Discovery of Novel Azaindoles as Potent and Selective PI3Kδ Inhibitors for Treatment of Multiple Sclerosis.

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 vitro assay showed that 31 exhibited superior activity on T lymphocytes to inhibit the proliferation of CD4+, CD8+, and CD3+ T cells. In the experimental autoimmune encephalomyelitis (EAE) model, 31 showed a comparable therapeutical efficacy with Dexamethasone to significantly ameliorate EAE symptoms. Mechanistic studies showed that compound 31 could 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.

Discovery of Potent and Selective PI3Kδ Inhibitors for the Treatment of Acute Myeloid Leukemia.

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)-36 exhibited 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)-36 could 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)-36 could robustly inhibit the PI3K/AKT pathway for significant suppression of cell proliferation and remarkable induction of apoptosis both in vitro and in vivo. Thus, compound (S)-36 represents a promising PI3Kδ inhibitor for the treatment of acute myeloid leukemia with high efficacy.

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.

A Pan-Cancer Analysis of the Immunological and Prognostic Role of BUB1 Mitotic Checkpoint Serine/Threonine Kinase B (BUB1B) in Human Tumors.

BACKGROUND: BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) is a member of the spindle assembly checkpoint family and is related to cancer disease progression, invasion, metastasis, and functional promotion of angiogenesis. Several studies have noted that the BUB1B gene is frequently upregulated in various types of cancers. However, the expression patterns of BUB1B across different cancer types and its diagnostic and prognostic potential have not been investigated from a pan-cancer perspective. METHODS: The Cancer Genome Atlas (TCGA) data were used to explore the diagnostic and prognostic immunological potential of BUB1B in 33 cancer types. RESULTS: BUB1B was almost universally upregulated across all cancers, with increased protein expression in at least six cancer types and an enhanced phosphorylation level of S670 in two cancer types. Furthermore, BUB1B expression was negatively associated with clinical progression and prognosis in most cancers. BUB1B expression was positively associated with tumor mutational burden and microsatellite instability in 17 and 7 cancer types, respectively, and there was a correlation between BUB1B expression and DNA methylation at multiple probes in 30 cancer types. Additionally, a positive relationship existed between BUB1B expression and the infiltration levels of Th2, Tcm, and T helper cells, whereas BUB1B showed a negative correlation with the infiltration levels of other immune cells in multiple cancers. Moreover, functions associated with cell cycle progression and ubiquitin-mediated proteolysis were involved in the functional mechanism of BUB1B. CONCLUSIONS: Our pan-cancer study offers a comprehensive understanding of the role of BUB1B in tumorigenesis and tumor immunity across different types of cancer.

Construction of ceRNA Regulatory Network in Human Oocytes.

BACKGROUND: Cryogenic freezing, often known as cryopreservation, is a technique for preserving human oocytes. METHODS: In this study, differentially expressed long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) were identified using the human frozen oocyte dataset GSE69768 from the Gene Expression Database (GEO). Subsequently, combined with the microRNA atlas database, the miRNAs combined with differentially expressed lncRNAs (DElncRNAs) were predicted, and the lncRNA-miRNA-mRNA interaction relationship and competitive endogenous (ceRNA) regulatory network were obtained. RESULTS: The results revealed that multiple DElncRNAs and DEmRNAs were involved in the ceRNA network of the human oocyte. Finally, GO functional annotation and KEGG pathway enrichment analysis were performed on the differentially expressed mRNA (DEmRNA) in the ceRNA network, and the biological processes and pathways that may be related to the ceRNA network in frozen oocytes were explored. CONCLUSIONS: In conclusion, in the ceRNA network for human oocyte, lncRNA, mRNA, and miRNA do not each operate via a distinct, independent mechanism. Not only does the RNA-RNA contact involve the ceRNA regulatory mechanism, but it also involves interactions between proteins that are encoded by genes. Furthermore, the negative effects of inter-individual variations and instability on the quality of high-throughput detection cannot be completely ruled out due to the paucity of human oocyte data containing both mRNA and lncRNA expression profiles.

Discovery of Highly Selective and Orally Bioavailable PI3Kδ Inhibitors with Anti-Inflammatory Activity for Treatment of Acute Lung Injury.

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)-29 was identified as a candidate with high PI3Kδ inhibitory activity, isoform selectivity, and high oral bioavailability. The in vivo administration of (S)-29 at 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)-29 is a potent PI3Kδ inhibitor which might be a promising candidate for the treatment of ALI.

The Mediating Role of Systemic Inflammation in the Effects of Fetal Famine Exposure on Cardiovascular Disease in Adults: A Cohort Study.

BACKGROUND: 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 study was to examine risk of CVD in adulthood after exposure to famine during the fetal stage and explore the mediating role of systemic inflammation. METHODS: A total of 59,416 participants of the Kailuan Study without CVD were included. All participants were divided into 3 groups based on date of birth, including the unexposed group (1963-1974), the fetal-exposed group (1959-1962), and the childhood-exposed group (1949-1958). Systemic immune-inflammation index (SII) (neutrophils × platelets / lymphocytes) and systemic inflammatory response index (SIRI) (neutrophils × monocytes / lymphocytes) are 2 novel systemic inflammation indexes that represent the level of systemic inflammation. Time-weighted Cox regression was used to test the effect of famine exposure on risk of CVD, and a mediation model was used to calculate the role of systemic inflammation. RESULTS: During a median follow-up period of 12.36 (12.69, 13.16) y, a total of 3772 cases of CVD were documented. Compared with unexposed participants, the fetal-exposed group had an increased risk of CVD (HR: 1.19; 95% CI: 1.04, 1.38) and stroke (HR: 1.28; 95% CI: 1.09, 1.51) but not MI. No association was observed in the childhood-exposed group. In mediation analysis, SII mediated an estimated 24.43% of the association between fetal exposure and CVD (24.61% for stroke and 23.27% for MI). For SIRI, this percentage was 30.20% for CVD (29.94% for stroke and 31.25% of MI). CONCLUSIONS: Fetal exposure to famine may increase risk of CVD in adulthood. Systemic inflammation may play an intermediary role in the effect of fetal famine exposure on CVD.

Increased expression of TBC1D10B as a potential prognostic and immunotherapy relevant biomarker in liver hepatocellular carcinoma.

The TBC1 domain family member 10B (EPI64B/TBC1D10B), a member of the RabGAP EPI64 subfamily, contains a TBC domain that confers GTPase-activating protein activity. Even though overexpression of TBC1D10B has been reported to promote tumor invasion and metastasis in gastric adenocarcinoma, the prognostic value of TBC1D10B and its correlation with DNA methylation and immune infiltration in hepatocellular carcinoma are still not known. Transcriptional expression profiles of TBC1D10B between hepatocellular carcinoma tissues and normal tissues were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus. The Clinical Proteomic Tumor Analysis Consortium and the Human Protein Atlas were used to assess the TBC1D10B protein expression. The biological functions of TBC1D10B were evaluated by the Metascape database and by Gene Set Enrichment Analysis (GSEA). Receiver operating characteristic (ROC) curve analysis was used to distinguish hepatocellular carcinoma from adjacent normal tissues. The effect of TBC1D10B on survival was estimated using the Kaplan-Meier method. DNA methylation in the TBC1D10B gene was assessed using the online MEXPRESS and MethSurv tools. The association between TBC1D10B mRNA expression and immune cell infiltration was investigated by the TIMER2 web server, tumor immune estimation resource and single-sample GSEA. This study found that TBC1D10B is highly expressed in hepatocellular carcinoma and that increased TBC1D10B mRNA expression is associated with female sex, lower Body Mass Index, high level of alpha fetal protein, and worse clinical stages. The mRNA and protein levels of TBC1D10B were verified in cells. Functional annotation indicated enrichment with negative regulation of the cell cycle, extracellular matrix, and corresponding pathways in the high-TBC1D10B phenotype. The ROC curve analysis showed that, with a cutoff level of 2.912, the accuracy, sensitive, and specificity in differentiate TBC1D10B hepatocellular carcinoma from adjacent controls were 0.931, 0.920, and 0.802, respectively. Kaplan-Meier survival analysis showed that hepatocellular carcinoma patients with high TBC1D10B had a worse prognosis than those with low TBC1D10B, especially in patients with a weight below 70 kg, height above 170 cm, and histological G2 and G3. We also found that the methylation of TBC1D10B was associated with the prognosis in patients with hepatocellular carcinoma. Moreover, correlation analysis indicated that TBC1D10B mRNA expression was positively correlated with infiltration levels of most immune cells, but negatively correlated with Th17 and cytotoxic cells infiltration. Our study indicates that increased TBC1D10B expression in hepatocellular carcinoma may play a role in tumorigenesis by regulating the cell cycle and extracellular matrix. TBC1D10B may be a novel prognostic and predictive marker and immune therapeutic target in hepatocellular carcinoma patients.

Association Between Fresh Embryo Transfers and Frozen-Thawed Embryo Transfers Regarding Live Birth Rates Among Women Undergoing Long Gonadotropin-Releasing Hormone Antagonist Protocols.

Background: The availability and use of frozen-thawed embryos after controlled ovarian hyperstimulation for assisted reproduction have increased with improvements in vitrification techniques and the rise of gonadotropin-releasing hormone (GnRH) antagonist protocols. Although evidence has shown that frozen-thawed embryo transfers (FETs) result in higher live birth rates than fresh embryo transfers, it is uncertain whether this association exists in cycles employing the GnRH antagonist protocol. Objective: To test the hypothesis that FETs are more likely to result in a live birth than fresh embryo transfers in a GnRH antagonist protocol cycle and to investigate whether frozen blastocyst transfer increases live birth rates compared to fresh blastocyst transfer. Design: A retrospective historical cohort study was conducted using data collected from the Department of Reproductive Medicine of Liuzhou Maternity and Child Healthcare Hospital for 1,437 patients who underwent the GnRH antagonist protocol between 1 January 2015, and 31 December 2020. The primary outcome was the live birth rate, which was compared between fresh embryo transfer and FET, and the secondary outcomes were clinical pregnancy rate and miscarriage rate, which were compared between the two groups. Analyses were adjusted to account for the age of the patient, number of embryo transfers, day of embryo transfer, and type of infertility. Results: Fresh embryo transfers accounted for 1,026 (71.4%) of the 1,437 patients who underwent the GnRH antagonist protocol in our analysis, while FETs accounted for 411 (28.6%). Patients with fresh and frozen-thawed embryos had comparable median body mass index (body mass index; 22.3 [IQR, 24.6-20.0] vs. 22.0 [IQR, 24.5-19.9]). There was a significant difference in the median age of the fresh embryo transfer group (34.0 [IQR, 39.0-30.0]) and the Frozen-thawed embryo transfer group (32.0 [IQR, 37.0-29.0]). Blastocysts were transferred in 14.6% of the fresh embryo transfer cycles and 45.5% of the FET cycles, whereas they account for 10.4% and 13.0% of all patients, respectively. The mean number of embryos transferred was 2 (IQR, 2.0-1.0) for the fresh embryo transfer group and 1 (IQR, 2.0-1.0) for the FET group, with a significant difference in the mean number of embryos transferred. The live birth rate after fresh embryo transfer vs. FET was 28.7% vs. 34.5% (absolute difference, 5.9%; adjusted relative risk [aRR], 1.15 [95% CI, 0.88-1.51]). The clinical pregnancy rates were 39.9% vs. 46.0%, respectively (absolute difference, 6.1%; aRR, 1.10 [95% CI, 0.85-1.43]). The miscarriage rates were 22.5% vs. 23.8%, respectively (absolute difference, 1.3%; aRR, 1.13 [95% CI, 0.75-1.70]). Conclusion: In this retrospective study of women who underwent assisted reproduction using GnRH antagonists, FETs resulted in a higher live birth rates and clinical pregnancy rates than fresh embryo transfers, which parts of these differences were attributable to embryo stage. However, the interpretation of the findings is limited by the possibility of selection and confounding biases.

Discovery of Novel Indazoles as Potent and Selective PI3Kδ Inhibitors with High Efficacy for Treatment of Hepatocellular Carcinoma.

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 9x with good isoform selectivity, PK profile, and potency. Compared to Idelalisib and Sorafenib, the pharmacodynamic (PD) studies showed that 9x exhibits superior efficacy in HCC cell lines and xenograft models, and the mechanistic study showed that 9x robustly 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.

Comparison of Electrocoagulation Tuboplasty and Continued Medical Therapy for Treating Persistent Eustachian Tube Dysfunction With Hypertrophic Mucosa Disease.

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.

A Pan-Cancer Analysis of the Oncogenic Role of Integrin Beta4 (ITGB4) in Human Tumors.

BACKGROUND: Integrin beta4 (ITGB4) is a transmembrane receptor that plays a key role in tumorigenesis and tumor development. However, there are no pan-cancer analyses of ITGB4. METHODS: This study demonstrates the first potential oncogenic roles of ITGB4 across 33 tumors based on the dataset of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). RESULTS: ITGB4 is highly expressed in many cancers, and distinct correlations exist between ITGB4 expression and the prognosis of tumor patients. We also found that the methylation and genetic alteration level of ITGB4 was associated with some cancer prognosis. Furthermore, we found a reduced phosphorylation of ITGB4 at S1457 in several tumors, such as breast and ovarian cancers. Finally, ITGB4 expression was correlated with cancer-associated fibroblasts in liver hepatocellular carcinoma and prostate adenocarcinoma, and the infiltration level of NK cells and neutrophils was observed in other cancers, such as breast invasive carcinoma and lung adenocarcinoma. Moreover, RNA metabolism and protein processing-associated functions are involved in the functional mechanism of ITGB4. CONCLUSION: Our first pan-cancer study may offer a relatively comprehensive understanding of the oncogenic roles of ITGB4 across different tumors.

Is no de-squamatization of the TM reliable for cartilage over-underlay myringoplasty without external auditory canal packing?

OBJECTIVE: We evaluated the graft and hearing outcomes of patients with chronic perforations treated via the cartilage-perichondrium over-underlay technique without de-squamatization of the TM and external auditory canal (EAC) packing. MATERIALS AND METHODS: Thirty-nine patients with chronic perforations and residual tympanic membranes around the perforation margins were treated using the cartilage-perichondrium over-underlay technique without de-squamatization of the TM and EAC packing. Patients were followed-up for 6 months. RESULTS: For all 39 patients with unilateral perforations, the graft success rate was 100% (39/39) at 6 months after surgery. The mean air-bone gap significantly (P < 0.05) improved from 13.41 ± 8.34 dB preoperatively to 7.45 ± 3.81 dB postoperatively in patients with small and medium perforations; the mean air-bone gap significantly improved from 20.57 ± 9.41 dB preoperatively to 9.84 ± 2.41 dB postoperatively in patients with large perforations. The lateral perichondrium gradually became necrotic and crust at postoperative 2-3 months and migrated into the EAC in all patients. CONCLUSIONS: The cartilage-perichondrium over-underlay myringoplasty without de-squamatization of the TM and EAC packing is feasible, affording a high graft success rate and good hearing improvement. The lateral perichondrium may gradually become necrotic and crusted, and migrate along the EAC over time.

[Dietary quality among heat-exposed steelworkers in Tangshan City in 2015].

OBJECTIVE: To evaluate the dietary quality and find the dietary problems among heat-exposed steelworkers. METHODS: During May and June of 2015, 301 heat-exposed steelworkers were recruited using a cluster sampling method from three workshops in steel works of the Tangshan Iron & Steel Group. In the study, 3 day twentyfour hour(24 h) recall method was used to conduct the dietary survey. The adjusted diet balance index(DBI)-2007 was used to evaluate the dietary quality. RESULTS: The low bound score(LBS) and high bound score(HBS) of heat-exposed steelworkers were 26-39 and 14-20, their diet quality distance(DQD) was 49. 85±7. 3. About 159(52. 8%)and 131(43. 5%) workers were in moderate and high dietary imbalance status. The LBS and DQD of the workers at occupational exposure to heat stress level IV((33. 7±6. 3) and(51. 1±7. 1)) were higher than those of the workers at heat stress level Ⅱ((27. 7±6. 0)and(44. 9±7. 2)) and Ⅲ((28. 5 ± 5. 7) and(45. 1 ± 6. 1))(P < 0. 001). The main dietary pattern of 43. 5% workers was pattern E. The percentages of worker 's intake meeting to high temperature recommended amount(score 0-1) of vegetable, fruit, bean, salt and drinking water in working were respectively 9. 3%, 11. 0%, 43. 8%, 1. 7% and17. 3%. All(100%) workers ' intakes of milk and fish did not meet diet pagoda recommended amount. 278(92. 4%) and 254(84. 4%) workers' meat and egg intakes achieved or exceeded diet pagoda recommended amount. CONCLUSION: nutritional structure of heat-exposed steelworkers was still unreasonable. The intakes of water during working, vegetables, fruits, milk, beans, fish and shrimp and salt were insufficient, while the intakes of grains and meat were excessive. The main dietary pattern of workers was pattern E, which reflect middle insufficient intake and excessive intake. No workers was pattern A, which reflect optimal dietary pattern with less insufficient intake and excessive intake.

Discovery of novel inhibitors of phosphodiesterase 4 with 1-phenyl-3,4-dihydroisoquinoline scaffold: Structure-based drug design and fragment identification.

Currently, it is in urgent need to develop novel selective PDE4 inhibitors with novel structural scaffolds to overcome the adverse effects and improve the efficacy. Novel 1-phenyl-3,4-dihydroisoquinoline amide derivatives were developed as potential PDE4 inhibitors based on the structure-based drug design and fragment identification strategy. A SARs analysis was performed in substituents attached in the C-3 side chain phenyl ring, indicating that the attachment of methoxy group or halogen atom substitution at the ortho-position of the phenyl ring was helpful to enhance both inhibitory activity toward PDE4B and selectivity. Compound 15 with excellent selectivity, exhibited the most potent inhibition in vitro and in vivo, which is a promising lead for development of a new class of selective PDE4 inhibitors.

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.

Structure-based design and structure-activity relationships of 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors.

This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1,2,3,4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNFα release. Among them, compound 19 exhibited the strongest inhibition against PDE4B with an IC50 of 0.88 µM and 21 times more potent selectivity toward PDE4B over PDE4D when compared to rolipram. A primary structure-activity relationship study showed that the attachment of CH3O group or CF3O group to the phenyl ring at the para-position was helpful to enhance the inhibitory activity against PDE4B. Moreover, sulfonamide group played a key role in improving the inhibitory activity against PDE4B and subtype selectivity. In addition, the attachment of the additional rigid substituents at the C-3 position of 1,2,3,4-tetrahydroisoquinoline ring was favored to subtype selectivity, which was consistent well with the observed docking simulation.

Design, Synthesis and Structure-Activity Relationship of Novel Aphicidal Mezzettiaside-Type Oligorhamnosides and Their Analogues.

Oligosaccharides have been used for an environmentally friendly insect control in the agricultural industry. In order to discover novel eco-friendly pesticides, a series of partially acetylated oligorhamnoses mezzettiasides, 2-8, and their analogues, 9-14, with biosurfactant characteristics were designed and synthesized, some of which exhibited comparable to or even stronger aphicidal activity than pymetrozine. Preliminary SAR studies demonstrated that the aphicidal activity of mezzettiasides analogs is highly dependent on their structures, including both the sugar length and the substitutes on the sugar. Among them, trirhamnolipid 9 displayed the strongest aphicidal activity, with an LC50 of 0.019 mmol/L, indicating that the biosurfactant 9 may have potential for use as an environmentally friendly agricultural pesticide.

[Effects of the nutritional education and dietary intervention on nutritional status and bone mineral density of middle-aged and senile patients with osteoporosis].

OBJECTIVE: To study the effect of the nutritional education and dietary intervention on nutritional status and bone mineral density (BMD) of middle-aged and senile patients with osteoporosis. METHODS: Ninty middle-aged and senile osteoporosis patients were enrolled. They were randomly divided into two groups (intervention and control group) with 45 cases each. The control group was received conventional therapy and the intervention group added with nutritional education and dietary intervention for six months on the basis of conventional therapy. The methods of education and intervention included seminars, brochures distribution, dietary survey and individual guidance. The nutritional status and BMD were analyzed at the beginning and the end of the intervention respectively. RESULTS: After the intervention, the ratios of subjects whose intake of grain, vegetables, fruits, eggs, milk and beans in line with recommended intake of the intervention group were higher than those of the control group (P < 0.05). After the intervention, frequencies of coarse grain, dairy, beans and seafood consumption of the intervention group were higher than those of the control group (P < 0.05). After the intervention, the daily intakes of protein, VA, VC, calcium, zinc, magnesium, dietary fiber of the intervention group were significantly superior to the control group (P < 0.05). BMDs of lumbar spine and femoral neck in the intervention group were significantly higher than those in the control group (P < 0.05). CONCLUSION: The nutritional education and dietary intervention could promote middle-aged and senile patients' reasonable diet, improve their nutritional status, enhance bone mineral density and improve the effect of conventional therapy for osteoporosis.

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.