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Three new bufadienolides 14β, 16β-dihydroxy-3β-[β-D-glucopyranosyl-(1→6)-(β-D-glucopyranosyl)oxy]-5α-bufa-20, 22-dienolide (1), 14β-hydroxy-3β-[β-D-glucopyranosyl-(1→4)-(β-D-glucopyranosyl)oxy]-5α-bufa-20, 22-dienolide (2) and hellebrigenin-3-O-β-D-glucosyl-(1→4)-β-D-glucoside (3), together with eight known bufadienolides (4–11) were isolated from the roots and rhizomes of Helleborus thibetanus. Their structures were elucidated by extensive spectroscopic methods and acid hydrolysis. Compounds 1–7 were evaluated for their cytotoxic activity against HCT116, A549 and HepG2 tumor cell lines. Compound 1 exhibited moderate cytotoxicity against HepG2 cells with IC50 value of 15.1 ± 1.72 μM. Compounds 5 and 6 exhibited moderate cytotoxicity against HCT116 cells with IC50 values of 15.12 ± 0.58 μM and 13.17 ± 2.34 μM, respectively. [ABSTRACT FROM AUTHOR]

Phosphoinositol 3-kinases (PI3Ks) γ and δ are primarily expressed in leukocytes and play crucial roles in regulation of the immune system. Dual inhibition of PI3Kγ/δ has emerged as an effective approach to regulate the tumor microenvironment. Here, we report the exploration of structure-activity relationship optimization which led to the discovery of a potent PI3Kγ/δ dual inhibitor 15u (IHMT-PI3K-455). 15u exhibits strong potency in biochemical and cellular assays and it repolarizes M2 phenotype toward M1 phenotype in THP-1 and BMDM macrophages. In addition, it shows suitable in vivo properties as demonstrated through pharmacokinetic studies in rats and pharmacodynamics properties in a MC38 xenograft model. [Display omitted] • Medicinal chemistry optimization led to a novel potent PI3Kγ/δ dual inhibitor 15u. • 15u exhibited strong potencies against PI3Kγ/δ in biochemical and cellular assays. • 15u repolarized M2 phenotype toward M1 phenotype in THP-1 and BMDM macrophages. • 15u inhibited the tumor growth in a MC38 xenograft mouse model. [ABSTRACT FROM AUTHOR]

PI3Kδ, which is mainly expressed in leukocytes, plays a critical role in B-cell receptor mediated signaling pathway and has been extensively studied as a drug discovery target for B cell malignances such as AML, CLL etc. In this manuscript, we report the discovery, SAR optimization and pharmacological evaluation of a novel series of aminothiazole-pyridine containing PI3Kδ inhibitors. Among them compound 15i (CHMFL-PI3KD-317) displays an IC 50 of 6 nM against PI3Kδ in the ADP-Glo biochemical assays. It also exhibits over 10–1500 fold selectivity over other class I, II and III PIKK family isoforms. In addition, in the cellular context, 15i can selectively and potently inhibit PI3Kδ mediated phosphorylation of Akt T308 but not PI3Kα, β, γ mediated Akt phosphorylation. 15i also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 μM. 15i has acceptable pharmacokinetic properties and can dose-dependently inhibit the tumor growth of AML cell line MOLM14 inoculated xenograft mouse model. The high selectivity and potency makes 15i a potential valuable addition to the current PI3Kδ armory. [ABSTRACT FROM AUTHOR]

Depression and anxiety in children and adolescents have become one of the major public health threats. This study aimed to provide a comprehensive and accurate understanding of the current status of depression and anxiety in primary and secondary school students in Urumqi and to provide a basis for early intervention in depressed and anxious individuals. All primary and secondary school students in 13 schools in the Urumqi S district were surveyed from March 2021 to November 2021, and depression and anxiety were screened using the Self-rating Depression Scale (SDS) and the Self-rating Anxiety Scale (SAS). Overall, 17,086 students participated, with 16,462 valid questionnaires and an effective rate of 96.3%; the numbers of primary, middle, and high school students were 3351, 10,469, and 2642, respectively, with 8493 male students and 7969 female students. The overall depression and anxiety detection rates of primary and secondary school students were 10.74 % and 14.85 %, respectively; the depression detection rates were 5.97 %, 12.05 %, and 11.62 % in elementary, middle, and high schools, respectively (x 2 =114.8, P < 0.001), while that of anxiety were 9.16 %, 16.75 %, and 14.53 %, respectively (x 2 =127.5, P < 0.001); the overall depression combined with anxiety detection rate was 8.61 %, and the depression combined with anxiety detection rates in elementary, middle, and high school were 0.95 %, 6.27 %, and 1.39 %, respectively (x 2 =86.34, P < 0.001). SDS scores in elementary, middle, and high school were (33.21 ± 10.16), (36.66 ± 12.83), and (36.90 ± 11.97), respectively, and SAS scores were (39.64 ± 8.41), (41.88 ± 10.03), (40.71 ± 9.26), respectively. The depression and anxiety scores of primary and secondary school students in Urumqi were lower than those of domestic norm; female students in the middle school group had the highest depression and anxiety scores among all school periods. The SDS and SAS individual scores showed differences in the frequency of specific symptoms and subjective feelings of depression and anxiety among students of different sex and school periods. Depression and anxiety detection rates were highest in secondary school and lowest in primary school; the detection rates of depression and anxiety were significantly higher in female students than in male students. Depression and anxiety scores were significantly lower in the primary school group than in the middle and high school groups, and depression and anxiety levels were significantly higher in female than in male students in each academic period. Female students were 2.045 (95 % confidence interval [CI]: 1.845–2.267) and 2.006 (95 % CI: 1.835–2.193) times more likely to have symptoms of depression and anxiety than male students, respectively. Middle school students were 7.112 (95 % CI: 3.639–13.898) and 5.499 (95 % CI: 3.302–9.155) times and high school students were 7.504(95 % CI: 3.740–15.058) and 5.093 (95 % CI: 2.966–8.744) times more likely to have symptoms of depression and anxiety than elementary school students, respectively. The pandemic may have impacted the results of the study, and this study did not explore the influencing factors of anxiety and depression. Depression and anxiety symptoms exist in some primary and secondary school students in S District, Urumqi. • Depression and anxiety in children and adolescents are major public health threats. • Children and adolescents' mental health problems are increasing yearly. • Specific degrees of depression and anxiety manifested differently in men and women. • Approximately 50 % of patients with depression are students. • Depression is a persistent feeling of sadness and loss of interest. [ABSTRACT FROM AUTHOR]

Colony stimulating factor 1 receptor kinase (CSF1R) plays an integral role in tumor-associated macrophage repolarization and has emerged as a novel therapeutic target for cancer immunotherapy. Most of the current CSF1R kinase inhibitors lack selectivity between CSF1R kinase and other type III growth factor receptor members. Herein, we report a potent and selective CSF1R inhibitor 18h , which displays an IC 50 value of 5.14 nM against CSF1R and achieves selectivity over other type III receptor tyrosine kinases (>38-fold). 18h inhibits the phosphorylation of CSF1R and its downstream signaling pathway in RAW264.7, THP-1, and M–NFS–60 cells. Treatment with this compound leads to alteration of the macrophage polarization in RAW264.7 macrophages in a dose-dependent manner. In vivo, 18h demonstrates acceptable pharmacokinetic profiles and suppresses the tumor growth in a mouse xenograft model inoculated with M–NFS–60 cells. [Display omitted] • Medicinal chemistry optimization leads to a novel CSF1R kinase inhibitor 18h • 18h increases the M1 macrophage phenotype dose-dependently in RAW264.7 macrophages • 18h inhibits the tumor growth in a M–NFS–60 tumor xenograft model [ABSTRACT FROM AUTHOR]

Specific targeting of tumor cells to achieve higher drug levels in tumor tissue and to overcome side effects is the major goal in cancer chemotherapy. In this study, we used a tumor targeting peptide, GE11, to conjugate onto the surface of doxorubicin encapsulated phospholipid micelles. The GE11 peptide triggered specific binding to epidermal growth factor receptor (EGFR), leading to enhanced cellular uptake and cytotoxicity in vitro and highly accumulation in the tumors in vivo. The results indicated that GE11 conjugated phospholipid micelles should have potential applications in cancer therapy. [ABSTRACT FROM AUTHOR]