Synthesis and bioactivity of 3,5-dimethylpyrazole derivatives as potential PDE4 inhibitors.

A series of 3,5-dimethylpyrazole derivatives containing 5-phenyl-2-furan moiety were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. Bioassay results showed that the title compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNFα release. Among the designed compounds, compound If showed the best inhibitory activity against PDE4B with the IC50 value of 1.7 µM, which also showed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary structure-activity relationship (SAR) study and docking results suggested that introduction of the substituent groups to the phenyl ring at the para-position, especially methoxy group, was helpful to enhance inhibitory activity against PDE4B.

TYM-3-98, a novel selective inhibitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B-cell lymphomas.

AIMS: PI3Kδ is expressed predominately in leukocytes and is commonly found to be aberrantly activated in human B-cell lymphomas. Although PI3Kδ has been intensively targeted for discovering anti-lymphoma drugs, the application of currently approved PI3Kδ inhibitors has been limited due to unwanted systemic toxicities, thus warranting the development of novel PI3Kδ inhibitors with new scaffolds. MAIN METHODS: We designed TYM-3-98, an indazole derivative, and evaluated its selectivity for all four PI3K isoforms, as well as its efficacy against various B-cell lymphomas both in vitro and in vivo. KEY FINDINGS: We identified TYM-3-98 as a highly selective PI3Kδ inhibitor over other PI3K isoforms at both molecular and cellular levels. It showed superior antiproliferative activity in several B-lymphoma cell lines compared with the approved first-generation PI3Kδ inhibitor idelalisib. TYM-3-98 demonstrated a concentration-dependent PI3K/AKT/mTOR signaling blockage followed by apoptosis induction. In vivo, TYM-3-98 showed good pharmaceutical properties and remarkably reduced tumor growth in a human lymphoma xenograft model and a mouse lymphoma model. SIGNIFICANCE: Our findings establish TYM-3-98 as a promising PI3Kδ inhibitor for the treatment of B-cell lymphoma.

Selective PI3Kδ inhibitor TYM-3-98 suppresses AKT/mTOR/SREBP1-mediated lipogenesis and promotes ferroptosis in KRAS-mutant colorectal cancer.

Colorectal cancer (CRC) is one of the most common tumors of the digestive system worldwide. KRAS mutations limit the use of anti-EGFR antibodies in combination with chemotherapy for the treatment of CRC. Therefore, novel targeted therapies are needed to overcome the KRAS-induced oncogenesis. Recent evidence suggests that inhibition of PI3K led to ferroptosis, a nonapoptotic cell death closely related to KRAS-mutant cells. Here, we showed that a selective PI3Kδ inhibitor TYM-3-98 can suppress the AKT/mTOR signaling and activate the ferroptosis pathway in KRAS-mutant CRC cells in a concentration-dependent manner. This was evidenced by the lipid peroxidation, iron accumulation, and depletion of GSH. Moreover, the overexpression of the sterol regulatory element-binding protein 1 (SREBP1), a downstream transcription factor regulating lipid metabolism, conferred CRC cells greater resistance to ferroptosis induced by TYM-3-98. In addition, the effect of TYM-3-98 was confirmed in a xenograft mouse model, which demonstrated significant tumor suppression without obvious hepatoxicity or renal toxicity. Taken together, our work demonstrated that the induction of ferroptosis contributed to the PI3Kδ inhibitor-induced cell death via the suppression of AKT/mTOR/SREBP1-mediated lipogenesis, thus displaying a promising therapeutic effect of TYM-3-98 in CRC treatment.

Prognosis and outcome of the tympanic membrane flap at traumatic tympanic membrane perforation edge.

This study aimed to retrospectively evaluate the prognosis and outcome of tympanic membrane perforations with a particular focus on the fate of the perforation edge flaps.Chart records of 329 patients with a single ear traumatic tympanic membrane perforation were retrieved and analyzed. Of these patients, 70 were left to heal spontaneously, 93 received gelatin sponge patching treatment and 114 were subjected to otoendoscopic eardrum repair before gelatin sponge patching. The complete perforation closure rate at 3 months was 94.29% (66/70), 98.92% (92/93) and 98.24% (112/114) in the 3 groups, respectively, with no statistically significant difference (p = 0.608). The mean closure time was 28.2 ± 3.6 days in the spontaneous healing group, which was significantly longer than that in the sponge patching group (11.1 ± 2.1 days, p = 0.0017) and in the eardrum repair + sponge patching group (12.5 ± 1.9 days, p = 0.0032), while there was no significant difference between the 2 gelatin sponge patching groups (p = 1.86). The hearing ability improved in the 3 groups (6.4 ± 0.83, 7.2 ± 1.65 and 9.6 ± 2.37 dB, respectively), with no statistically significant difference (p >0.05). In the gelatin sponge patching group, new tympanic membrane tissue of the eardrum flap edge proliferated, and the contour of the eardrum flap was not obvious. In the eardrum flap repair group, the eardrum flap retracted to the perforation edge. In conclusion, the eardrum flap of the perforation edge does not have any obvious effect on the perforation closure so that it is unnecessary to conduct an intervention procedure on the flap in the clinical treatment.

Relation between eardrum flap area and healing outcome of traumatic eardrum perforation.

OBJECTIVE: To retrospectively study the clinical effects of eardrum flap area on the healing outcome following traumatic perforation. METHODS: Totally 291 traumatic eardrum perforations with in-/everted edges were included in this study. They were randomly divided into three groups and received conservative treatment, epidermal growth factor (EGF) via Gelfoam patching, or edge-approximation plus Gelfoam patching respectively. Patients in each group were further divided into two subgroups according to the eardrum flap area less than or equal to 1/2 or >1/2 of the perforation size. The healing rate and mean closure time after tympanic membrane perforation were evaluated at three months. RESULTS: Of the total 291 participants, 281 were included in the final statistical analysis. The area of curled edge did not affect the healing outcome significantly in any groups (P>0.05). The healing rate varied slightly: 90.7% vs 92.3% in spontaneous healing group, 98.2% vs 97.4% in EGF via Gelfoam patching group, and 96.5% vs 100% in edge-approximation plus Gelfoam patching group. In addition, in all groups the area of curled edge did not affect the mean closure time significantly (P>0.05). The closure time was (32.3+/-2.4) d vs (30.6+/-3.1) d in sponaneous healing group, (13.4+/-2.5) d vs (13.1+/-1.9) d in EGF via Gelfoam patching group, and (11.9+/-3.1) d vs (12.2+/-2.1) d in edge-approximation plus Gelfoam patching group. CONCLUSION: The eardrum flap area of traumatic eardrum perforation does not significantly affect the clinical outcomes.

[Effects of iron deficiency anemia on immunity and infectious disease in pregnant women].

OBJECTIVE: To review the changes in immune function and incidence of infectious diseases in pregnant women with iron deficiency anemia (IDA), especially marginalde-ficiency of iron. METHODS: T lymphocyte subsets level (CD3+, CD4+ and CD8+), nature kill cells activity (CD16), interleukin-2 (IL-2) and serum IgA, IgG, IgM and complement C3 were determined in 3 different wormen groups, including 69 IDA pregnant women who were diagnosed by Hemoglobin, concentrations of free erythocyte porphrin and serum ferritin from 280 pregnant women during 30-38weeka of gestation, 52 random sampling normal pregnant women and 50 no pregnant women examined before marriage. RESULTS: The prevalenoe of IDA for pregnant women is 24.6%. The average concentration of Hb for pregnant women of IDA is 102.00(6.00 g/L The level of CD3+ and CD4+ cells, the ratio of CD4+/CD8+ cells, serum IL-2 as well as IgG levels in the pregnant women were significantly lower than that of those normal pregnant women (P < 0.01, P < 0.05, P < 0.05, P < 0.01). With the decreasing extent of Hb, these significant immunological indices of pregnant women will degrease. The incidence of infectious diseases in IDA pregnant women was significantly higher than that in normal pregnant women (P < 0.05). CONCLUSION: There are significantly effects of IDA on cellular immune function and infectious disease during pregnancy. The study on effects of IDA during pregnancy on nature kill cells activity (CD16) and incidence of infectious diseases during puerperium should be continued by increasing sample's number.

Relationships between micronutrient losses in sweat and blood pressure among heat-exposed steelworkers.

We aimed to examine the effect of micronutrient losses through sweat on blood pressure (BP) among heat-exposed steelworkers. A total of 224 heat-exposed male steelworkers from an ironworks facility were evaluated in July 2012. We measured the Wet Bulb Globe Temperature Index to evaluate the level of heat stress in the workplace. We collected sweat from the workers during an eight-hour work, and then we measured the micronutrients in the sweat. We also measured the BP of each worker. The results revealed that vitamin C, potassium, and calcium losses in sweat were positively correlated with systolic (SBP) and diastolic (DBP) blood pressure (all P<0.05). A linear stepwise regression analysis revealed that potassium, and calcium losses in sweat adversely affected SBP and DBP (all P<0.05). An analysis of covariance showed that SBP increased when potassium or calcium losses in sweat were >900 mg, or >100 mg, respectively. Further, DBP increased when potassium or calcium losses in sweat were >600 mg or >130 mg, respectively. Therefore, vitamin C, potassium, and calcium losses in sweat may adversely effect BP. To help steelworkers maintain healthy BP, facilities with high temperatures should try to lower environmental temperatures to reduce vitamin C, potassium, and calcium losses in sweat. Additionally, heat-exposed steelworkers may need to increase their dietary intakes of vitamin C, potassium, and calcium. Further research is needed to confirm these findings and support these recommendations.

Effect of treatment at different time intervals for traumatic tympanic membrane perforation on the closure.

CONCLUSION: Treatment of traumatic tympanic membrane (TM) perforation with everted or involute edge flaps at different time intervals within 1 week after the injury did not affect the perforation closure rate and mean closure time. OBJECTIVE: To retrospectively analyze the effect of treatment at different time intervals for traumatic tympanic membrane perforation with gelatin sponge patch and edge approximation plus gelfoam patching. METHODS: Patients with traumatic TM perforation visited at different days since the injury for medical treatment (1, 2, 3, 4, and 5-7 days post trauma). These patients were treated with the following prominent methods of treatment: gelatin sponge patch treatment and edge approximation plus gelfoam patching. Measurement indicators were perforation closure rate and mean closure time at 3 months. RESULTS: In the group treated with the gelatin sponge patch technique, the patients sought medical treatment at different time intervals since the injury. Accordingly, the outcome of the treatment varied in terms of the perforation closure rates achieved in different patients in this group. The respective perforation closure rates were 100%, 100%, 96%, 94%, and 89% in accordance with the time interval at which the patients were treated since the injury. The results were not significantly different when compared by statistical analysis (p > 0.05); the mean closure times in each of the different sets of cases in this group were calculated and the following values were reported: 7.1 ± 2.3, 8.2 ± 1.6, 8.7 ± 1.2, 9.2 ± 3.1, and 10.7 ± 3.9 days. On the other hand, in the edge approximation plus gelfoam patching group, the perforation closure rates were 100%, 97%, 96%, 97%, and 94%, respectively. This was in accordance with the time elapsed since the injury for the patients who visited the hospital on different days. Statistical analysis confirmed that the perforation closure rates for the different cases of this group did not have any significant difference (p > 0.05); the mean closure times were 7.6 ± 1.9, 7.9 ± 2.2, 9.2 ± 2.8, 8.5 ± 3.6, and 11.2 ± 4.1 days, respectively, indicating that differences were not significant even in terms of mean closure rates for the different cases of this group (p > 0.05).

[Study on genetic instability of NM23H1 gene in Chinese with the epithelial ovarian tumor].

The aim of this study was to examine microsatellite instability (MSI) and loss of heterozygosity (LOH) of locus D17S396 on chromosome 17 and their influence on the expression of nm23H1 in the epithelial ovarian tumors, which may provide experimental basis for the mechanism of nm23H1 gene and tumor metastasis. Techniques such as DNA extraction from formalin-fixed paraffin-embedded tissues, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), ordinary silver stain were used to study MSI and LOH of locus D17S396. Envision immunohistochemistry and Leica-Qwin computer imaging techniques were used to assess the expression of nm23H1 gene. In our experiments, the frequency of heredity instability of malignant ovarian tumors was 40%, which is higher than that of borderline ovarian tumors, while there were no heredity instability occurred in benign ovarian tumors and normal ovarian tissue. Among 25 epithelial ovarian carcinomas, the frequency of LOH in lymph node metastasis cases (66.67%) was significantly higher than those without metastasis (10.53%). Moreover, the frequency of LOH was higher in FIGO stage III and IV than in stage I and II. However, the frequency of MSI showed no correlation with any clinicopathologic characteristics. The positive frequency of nm23H1 protein in the ovarian epithelial carcinoma and borderline tumors were 56.00% and 57.14%, respectively. They were both higher than those of the benign tumors and normal ovarian tissue. In the epithelial ovarian carcinomas, the positive frequency of nm23H1 protein in lymph node metastasis case was significantly lower than those without metastasis. FIGO stage III and IV also exhibited lower positive frequency of nm23H1 protein compared with stage I and II. Furthermore, there was no difference in nm23H1 protein expression intensity analyzed by computer imaging. In the epithelial ovarian carcinomas, the positive frequency of nm23H1 protein in LOH positive group was 0.00%, which is lower than that of LOH negative group (P < 0.01). The results indicated that the heredity instability of nm23H1 gene might be implicated in pathogenesis and progression of epithelial ovarian tumor. The occurrence of LOH might be the molecule marker of the deteriorism of ovarian tissue. Both MSI and LOH of nm23H1 gene controlled development of the epithelial ovarian tumor independently in different paths. LOH could inhibit the expression of nm23H1 in local tissue of the epithelial ovarian carcinoma, which endowed it with high aggressive and poor prognosis. Increasing the amount of nm23H1 protein expression could effectively restrain metastasis of the ovarian epithelial carcinoma and improve prognosis of patients.