoperatively did not provide sufficient add-on effect for acute and chronic pain management after laparoscopic cholecystectomies in patients who received standard postoperative MMA. Intramuscular injection of 150 mg SDE in patients with average body mass causes adverse events that could have been overlooked. More clinical studies are warranted to determine the target populations who may benefit from SDE injections for improvement of acute and chronic postsurgical pain management.

Alveolar macrophages are the front‑line defense against environmental pathogens. However, to the best of our knowledge, differences in function and phenotypic expression levels of macrophages between neonatal and adult lungs have not previously been determined. The present study investigated lung tissues and analyzed blood samples to find cell markers of M1 and M2 macrophages in neonatal and adult rats. Pulmonary sepsis was induced by intrapleural instillation of lipopolysaccharide (LPS; 20 mg/kg) and survival time after administration of LPS was measured. In certain neonates, a selective inducible nitric oxide synthase (iNOS) inhibitor, 1400w, was administered prior to induction of pulmonary sepsis. Compared with adults, fetal and neonatal lung tissues had significantly higher levels of iNOS and CD86 (M1 markers), whereas the expression levels of CD206 and arginase‑1 (M2 markers) were lower in the neonatal lung. The circulating cells that co‑expressed CD68 (monocytes and macrophages) and CD86 in the blood were also significantly higher in neonates than in adults (25.9±6.6 vs. 11.6±2.2%; P=0.007. At basal unstimulated conditions, lung tissue concentrations of nitrite and nitrate (NOx) were significantly lower in the neonates than in adults (112.1±55.9 vs. 340.9±124.9 µM/g; P<0.001). However, NOx was increased following administration of LPS. Administration of 1400w suppressed lung tissue levels of NOx and improved the survival time in neonatal rats treated with LPS. The present study demonstrated that M1 is the primary macrophage phenotype in the neonatal lung and that higher iNOS expression levels do not have a protective effect against pulmonary endotoxins in neonates. Overproduction of NO by iNOS in neonatal alveolar macrophages may result in detrimental effects during pulmonary inflammation.

Although chemotherapy is the preferred treatment for gastric cancer, the therapeutic drugs currently available have limited efficacy and severe side effects. Cancer stem cells within tumor masses have the distinctive properties of self-renewal, maintenance, and resistance to chemotherapy. Hence, agents capable of targeting stemness in gastric tumors with minimal side effects are urgently required. Enzymes that generate reactive oxygen species contribute to the high oxidation levels observed in tumors. Additionally, nuclear factor erythroid 2-related factor 2 (Nrf2), an antioxidant transcription factor, regulates cancer stemness. Increasing evidence highlights the potential of nutritional supplementation to treat cancer stemness. ω-3 polyunsaturated fatty acids support human health and offer benefits for cancer treatment. Linolenic acid (LA), an ω-3 polyunsaturated fatty acid, inhibits the expression of proteins associated with stemness and promotes apoptosis in gastric cancer cells. Our findings indicated that LA treatment substantially inhibited key characteristics of gastric cancer stemness and induced oxidative stress and caspase-3-mediated apoptosis by downregulating Nrf2-mediated expression. These results suggest that LA is a promising nutritional supplement for targeting cancer stemness in the treatment of gastric cancer.