Identification and Validation of SLC9A2 as A Potential Tumor Suppressor in Colorectal Cancer: Integrating Bioinformatics Analysis with Experimental Confirmation.

OBJECTIVE: To uncover the mechanisms underlying the development of colorectal cancer (CRC), we applied bioinformatic analyses to identify key genes and experimentally validated their possible roles in CRC onset and progression. METHODS: We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis on differentially expressed genes (DEGs), constructed a protein-protein interaction (PPI) network to find the top 10 hub genes, and analyzed their expression in colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ). We also studied the correlation between these genes and immune cell infiltration and prognosis and validated the expression of SLC9A2 in CRC tissues and cell lines using qRT-PCR and Western blotting. Functional experiments were conducted in vitro to investigate the effects of SLC9A2 on tumor growth and metastasis. RESULTS: We found 130 DEGs, with 45 up-regulated and 85 down-regulated in CRC. GO analysis indicated that these DEGs were primarily enriched in functions related to the regulation of cellular pH, zymogen granules, and transmembrane transporter activity. KEGG pathway analysis revealed that the DEGs played pivotal roles in pancreatic secretion, rheumatoid arthritis, and the IL-17 signaling pathway. We identified 10 hub genes: CXCL1, SLC26A3, CXCL2, MMP7, MMP1, SLC9A2, SLC4A4, CLCA1, CLCA4, and ZG16. GO enrichment analysis showed that these hub genes were predominantly involved in the positive regulation of transcription. Gene expression analysis revealed that CXCL1, CXCL2, MMP1, and MMP7 were highly expressed in CRC, whereas CLCA1, CLCA4, SLC4A4, SLC9A2, SLC26A3, and ZG16 were expressed at lower levels. Survival analysis revealed that 5 key genes were significantly associated with the prognosis of CRC. Both mRNA and protein expression levels of SLC9A2 were markedly reduced in CRC tissues and cell lines. Importantly, SLC9A2 overexpression in SW480 cells led to a notable inhibition of cell proliferation, migration, and invasion. Western blotting analysis revealed that the expression levels of phosphorylated ERK (p-ERK) and phosphorylated JNK (p-JNK) proteins were significantly increased, whereas there were no significant changes in the expression levels of ERK and JNK following SLC9A2 overexpression. Correlation analysis indicated a potential link between SLC9A2 expression and the MAPK signaling pathway. CONCLUSION: Our study suggests that SLC9A2 acts as a tumor suppressor through the MAPK pathway and could be a potential target for CRC diagnosis and therapy.

lncRNA SNHG1 promotes the progression of hepatocellular carcinoma by regulating the miR-7-5p/IGF2BP2 axis.

Long noncoding RNA small nucleolar RNA host gene 1 (lncRNA SNHG1) plays a crucial role in the occurrence and progression of various tumors. This study investigates the function of lncRNA SNHG1 in hepatocellular carcinoma (HCC). We discovered that lncRNA SNHG1 is significantly upregulated in HCC and markedly enhances cell proliferation, migration, and invasion, while simultaneously suppressing apoptosis in HCC cells. Furthermore, lncRNA SNHG1 was found to downregulate miR-7-5p expression. Overexpression of lncRNA SNHG1 counteracted the suppression of HCC cell migration, proliferation, and invasion caused by miR-7-5p mimics, and reversed the miR-7-5p mimics' enhancement of apoptosis in HCC cells. Additionally, miR-7-5p was shown to negatively regulate IGF2BP2, with the silencing of IGF2BP2 diminishing the abilities of HCC cells to proliferate, migrate, and invade, and increasing their propensity for apoptosis. Overexpression of lncRNA SNHG1 negated these effects. Thus, lncRNA SNHG1 fosters HCC progression by upregulating IGF2BP2 expression through targeting miR-7-5p.

Food Effect on the Pharmacokinetics of VC004, a Tropomyosin Receptor Kinase Inhibitor: A Randomized Crossover Trial in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVE: VC004 is a novel next-generation tropomyosin receptor kinase (TRK) inhibitor that is approved for the treatment of advanced or metastatic NTRK fusion-positive solid tumors and abrogated the drug resistance of the first-generation TRK inhibitors. The objective of the present study was to evaluate the effect of food on the pharmacokinetics and safety of VC004. METHODS: The study was a randomized, open-label, two-period crossover, single-dose, phase I clinical trial. A total of 16 healthy subjects participated the trial. Subjects fasted for 10 h before drug administration in both fasting and fed states. Subjects received VC004 50 mg orally in the fasting state and after a high caloric food in the fed state. Blood samples at the designated time points were collected to determine the plasma concentration of VC004. Safety evaluation in both the fasted and fed periods were assessed via vital sign monitoring and clinical laboratory tests. RESULTS: The maximum plasma concentration (Cmax) of VC004 in fed group decreased by 32.8%, corresponding with the slower absorption rate (time to Cmax (Tmax) delayed by almost 3 h) compared with the fasting group. Ratios of geometric means (GMRs) and 90% confidence intervals (90% CIs) of Cmax, the area under the curve of plasma concentration-time from zero to the last measurable concentration (AUC0-t), and AUC from zero to infinity (AUC0-∞) for VC004 between the two states were 67.18 (58.16-77.60), 103.59 (95.04-112.92) and 103.55 (95.63-112.11), respectively. No serious adverse events (AEs) occurred; only three grade 1 or grade 2 adverse events occurred in the fasted group, who recovered by the end of the study. CONCLUSIONS: The intake of high calorie food decreased the absorption rate and increased the Tmax of VC004, while the AUC values were similar in both groups. No serious adverse event was reported. In conclusion, food does not alter the pharmacokinetics and safety profile of VC004 in a clinically meaningful manner. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT055528120.

Inhibitory Effects of Epithelial Cells on Fibrosis Mechanics of Microtissue and Their Spatiotemporal Dependence on the Epithelial-Fibroblast Interaction.

Cell-generated contraction force is the primary physical drive for fibrotic densification of biological tissues. Previous studies using two-dimensional culture models have shown that epithelial cells inhibit the myofibroblast-derived contraction force via the regulation of the fibroblast/myofibroblast transition (FMT). However, it remains unclear how epithelial cells interact with fibroblasts and myofibroblasts to determine the mechanical consequences and spatiotemporal regulation of fibrosis development. In this study, we established a three-dimensional microtissue model using an NIH/3T3 fibroblast-laden collagen hydrogel, incorporated with a microstring-based force sensor, to assess fibrosis mechanics. When Madin-Darby canine kidney epithelial cells were cocultured on the microtissue's surface, the densification, stiffness, and contraction force of the microtissue greatly decreased compared to the monocultured microtissue without epithelial cells. The key fibrotic features, such as enhanced protein expression of α-smooth muscle actin, fibronectin, and collagen indicating FMT and matrix deposition, respectively, were also significantly reduced. The antifibrotic effects of epithelial cells on the microtissue were dependent on the intercellular signaling molecule prostaglandin E2 (PGE2) with an effective concentration of 10 µM and their proximity to the fibroblasts, indicating paracrine cellular signaling between the two types of cells during tissue fibrosis. The effect of PGE2 on microtissue contraction was also dependent on the time point when PGE2 was delivered or blocked, suggesting that the presence of epithelial cells at an early stage is critical for preventing or treating advanced fibrosis. Taken together, this study provides insights into the spatiotemporal regulation of mechanical properties of fibrosis by epithelial cells, and the cocultured microtissue model incorporated with a real-time and sensitive force sensor will be a suitable system for evaluating fibrosis and drug screening.

[Different operation sequences between acupuncture and cupping therapy for lumbar muscle strain with cold and dampness: a randomized controlled trial].

OBJECTIVE: To compare the clinical efficacy on lumbar muscle strain with cold and dampness between the different operation sequences of acupuncture and cupping therapy. METHODS: Seventy-six patients with lumbar muscle strain with cold and dampness were randomly divided into an acupuncture + cupping group (A + C group, 38 cases) and a cupping + acupuncture group (C + A group, 38 cases, 1 case dropped off). In the A + C group, cupping therapy was delivered 10 min after the end of treatment with acupuncture, while in the C + A group, acupuncture therapy was exerted 10 min after the end of treatment with cupping. Acupuncture was applied to Mingmen (GV 4), Yaoyangguan (GV 3), ashi point and bilateral Shenshu (BL 23), Dachangshu (BL 25), Weizhong (BL 40) and Yanglingquan (GB 34), and the needles were retained for 30 min in each intervention. Flash cupping was operated along the bilateral sides of the lumbar spine for 3 min, and the cups were retained for 10 min at bilateral Shenshu (BL 23), Dachangshu (BL 25) and ashi points. The intervention was delivered once every two days, 3 times weekly, for 3 weeks totally in each group. The scores of visual analogue scale (VAS) and Oswestry disability index (ODI), TCM syndrome score and the mean temperature of the lumbar region before and after treatment were compared between the two groups. The safety and the clinical efficacy were assessed for the interventions of the two groups. RESULTS: Compared with the values before treatment, except for the sleep score of ODI, the VAS scores, ODI scores and TCM syndrome scores were decreased after treatment (P<0.01, P<0.05); while the mean temperature of the lumbar region was increased (P<0.01) in both groups. After treatment, the VAS score and the pain score of ODI in the C + A group were lower than those in the A + C group (P<0.05). The incidence rate of adverse reactions of the C + A group was lower than that of the A + C group (P<0.01). The effective rate in the A+C group was 92.1% (35/38), that in the C+A group was 94.6%(35/37), there was no statistical difference between the two groups (P>0.05). CONCLUSION: Different operation sequences between acupuncture and cupping therapy obtain the similar efficacy on lumbar muscle strain with cold and dampness, but cupping therapy delivered prior to acupuncture has certain advantages in relieving pain and improving safety.

Effect of a moderate CYP3A inducer efavirenz on the pharmacokinetics of fuzuloparib: An open-label, fixed sequence study in Chinese healthy male subjects.

To evaluate the potential drug-drug interaction (DDI), safety and tolerability of fuzuloparib co-administered with a moderate CYP3A inducer efavirenz in healthy male subjects. Eighteen healthy male subjects were enrolled in a single-center, single-arm, open-label, fixed-sequence study. Fuzuloparib was administered as a single oral 50 mg under a fasting state on day 1, efavirenz (600 mg once daily) was given on days 4-17 before bed time, concomitantly with fuzuloparib on day 18, and for the follow-up 3 additional days (days 19-20). Pharmacokinetic sampling was performed following each fuzuloparib dose. Safety and tolerability were assessed during the whole process via clinical laboratory tests. Ratios of least-squares means (GMRs) and 90% geometric confidence interval (90% CI) of maximum plasma concentration (Cmax), the area under the curve of plasma concentration-time from zero to the last measurable concentration (AUC0 - t) and the area under the curve of blood concentration from zero to infinity (AUC0-∞) for fuzuloparib combined with efavirenz to fuzuloparib alone were 0.473 (0.394, 0.568), 0.220 (0.185, 0.263) and 0.221 (0.185, 0.263), respectively. Co-administration with efavirenz led to 53% and 78% decreases in fuzuloparib Cmax and AUC0-∞. All 18 subjects enrolled in this study were included in the safety analysis set. A total of 16 subjects had 62 AEs during the study period. No serious adverse events (SAE) were reported. Most treatment-emergent adverse events were grade 1 or 2 based on CTCAE. Only one grade 3 adverse event was observed. Concomitant intake of fuzuloparib with the moderate CYP3A inhibitor efavirenz resulted in a decrease in fuzuloparib AUC0-∞ and Cmax of 78% and 53% respectively. The results suggested that concomitant moderate CYP3A inducers should be avoided during the administration of fuzuloparib, or else the dosage adjustments should be required. (This trial was registered at http://www.chinadrugtrials.org.cn . The registration No. is CTR20211022, and the date of registration is 2021-05-13).

Phase I study to evaluate of the gastric pH-dependent drug interaction between famitinib and the proton pump inhibitor omeprazole in healthy subjects.

To evaluate the potential gastric pH-dependent drug-drug interaction (DDI), safety and tolerability of famitinib co-administered with omeprazole in healthy subjects. Twenty healthy subjects were enrolled in a single-center, single-arm, open-label, fixed-sequence study. Famitinib was administered as a single oral 25 mg under a fasting condition on day 1, omeprazole (40 mg once daily) was given on days 10-14, concomitantly with famitinib on day 15, and for the follow-up 7 additional days (days 16-22). Blood samples were collected for the pharmacokinetic analysis of famitinib and its metabolite SHR116637 following each famitinib dose. Safety and tolerability were assessed during the whole progress via clinical laboratory tests. The least-squares geometric mean ratios (GMRs) (90% CI) of Cmax, AUC0-t and AUC0-∞ for famitinib combined with omeprazole to famitinib alone were 0.989 (0.953, 1.027), 0.956 (0.907, 1.007) and 0.953(0.905, 1.005) respectively. For the metabolite SHR116637, their GMRs (90% CI) of the above parameters were 0.851 (0.786, 0.920), 0.890 (0.838, 0.946)and 0.887 (0.835, 0.943), indicating the absence of significant differences in the parameters. During the treatment period, 9(45%) subjects reported 16 treatment emergent adverse events (TEAE), among which 6 subjects (30%) reported 9 TEAEs and 1 subject (5%) reported 1 TEAE during famitinib or omeprazole administered alone respectively, 5 subjects (25.0%) reported 6 TEAEs during in the combined administration phase. Omeprazole did not have a significant influence on the pharmacokinetics (PK) of famitinib and SHR116637, and the safety profile was good upon co-administration. ClinicalTrials.gov identifier NCT 05,041,920.

Effects of rifampicin on antineoplastic drug pyrotinib maleate pharmacokinetics in healthy subjects.

PURPOSE: Pyrotinib (PTN), an irreversible EGFR/HER2 dual tyrosine kinase inhibitor used for treating HER2-positive breast cancer, is primarily metabolized by cytochrome P450 (CYP)3A4 isozyme. Rifampicin (RIF) is a strong index CYP3A4 inducer. Therefore, the study aimed to elucidate the effect of RIF on PTN pharmacokinetics (PK) in Chinese healthy volunteers. METHODS: This phase I, open-label study investigated the effects of steady-state RIF administration on single-dose PK of PTN. 18 healthy participants were enrolled in this trial, who received a single oral dose of 400 mg of PTN on days 1 and 13, and were administrated with RIF 600 mg qd on days 6 through 16. RIF was administrated on an empty stomach, PTN were administrated orally in the morning 30 min after the start of the standard meal. Serial PK samples for PTN were collected on days 1 and days 13. Safety assessments were performed via clinical laboratory tests throughout the study. RESULTS: 18 subjects were enrolled and 16 completed the study. RIF significantly reduced PTN exposure: Geometric least-squares mean ratios (90% CI) for PTN + RIF versus PTN alone were 0.04 (0.034,0.049), 0.04 (0.037,0.054), and 0.11 (0.09,0.124) for area under the curve from time zero to time of last quantifiable concentration (AUC0 - t), area under the curve from time zero to infinity (AUC0-∞ ), and maximum observed plasma concentration(Cmax), respectively. PTN alone and co-administered with RIF was well tolerated. CONCLUSION: The exposure of PTN was significantly affected by the action of RIF. The findings suggest that concomitant strong CYP3A4 inducers should be avoided during PTN treatment. Concurrent administration of PTN and RIF was well tolerated.

Comparison of the Value of Color Doppler Ultrasound and Multislice Spiral CT in the Differential Diagnosis of Benign and Malignant Nodules in the Liver.

OBJECTIVE: This study aimed to explore the value of color Doppler ultrasound and multislice spiral CT (MSCT) in the differential diagnosis of benign and malignant nodules in the liver. METHODS: The clinical imaging data of 102 patients with nodular hepatocellular carcinoma (hepatocellular carcinoma group) and 50 patients with focal nodular hyperplasia (FNH) of the liver (FNH group) admitted to our hospital were collected, and their color Doppler ultrasound and MSCT imaging features were retrospectively analyzed to explore the value of their clinical application in the differential diagnosis of benign and malignant nodules in the liver. RESULTS: The sensitivity, accuracy, and negative predictive value of MSCT in the diagnosis of nodular liver cancer were 94.12%, 92.76%, and 88.24%, respectively, which were significantly higher than those of color Doppler ultrasound 79.41%, 84.21%, and 69.12%, and the difference was statistically significant (P < 0.05). CONCLUSION: In conclusion, the value of MSCT in the differential diagnosis of benign and malignant liver nodules was significantly better than color Doppler ultrasound.

Preparation of municipal solid waste incineration fly ash-based ceramsite and its mechanisms of heavy metal immobilization.

With an increase in municipal solid waste incineration (MSWI) fly ash and its dangerous characteristics, the manner of its disposal has caused widespread concerns. In this study, ceramsite was prepared by using MSWI fly ash, civil sludge, and contaminated soil as the main raw materials; then, a certain proportion of clay was added as an additive. The optimum MSWI fly ash content and sintering conditions were investigated, and the immobilization mechanisms of heavy metals were explored. Based on the obtained results, the optimum preparation conditions were a preheating temperature of 400 °C, a preheating time of 10 min, a sintering temperature of 1150 °C, and a sintering time of 20 min. Moreover, the optimal raw material ratio of MSWI fly ash, civil sludge, contaminated soil, and flint clay was 30%:40%:15%:15%. Under these optimum preparation conditions, the obtained ceramsite showed the following excellent performance parameters: a 1-h water absorption of 0.97%, bulk density of 998.7 kg/m3, and cylindrical compressive strength of 37.84 MPa. Furthermore, the leaching of heavy metals was far less than the standard GB5085.3-2007. The immobilization of heavy metals in the ceramsite was mainly caused by the glass phase encapsulation and the formation of new crystal phase with the heavy metals. In addition, the generation of aluminosilicates played a positive role in the immobilization of heavy metals. Thus, the reuse of MSWI fly ash by preparing fly ash-based ceramsite is one of the effective methods for reducing solid wastes.

Sublethal toxicity of graphene oxide in Caenorhabditis elegans under multi-generational exposure.

Nanomaterials have received increasing attentions owing to their potential hazards to the environment and human health; however, the multi-generational toxicity of graphene oxide under consecutive multi-generational exposure scenario still remains unclear. In the present study, Caenorhabditis elegans as an in vivo model organism was employed to explore the multi-generational toxicity effects of graphene oxide and the underlying mechanisms. Endpoints including development and lifespan, locomotion behaviors, defecation cycle, brood sizes, and oxidative response were evaluated in the parental generation and subsequent five filial generations. After continuous exposure for several generations, worms grew smaller and lived shorter. The locomotion behaviors were reduced across the filial generations and these reduced trends were following the impairments of locomotion-related neurons. In addition, the extended defecation cycles from the third filial generation were in consistency with the relative size reduction of the defecation related neuron. Simultaneously, the fertility function of the nematode was impaired under consecutive exposure as reduced brood sizes and oocytes numbers, increased apoptosis of germline, and aberrant expression of reproductive related genes ced-3, ced-4, ced-9, egl-1 and ced-13 were detected in exposed worms. Furthermore, the antioxidant enzyme, SOD-3 was significantly increased in the parent and filial generations. Thus, continuous multi-generational exposure to graphene oxide caused damage to the neuron development and the reproductive system in nematodes. These toxic effects could be reflected by indicators such as growth inhibition, shortened lifespan, and locomotion behavior impairment and induced oxidative response.

Diagnostic accuracy of transvaginal ultrasound examination for assigning a specific diagnosis to adnexal masses: A meta-analysis.

Transvaginal ultrasound (TVUS) is a standard imaging modality for differentiating patients with benign or malignant suspected adnexal mass. To date, numerous studies have assessed the diagnostic accuracy of TVUS in various settings but with variable results. Therefore, the purpose of the present study was to perform a meta-analysis to evaluate the diagnostic accuracy of TVUS for the differentiation of adnexal masses. An electronic search in the Medline, Scopus, Cochrane and Embase databases from inception till November 2019 was carried out. Meta-analysis was performed to obtain pooled sensitivity and specificity of TVUS to distinguish malignant from benign adnexal masses. The quality assessment of diagnostic accuracy studies-2 tool was used to assess the quality of trials. A total of 41 studies with 18,391 patients were included. The pooled sensitivity and specificity of TVUS was 92% (95% CI: 90-94%) and 89% (95% CI: 85-92%), respectively. The area under the receiver operating characteristic curve was 0.96 (95% CI: 0.84-1.00). There was considerable heterogeneity with a statistically significant chi-square test (P<0.001) and I2 of 99%. Meta-regression results indicated that index test standards, patient selection bias and study design were potential sources of heterogeneity (P<0.05). The funnel plot was symmetrical and low publication bias was confirmed by an insignificant Deek's test (P=0.90). The present systematic review and meta-analysis indicated that TVUS is useful in differentiating between benign and malignant tumours among patients with suspected adnexal mass with high sensitivity and specificity.

Clinical value of TV-CDS combined with serum tumor markers in diagnosis of ovarian cancer.

Clinical application value was investigated of transvaginal color Doppler ultrasound (TV-CDS) combined with serum tumor markers carbohydrate antigen 125 (CA125), vascular endothelial growth factor (VEGF) and osteopontin (OPN) in the diagnosis of ovarian cancer (OC). One hundred and six patients with OC [malignant tumor group (MTG)] and fifty patients with benign ovarian diseases [benign control group (BCG)] were selected. Both groups of patients underwent TV-CDS examination. The lesion morphology and internal structure were observed, and the tumor blood flow signal, resistance index (RI) and pulsability index (PI) under ultrasound were determined. Serum CA125 was detected by electrochemiluminescence, and VEGF and OPN levels were detected by enzyme-linked immunosorbent assay. The incidence of irregular lesion morphology, unclear boundary, uneven internal echo, microcalcification and side-acoustic images in OC group (OCG) was significantly higher than that in BCG (P<0.01). As for blood flow grading, most patients in the MTG were in grade II and III, while most patients in the BCG were in grade 0. Compared with BCG, the flow RI and PI in the OCG were significantly reduced (P<0.01). The levels of serum CA125, VEGF and OPN in OCG were significantly higher than those in BCG. The expression levels of serum CA125, VEGF and OPN in OC patients with clinical high stage (stage III and IV), poorly differentiated, ascites, recurrence and metastasis were significantly higher than those in patients with clinical low stage (stage I and II), well differentiated, no ascites and no recurrence and metastasis (P<0.05). With the disappearance of the tumor or the decrease of tumor load, the serum marker levels after treatment were significantly lower than that before treatment (P<0.05). The sensitivity and accuracy of the combined examination in the diagnosis of OC were obviously improved compared with the single and partial combined examinations (P<0.05). In conclusion, combined examination can significantly improve the sensitivity and accuracy of OC, which is conducive to early diagnosis and clinical intervention of OC.

Indirect Regulation and Equilibrium of p35 and p40 Subunits of Interleukin (IL)-12/23 by Ustekinumab in Psoriasis Treatment.

BACKGROUND Ustekinumab, a human-derived monoclonal antibody that targets the p40 subunit of interleukin (IL)-12 and IL-23, has excellent clinical efficacy and safety in treating psoriasis, with a long half-life. However, no reports have described the use of human skin/serum samples to elucidate its molecular mechanisms. MATERIAL AND METHODS Twenty-four psoriasis patients were enrolled in our double-blind study and randomly divided into placebo and ustekinumab-administered groups. Dynamic changes in psoriasis area-severity index scores, and mRNA and protein levels of p35 and p40 were analyzed at 3 time points (before treatment and during the 12th and 24th weeks of treatment). RESULTS Ustekinumab initially increased and then decreased p35 mRNA expression, but increased p40 mRNA levels throughout the study. The p35 protein levels were not significantly altered, while p40 protein levels were increased after the first 2 injections but decreased after the third injection. CONCLUSIONS We concluded that 2 equilibria influence the efficacy of ustekinumab against psoriasis. First, because of the dual roles of p35 in psoriasis pathogenesis, homeostasis occurs between p35 and p40 expression levels. The second balance lies between the upregulation of p40 mRNA levels and the ability of ustekinumab to neutralize the function of the elevated p40 protein.

Synthesis and characterization of bis(pyrazolyl)borate Ni(ii) complexes: ligand rearrangement and transformation.

Five examples of bis(pyrazolyl)borate Ni(ii) complexes 2-5, exhibiting C-HNi interactions, were readily prepared from the reactions of K[BBN(3-R1-4-R2-pz)2] with Ni(ii) precursors (Ni(acac)2 or NiCl2(PPh3)2) in dichloromethane or toluene. When R1 = R2 = H, complex 2a with square-planar geometry around the Ni centre and showing an unusual C-HNi anagostic interaction was obtained. In contrast, when R1 = Me, R2 = H or R1 = Me, R2 = Br, tetrahedral complexes 3 or 4 were formed preferentially with strong C-HNi agostic interactions, respectively. Additionally, some differences in the formation and transformation of 3 and 4 were also found including a 1,2-borotropic shift during the formation of 3 and a further geometrical transformation from tetrahedral 3 to square-planar 2b by the second 1,2-borotropic shift under continuous heating; in contrast, no ligand change and further conversion were found in 4. When the more hindered 3-iPr-substituted ligand 1d was introduced in the reaction, the hydrolysis and cleavage of one B-N bond in the ligand occurred, leading to the singly hydroxo-bridged complex 5. The experimental and theoretical results indicate that the preference to form a thermodynamically stable complex and then balancing with orbital energy should be the intrinsic reason for the reaction selectivity.

Pancreatic fat content is associated with ß-cell function and insulin resistance in Chinese type 2 diabetes subjects.

The pathogenesis of type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and ß-cell dysfunction. Earlier studies reported that increased levels of pancreatic fat may lead to the development of ß-cell dysfunction and insulin resistance. The present study aimed to demonstrate the relationship between pancreatic fat content (PFC) and insulin secretion and insulin resistance in Chinese subjects with T2DM. Seventy-eight T2DM subjects and 35 non-diabetic volunteers were recruited in this study. All subjects were subjected to an oral glucose tolerance test (OGTT). We also measured PFC and liver fat content (LFC) by three-point Dixon method (3p-Dixon), and we examined the relations between PFC and OGTT-derived parameters. T2DM subjects had higher PFC than non-diabetic subjects (p < 0.01). PFC was correlated with body mass index (BMI), liver fat content (LFC) and age in two groups, however, it was only positively associated with insulin secretion, insulin resistance, early- and late-phase insulin secretion in male T2DM subjects, but not in non-diabetic and female T2DM subjects. After adjusting for BMI, LFC and age, the association still existed (all p < 0.05). Furthermore, the relationship was more obvious in male T2DM subjects with a shorter course of disease. PFC was associated with ß-cell dysfunction and insulin resistance in subjects with T2DM and was more obvious in male T2DM subjects with shorter duration of diabetes. Therefore, PFC might represent a potential risk factor for the development of T2DM.

Ustekinumab treats psoriasis by suppressing RORC and T-box but its suppression of GATA restrains its efficacy

Psoriasis is a T-cell mediated disease that involves IL-23/Th17 and IL-12/Th1 axes. Ustekinumab, a fully human monoclonal antibody targeting the p40 subunit of both IL-12 and IL-23, has proven to be efficient and safe for treating patients with psoriasis. Yet, there have been no reports with human skin/blood samples that would elucidate the molecular mechanisms by which ustekinumab calms psoriasis skin lesions. To investigate the efficacy and molecular pathway (RORC, t-BOX and GATA) of ustekinumab in treating patients with psoriasis skin lesions. A total of 30 patients with psoriasis were randomized into placebo group and treatment group. PASI of each patient was calculated at 0, 12 and 24 weeks post-treatment. The mRNA levels of RORC, t-BOX and GATA in peripheral blood mononuclear cells separated from patients' whole blood were analyzed using qPCR. Decreased mRNA of RORC, t-BOX and GATA were observed after continuous injections, indicating that ustekinumab exerts its effect by interacting with these molecules; while no significant difference in foxp3 mRNA levels were found between placebo group and treatment group.

Aphicidal Activity of Illicium verum Fruit Extracts and Their Effects on the Acetylcholinesterase and Glutathione S-transferases Activities in Myzus persicae (Hemiptera: Aphididae).

This study aims to explore the aphicidal activity and underlying mechanism of Illicium verum Hook. f. that is used as both food and medicine. The contact toxicity of the extracts from I. verum fruit with methyl alcohol (MA), ethyl acetate (EA), and petroleum ether (PE) against Myzus persicae (Sulzer), and the activities of acetylcholinesterase (AChE) and glutathione S-transferases (GSTs) of M. persicae after contact treatment were tested. The results showed that MA, EA, and PE extracts of 1.000 mg/l caused, respectively, M. persicae mortalities of 68.93%, 89.95% and 74.46%, and the LC50 of MA, EA, and PE extracts were 0.31, 0.14 and 0.27 mg/l at 72 h after treatment, respectively; the activities of AChE and GSTs in M. persicae were obviously inhibited by the three extracts, as compared with the control, with strong dose and time-dependent effects, the inhibition rates on the whole reached more than 50.00% at the concentration of 1.000 mg/l at 72 h after treatment. The inhibition of the extracts on AChE and GSTs activities (EA extract > PE extract > MA extract) were correlated with theirs contact toxic effects, so it is inferred that the decline of the metabolic enzymes activities may be one of important reasons of M. persicae death. The study results suggested that I. verum extracts have potential as a eco-friendly biopesticide in integrated pest management against M. persicae.

Analysis of epithelial-mesenchymal transition markers in psoriatic epidermal keratinocytes.

Psoriasis is similar to endpoints of epithelial-mesenchymal transition (EMT), a process of epithelial cells transformed into fibroblast-like cells. The molecular epithelial and mesenchymal markers were analysed in psoriatic keratinocytes. No obvious alteration of epithelial markers E-cadherin (E-cad), keratin 10 (K10), K14 and K16 was detected in psoriatic keratinocytes. However, significantly increased expression of Vim, FN, plasminogen activator inhibitor 1 (PAI-1) and Slug was seen. IL-17A and IL-13 at 50 ng ml(-1) strongly decreased expression of K10, Vim and FN. TGF-ß1 at 50 ng ml(-1) promoted the production of N-cad, Vim, FN and PAI-1. Slug was decreased by dexamethasone (Dex), but E-cad was upregulated by Dex. Silencing of ERK partially increased E-cad and K16, but remarkably inhibited K14, FN, Vim, ß-catenin, Slug and α5 integrin. Moreover, inhibition of Rho and GSK3 by their inhibitors Y27632 and SB216763, respectively, strongly raised E-cad, ß-catenin and Slug. Dex decreased Y27632-mediated increase of ß-catenin. Dex at 2.0 µM inhibited SB216763-regulated E-cad, ß-catenin and slug. In conclusion, EMT in psoriatic keratinocytes may be defined as an intermediate phenotype of type 2 EMT. ERK, Rho and GSK3 play active roles in the process of EMT in psoriatic keratinocytes.