Synthesis and biological evaluation of novel 1,2,3-triazole hybrids of cabotegravir: identification of potent antitumor activity against lung cancer.

In pursuit of discovering novel anticancer agents, we designed and synthesized a series of novel 1,2,3-triazole hybrids based on cabotegravir analogues. These compounds were subjected to initial biological evaluations to assess their anticancer activities against non-small-cell lung cancer (NSCLC). Our findings indicated that some of these compounds exhibited promising antitumor abilities against H460 cells, while demonstrated less efficacy against H1299 cells. Notably, compound 5i emerged as the most potent, displaying an IC50 value of 6.06 µM. Furthermore, our investigations into cell apoptosis and reactive oxygen species (ROS) production revealed that compound 5i significantly induced apoptosis and triggered ROS generation. Additionally, Western blot analysis revealed the pronounced elevation of LC3 expression in H460 cells and γ-H2AX expression in H1299 cells subsequent to treatment with compound 5i. These molecular responses potentially contribute to the observed cell death phenomenon. These findings highlight the potential of compound 5i as a promising candidate for further development as an anticancer agent especially lung cancer.

Effects of dietary supplementation with N-carbamylglutamate on maternal endometrium and fetal development during early pregnancy in Inner Mongolia white cashmere goats.

This study investigated the effects of dietary supplementation with N-carbamylglutamate (NCG) on maternal endometrium and fetal development during early pregnancy of Inner Mongolia white cashmere goats. Forty-eight pregnant Inner Mongolia white cashmere goats (average age 3 years old, average lactation parity 2, and average body weight 43.81 ± 2.66 kg) were randomly allocated to three groups: a basal diet (control group, n = 16), a basal diet plus 0.30-g NCG/d (NCG1 group, n = 16), and a basal diet plus 0.40-g NCG/d (NCG2 group, n = 16). All of the does were housed in individual pens and the NCG treatment was conducted from Days 0 to 90 of pregnancy. At Days 17 and 90 of pregnancy, six representative pregnant does in each group were slaughtered. The current study results demonstrated that maternal NCG administration during early pregnancy effectively increased the arginine family of amino acids and the glucogenic amino acids concentrations and promoted the mRNA expression of osteopontin (OPN), αv and ß3 integrins, and endometrial development of Inner Mongolia white cashmere goats. The supplementation improved the fetal brown adipose tissue (BAT) stores and the mRNA expression of UCP-1 and BMP7, thereby helping to the fetal early development.

The Role of Nutrition in the Prevention and Intervention of Type 2 Diabetes.

Type 2 diabetes (T2D) is a rapidly growing epidemic, which leads to increased mortality rates and health care costs. Nutrients (namely, carbohydrates, fat, protein, mineral substances, and vitamin), sensing, and management are central to metabolic homeostasis, therefore presenting a leading factor contributing to T2D. Understanding the comprehensive effects and the underlying mechanisms of nutrition in regulating glucose metabolism and the interactions of diet with genetics, epigenetics, and gut microbiota is helpful for developing new strategies to prevent and treat T2D. In this review, we discuss different mechanistic pathways contributing to T2D and then summarize the current researches concerning associations between different nutrients intake and glucose homeostasis. We also explore the possible relationship between nutrients and genetic background, epigenetics, and metagenomics in terms of the susceptibility and treatment of T2D. For the specificity of individual, precision nutrition depends on the person's genotype, and microbiota is vital to the prevention and intervention of T2D.

Effects of photoperiod on circadian clock genes in skin contribute to the regulation of hair follicle cycling of Inner Mongolia white cashmere goats.

This study investigated how the effects of photoperiod on circadian clock genes in the skin contribute to the regulation of hair follicle cycling of Inner Mongolia white cashmere goats. Twenty-four female (non-pregnant) Inner Mongolia white cashmere goats aged 1 - 1.5 years old with similar live weights (mean, 20.36 ± 2.63 kg) were randomly allocated into two groups: a natural daily photoperiod group (NDPP group:10 - 16 hr Light, n = 12) and a short daily photoperiod group (SDPP group: 7 hr Light:17 hr Dark, n = 12). All goats were housed in individual pens from May 15 to October 15, 2015 and were fed the same diets. We detected the mRNA expression of brain and muscle arnt-like protein-1 (Bmal1), circadian locomotor output control kaput (Clock), cryptochrome-1 (Cry1), period homolog-1 (Per1) and Rev-erbα genes in the goat skin. ANOVA revealed a significant 24 hr (10:00 hr, 14:00 hr, 18:00 hr, 22:00 hr, 02:00 hr, 06:00 hr, 10:00 hr) variation between the SDPP and NDPP groups for three months (July, September, and October). In summary, the current results confirm that an intrinsic oscillating molecular clock exists in goat skin, and that the clock is important for potential timing mechanisms at the anagen phase of hair follicles, which would contribute to the regulation mechanisms of hair follicle cell proliferation.

Effects of photoperiod on nutrient digestibility, hair follicle activity and cashmere quality in Inner Mongolia white cashmere goats.

OBJECTIVE: This study investigated the effects of photoperiod on nutrient digestibility, hair follicle (HF) activity and cashmere quality in Inner Mongolia white cashmere goats. METHODS: Twenty-four female (non-pregnant) Inner Mongolia white cashmere goats aged 1 to 1.5 years old with similar live weights (mean, 20.36±2.63 kg) were randomly allocated into two groups: a natural daily photoperiod group (NDPP group:10 to 16 h light, n = 12) and a short daily photoperiod group (SDPP group: 7 h light:17 h dark, n = 12). All the goats were housed in individual pens and fed the same diets from May 15 to October 15, 2015. The digestibility of crude protein (CP), dry matter (DM), and neutral detergent fiber (NDF) were measured in different months, along with secondary hair follicle (SHF) activity, concentration of melatonin (MEL), and cashmere quality. RESULTS: Although there was no significant difference in the live weights of goats between the SDPP and NDPP groups (p>0.05), the CP digestibility of goats in the SDPP group was significantly increased compared to the NDPP group in July, September, and October (p<0.05). For the DM and NDF digestibility of goats, a significant increase (p<0.05) was found during in September in the SDPP group. Furthermore, compared to the NDPP group, the SHF activity in July, the MEL concentration in July, and the cashmere fiber length and fiber weight in October were significantly increased in the SDPP group (p<0.05). CONCLUSION: The cashmere production of Inner Mongolia white cashmere goats was increased without obvious deleterious effects on the cashmere fibers in the SDPP group (metabolizable energy, 8.34 MJ/kg; CP, 11.16%; short daily photoperiod, 7 h light:17 h dark).

Recent findings on fulminant type 1 diabetes.

Fulminant type 1 diabetes (fT1D) is a new subtype of type 1 diabetes proposed by Imagawa in 2000. It is a clinical syndrome characterized by a markedly rapid and almost complete destruction of pancreatic ß cells. Metabolic derangement is more severe in this subtype than in autoimmune type 1 diabetes. The incidence of fT1D is associated with HLA DRB1*04:05DQB1*04:01; both innate and acquired immune disorders might contribute to the development of fT1D. The presence of specific innate immune responses to enterovirus infection connected with enhanced adaptive immune pathways responsible for aggressive ß cell toxicity in fT1D. The process of ß cell destruction is extremely rapid in fT1D, and the insulin secretary capacity rarely recovers after the onset. The serum glycated albumin to glycated haemoglobin ratio is significantly higher in fT1D; a cut-off value of 3.2 for serum glycated albumin to glycated haemoglobin ratio yielded 97% sensitivity and 98% specificity for differentiating fT1D from type 2 diabetes. Fulminant type 1 diabetes is associated with pregnancy. This article also updates the diagnostic criteria for fT1D by the Japanese Diabetes Association in 2012.

A network meta-analysis on the efficacy of sixteen targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer.

OBJECTIVE: A network meta-analysis was conducted comparing the short-term efficacies of 16 targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer (CRC). RESULTS: Twenty-seven RCTs were ultimately incorporated into this network meta-analysis. Compared with chemotherapy alone, bevacizumab + chemotherapy, panitumumab + chemotherapy and conatumumab + chemotherapy had higher PR rate. Bevacizumab + chemotherapy, cetuximab + chemotherapy, panitumumab + chemotherapy, trebananib + chemotherapy and conatumumab + chemotherapy had higher ORR rate in comparison to chemotherapy alone. Furthermore, bevacizumab + chemotherapy had higher DCR rate than chemotherapy alone. The results of our cluster analysis showed that chemotherapy combined with bevacizumab, cetuximab, panitumumab, conatumumab, ganitumab, or brivanib + cetuximab had better efficacies for the treatment of advanced/metastatic CRC in comparison to chemotherapy alone. MATERIALS AND METHODS: Electronic databases were comprehensively searched for potential and related randomized controlled trials (RCTs). Direct and indirect evidence were incorporated for evaluation of stable disease (SD), progressive disease (PD), complete response (CR), partial response (PR), disease control rate (DCR) and overall response ratio (ORR) by calculating odds ratio (OR) and 95% confidence intervals (CI), and using the surface under the cumulative ranking curve (SUCRA). CONCLUSIONS: These results indicated that bevacizumab + chemotherapy, panitumumab + chemotherapy, conatumumab + chemotherapy and brivanib + cetuximab + chemotherapy may have better efficacies for the treatment of advanced/metastatic CRC.

[Small interfering RNA-mediated islet neogenesis associated protein gene silencing inhibits the proliferation of INS-1 islet cells].

OBJECTIVE: To investigate the effect of small interfering RNA (siRNA)-mediated islet neogenesis associated protein (INGAP) gene silencing on the proliferation of islet cells. METHODS: Different siRNAs targeting INGAP gene were designed and transfected into INS-1 islet cells, and the expression levels of INGAP mRNA and protein following the transfection were detected using RT-PCR, flow cytometry and Western blotting. The proliferation of the transfected INS-1 cells was evaluated using MTT assay. RESULTS: Compared with those in the irrelevant siRNA, empty vector control, and un-transfected groups, the expression levels of INGAP mRNA and protein in the cells transfected with siRNA6 were reduced significantly. The cell proliferation rate significantly increased after transfection with siRNA6 (P<0.05). CONCLUSION: siRNA targeting INGAP can effectively down-regulate INGAP expression and inhibit the proliferation of INS-1 cells.

[High glucose impairs mitochondrial respiratory chain function in pancreatic beta cells].

OBJECTIVE: To investigate the effect of high glucose on mitochondrial respiratory chain function in INS-1 cells. METHODS: The pancreatic beta cell line INS-1 was divided into the normal control (NC), high glucose (HG), and N-acetyl-L-cysteine (NAC) pretreatment groups, which were cultured for 72 h in the presence of 5.5 mmol/L glucose, 16.7 mmol/L glucose, and 16.7 mmol/L glucose with 1.0 mmol/L NAC, respectively. The activities of the enzyme complexes I and III of the respiratory chain in the cells were assessed with spectrophotometry, the ATP levels were examined using a luciferinluciferase kit, and insulin levels detected by radioimmunoassay. RESULTS: The activities of the respiratory chain enzyme complexes I and III were 1.53-/+0.24 and 1.08-/+0.22 micromol.mg(-1).min(-1) in high glucose group, respectively, significantly lower than those in the normal control group (2.31-/+0.33 and 1.92-/+0.39 micromol.mg(-1).min(-1), P<0.01). ATP and insulin levels also decreased significantly in high glucose group as compared with those in the normal control group (P<0.01). The addition of NAC partially inhibited high glucose-induced decreases in the enzyme complex activities, ATP levels and insulin secretion (P<0.05). CONCLUSION: The respiratory chain function is positively correlated to insulin secretion in INS-1 cells, and exposure to high glucose causes impairment of the two enzyme complexes activities through oxidative stress, resulting in the mitochondrial respiratory chain dysfunction. High glucose-induced damages of the mitochondrial respiratory chain function can be partially inhibited by NAC.

Development of goat embryos reconstituted with somatic cells: the effect of cell-cycle coordination between transferred nucleus and recipient oocytes.

The developmental ability and the nucleus and microtubule dynamics of nuclear transplanted goat embryos derived from in vitro matured oocytes were studied while controlling cell-cycle coordination of donor embryonic nuclei and recipient cytoplasts. Three groups of transfers were studied: G0/G1 (after the fibroblast cells grew to 100% confluence) and G2/M (nocodazole treated) phase fibroblasts transferred to MII cytoplasts (G0/G1-->MII and G2/M-->MII group, respectively), and G0/G1 phase fibroblasts transferred to preactivated cytoplasts, mostly at S-phase, (G0/G1-->Pre group) by electrical fusion. The results showed that fusion and developmental ability did not differ between G0/G1-->MII and G0/G1-->Pre groups. However the developmental rate of embryos in the G0/G1-->MII group was significantly higher than that of the G2/M-->MII group. Most fibroblast nuclei (G0/G1 and G2/M) transferred into MII oocytes underwent premature chromosome condensation (PCC). Normal spindle were only detected in the G0/G1-->MII group. In contract, fibroblast nuclei in pre-activated oocytes rarely underwent PCC, but formed a swollen nuclear structure. The data suggest that in vitro matured goat oocytes can support the development of somatic fibroblasts after nuclear transfer, G0/G1 -->MII and G0/G1-->S nuclear transfer might be effective ways for improving the developmental competence of the reconstituted embryos, and that G2/M-->MII nuclear transfer by electrical fusion (even in Ca2+-free fusion medium) induces abnormal chromosome ploidy.