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Background Apigenineffectively inhibits the growth of human gastric carcinoma SGC-7901 cells and induces apoptosis as well. This study investigated the effects of ATF6 and PERK signaling pathways in unfolded protein response (UPR) and endoplasmic reticulum stress (ERS) on the apoptosis induced by apigeninin human gastric carcinoma SGC-7901 cells.Materials and Methods SGC-7901 cells were cultured with apigeninand tunicamycin for 48 h or with apigeninfor 12–48 h. CCK-8 was used to determine cell viability. The mRNA expression level was detected by RT-qPCR. The expression of related proteins was explored by Western blot. The apoptosis rate of cells and cell-cycle arrest were evaluated by flow cytometer.Results The results of CCK-8 confirmed that apigenincould induce apoptosis of SGC-7901 cells. In the apigenin-treated cells group, the protein and mRNA levels of GRP78 and GRP94 dose- and time-dependently increased. Additionally, apigenin-activated UPR components PERK and ATF6. However, apigeninexerted no influence on CHOP expression or JNK activation. Pretreatment with 4-PBA significantly increased the apigenin-triggered apoptosis in SCG-7901 cells (p< 0.05).Conclusion The results revealed the protective effect of UPR performance on apigenin-triggered apoptosis in SGC-7901 cells.

A few studies have reported the association between famine exposure during fetal development and risk of CVD, but no mechanisms have been explored.

Objectives The objective of this trial was to compare outcomes of electrocoagulation tuboplasty and continued medical therapy for treating persistent Eustachian tube dysfunction (ETD) with hypertrophic mucosa disease in the Eustachian tube (ET) orifice.Study Design Prospective, case-control trial.Material and Methods Patients with persistent ETD were recruited and allocated to electrocoagulation tuboplasty and continued medical therapy groups. The ETD questionnaire-7 (ETDQ-7) score and objective parameters were compared between the groups at 6 and 12 months.Results The proportion of patients with a decrease in ETDQ-7 scores was greater in the electrocoagulation group than in the medical therapy group at the 6-month follow-up (53.49% and 34.38%, respectively; p= .158), but the difference was not statistically significant. However, at the 12-month follow-up, there was a significantly higher proportion of patients with a decrease in ETDQ-7 scores in the electrocoagulation group (88.37% and 40.63%, respectively; p= .001). Additionally, a significant difference was observed between the groups in terms of the proportion of patients who improved 12 months after the treatment (tympanometry: 72.09% and 9.38%, respectively; p= .001; air-bone gap: 79.07% and 25.00%, respectively; p= .001; tympanic membrane status: 62.79% and 0.00%, respectively). In addition, the proportion of patients with improvements in the ET inflammation score was significantly different between the groups at 6-month (67.44% and 34.38%, respectively; p= .009) and 12-month (93.02% and 34.38%; p= .001) follow-ups. No device- or procedure-related serious adverse events were reported in any patients.Conclusions Electrocoagulation Eustachian tuboplasty appears to be a safe and feasible procedure for adult persistent ETD with hypertrophic mucosa disease in the ET orifice, and is superior to continued medical management alone. The improvements in ETDQ-7 and objective parameters persisted for 12 months.

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system and the unmet need for MS treatment demands new therapeutic development. Particularly, PI3Kδ is a high-value target for autoimmune disease, while the investigation of PI3Kδ inhibitors for MS therapy is relatively scarce. Herein, we report a novel class of azaindoles as PI3Kδ inhibitors for MS treatment. Compound 31, designed via nitrogen bioisosterism, displayed excellent PI3Kδ inhibitory activity and selectivity. In vitroassay showed that 31exhibited superior activity on T lymphocytes to inhibit the proliferation of CD4+, CD8+, and CD3+T cells. In the experimental autoimmune encephalomyelitis (EAE) model, 31showed a comparable therapeutical efficacy with Dexamethasone to significantly ameliorate EAE symptoms. Mechanistic studies showed that compound 31could significantly inhibit the PI3K/AKT/mTOR signaling pathway and inhibited T-cell proliferation and differentiation. Overall, this work provides a new structural PI3Kδ inhibitor and a new vision for MS therapy.

PI3Kδ is an essential target correlated to the occurrence and development of acute myeloid leukemia (AML). Herein, we investigated the pyrazolo[3,4-d]pyrimidine derivatives as potent and selective PI3Kδ inhibitors with high therapeutic efficacy toward AML. There were 44 compounds designed and prepared in a four-round optimization, and the biological evaluation showed that (S)-36exhibited potent PI3Kδ inhibitory activity, high selectivity, and high antiproliferative activities against MV-4-11 and MOLM-13 cells, coupled with high oral bioavailability (F= 59.6%). In the MOLM-13 subcutaneous xenograft model, (S)-36could significantly suppress the tumor progression with a TGI of 67.81% at an oral administration dosage of 10 mg/kg without exhibiting obvious toxicity. Mechanistically, (S)-36could robustly inhibit the PI3K/AKT pathway for significant suppression of cell proliferation and remarkable induction of apoptosis both in vitroand in vivo. Thus, compound (S)-36represents a promising PI3Kδ inhibitor for the treatment of acute myeloid leukemia with high efficacy.

PI3Kδ is a promising target for the treatment of inflammatory disease; however, the application of PI3Kδ inhibitors in acute respiratory inflammatory diseases is rarely investigated. In this study, through scaffold hopping design, we report a new series of 1H-pyrazolo[3,4-d]pyrimidin-4-amine-tethered 3-methyl-1-aryl-1H-indazoles as highly selective and potent PI3Kδ inhibitors with significant anti-inflammatory activities for treatment of acute lung injury (ALI). There were 29 compounds designed, prepared, and subjected to PI3Kδ inhibitory activity evaluation and anti-inflammatory activity evaluation in macrophages. (S)-29was identified as a candidate with high PI3Kδ inhibitory activity, isoform selectivity, and high oral bioavailability. The in vivoadministration of (S)-29at 10 mg/kg dosage could significantly ameliorate histopathological changes and attenuate lung inflammation in lung tissues of LPS-challenged mice. Molecular docking demonstrated the success of scaffold hopping design. Overall, (S)-29is a potent PI3Kδ inhibitor which might be a promising candidate for the treatment of ALI.

PI3Kδ inhibitors have been developed for treatment of B-cell malignancies and inflammatory and autoimmune diseases. However, their therapeutic role in solid tumors like hepatocellular carcinoma (HCC) is rarely reported. Thus, the development of potent and selective PI3Kδ inhibitors with a new chemotype and therapy is highly desirable. Through the scaffold-hopping strategy, indazole was first described as the core structure of propeller-shaped PI3Kδ inhibitors. A total of 26 indazole derivatives were designed and prepared to identify a novel compound 9xwith good isoform selectivity, PK profile, and potency. Compared to Idelalisib and Sorafenib, the pharmacodynamic (PD) studies showed that 9xexhibits superior efficacy in HCC cell lines and xenograft models, and the mechanistic study showed that 9xrobustly suppresses the downstream AKT pathway to induce subsequent apoptotic cell death in HCC models. Therefore, this work provides a new structural design of PI3Kδ inhibitors for a novel and efficient therapeutic small molecule toward HCC.