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Programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) targeting therapy is widely applied in clinics for gastric cancer treatment. Nevertheless, the clinical response is not well acceptable due to the exosomal PD-L1. Hence, abrogation of the exosomal PD-L1 may be a strategy to sensitize the gastric cancer cell to PD-1 targeting therapy. With the aid of CD63 targeting antibody and PD-L1 targeting aptamer, HTRF based assay was established to quantify the exosomal PD-L1, and applied to our in-house compound library, resulting in the identification of moclobemide. Further optimization of moclobemide lead to EP16, which can inhibit the generation of exosomal PD-L1 with IC 50 = 0.108 μM. By applying EP16 to gastric cancer cell line coupled with T-cell activity related experiment, it was validated to activate T-cell and can promote the response of PD-1 targeting therapy for gastric cancer treatment in vitro and in vivo. Collectively, our findings give a promising tool to promote the sensitivity of anti-PD-1 for gastric cancer treatment, and EP16 can serve as a leading compound for exosomal PD-L1 abrogation. [Display omitted] • EP16 was designed by using phenotype-based assay and our in-house compound library. • EP16 inhibited the generation of exosomal PD-L1 with an IC 50 value of 0.108 μM. • EP16 promoted the response to PD-1/PD-L1 targeted therapy in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Macrocyclic compounds, characterized by cyclic structures, often originate from either modified forms of unicyclic canonical molecules or natural products. Within the field of medicinal chemistry, there has been a growing fascination with drug-like macrocycles in recent years, primarily due to compelling evidence indicating that macrocyclization can significantly influence both the biological and physiochemical properties, as well as the selectivity, when compared to their acyclic counterparts. The approval of contemporary pharmaceutical agents like Lorlatinib underscore the notable clinical relevance of drug-like macrocycles. Nonetheless, the synthesis of these drug-like macrocycles poses substantial challenges, primarily stemming from the complexity of ring-closing reactions, which are inherently dependent on the size and geometry of the bridging linker, impacting overall yields. Nevertheless, macrocycles offer a promising avenue for expanding the synthetic toolkit in medicinal chemistry, enabling the creation of bioactive compounds. To shed light on the subject, we delve into the clinical prowess of established macrocyclic drugs, spanning various therapeutic areas, including oncology, and infectious diseases. Case studies of clinically approved macrocyclic agents illustrate their profound impact on patient care and disease management. As we embark on this journey through the world of macrocyclic pharmaceuticals, we aim to provide a comprehensive overview of their synthesis and clinical applications, shedding light on the pivotal role they play in modern medicine. [Display omitted] • A summary of FDA-approved macrocyclic pharmaceuticals is systematically provided. • The clinical applications and synthetic routes of representative macrocycles are emphasized. • Challenges and prospects are briefly discussed to guide future design of macrocyclic drugs. [ABSTRACT FROM AUTHOR]

The study aims to investigate the intestinal (small and large intestine) clinical features and treatment of hamartoma. Nowadays, with the rapid development of new technologies, digestive system endoscopy has been proven to be an effective device for treatment, rather than just a diagnostic tool. Such development plays a revolutionary role in diagnosis and treatment for digestive diseases. And endoscopic treatment was used in this study (LED light source, wavelength 580 ∼ 595 nm, power 200 W). A retrospective analysis of 20 cases of intestinal hamartomas performed from January 2012 to January 2016 to summarize its clinical characteristics and follow-up study on the therapeutic effect of the patients. There were 8 cases for endoscopic operation, and 12 cases for surgical operation. Comparison of tumor size between endoscopic and surgical estimated by using Wilcoxon rank sum test for tumor length (Z = -3.134, p = 0.001), and for tumor diameter (Z = -2.920, p = 0.002). The results of this study showed that intestinal hamartomas and gender have no significant relationship. The incidence of the disease is concentrated under 60 years, the incidence of the small intestine is significantly higher than that of the large intestine, and the rate of misdiagnosis is high. Endoscopic and surgical treatment are the main treatment, the prognosis is good, and after the radical resection, the recurrence was less. [ABSTRACT FROM AUTHOR]

Abstract: Phosphodiesterase 4 (PDE4) isozyme plays important roles in inflammatory and immunomodulatory cells. In this study, piclamilast, a selective PDE4 inhibitor, was used to investigate the role of PDE4 in respiratory function and inflammation in a murine asthma model. Sensitized mice were challenged with aerosolized ovalbumin for 7 days, piclamilast (1, 3 and 10 mg/kg) and dexamethasone (2 mg/kg) were orally administered once daily during the period of challenge. Twenty-four hours after the last challenge, airway hyperresponsiveness to methacholine was determined by whole-body plethysmography, airway inflammation and mucus secretion by histomorphometry, pulmonary cAMP-PDE activity by HPLC, cytokine levels in bronchoalveolar lavage fluid and their mRNA expression in lung by ELISA and RT-PCR, respectively. In control mice, significant induction of cAMP-PDE activity was parallel to the increases of hyperresponsiveness, inflammatory cells, cytokine levels, mRNA expression as well as goblet cell hyperplasia. However, piclamilast dose-dependently and significantly improved airway resistance and dynamic compliance, and the maximal effect was similar to that of dexamethasone. Piclamilast treatment dose-dependently and significantly prevented the increase in inflammatory cell number and goblet cell hyperplasia, as well as production of cytokines, including eotaxin, TNFα and IL-4. Piclamilast exerted a weaker inhibitory effect than dexamethasone on eosinophils and neutrophils, had no effect on lymphocyte accumulation. Moreover, piclamilast inhibited up-regulation of cAMP-PDE activity and cytokine mRNA expression; the maximal inhibition of cAMP-PDE was greater than that exerted by dexamethasone, and was similar to dexamethasone on cytokine mRNA expression. This study suggests that inhibition of PDE4 by piclamilast robustly improves the pulmonary function, airway inflammation and goblet cell hyperplasia in murine allergenic asthma. [Copyright &y& Elsevier]

Gastrointestinal (GI) cancers encompass a group of malignancies affecting the digestive system, including the stomach, esophagus, liver, colon, rectum and pancreas. These cancers represent a significant global health burden, necessitating effective treatment strategies. Small-molecule drugs have emerged as crucial therapeutic options in the fight against GI cancers due to their oral bioavailability, targeted mechanisms of action, and well-established safety profiles. The review then elucidates the clinical applications and synthetic methods of clinically approved small-molecule drugs for the treatment of GI cancer, shedding light on their mechanisms of action and their potential in mitigating GI cancer progression. The review also discusses future prospects and the evolving landscape of small-molecule drug development in GI oncology, highlighting the potential for personalized medicine. In summary, this review provides valuable insights into cutting-edge strategies for harnessing clinically approved small-molecule drugs to combat GI cancer effectively. [Display omitted] • An organization of small-molecule drugs for gastrointestinal cancer treatment is provided. • Synthetic pathways and clinical application of these drugs are emphasized. • Challenge and prospect are also discussed to guide gastrointestinal cancer treatment. [ABSTRACT FROM AUTHOR]

• Depth prediction methods are used during cooling time in square-heating thermography. • Depth prediction methods suit materials with lower thermal diffusivity and deeper defects. • The logarithmic characteristic time and logarithmic depth show a linear relationship. • Two of the four depth prediction methods do not require a reference area. Square-heating thermography was used to predict the depth of glass fiber reinforced plastic (GFRP) flat-bottom holes during its cooling period. Four methods were proposed for depth prediction using a specified characteristic peak time. Square-heating thermography cooling theory was analyzed using numerical methods, the linear relationship between the logarithmic characteristic time and logarithmic depth of the GFRP's flat-bottom holes was obtained, and the slope and intercept of the linear curve were mainly related to the thermal diffusivity and the heating time. Finally, the flat-bottom hole depth was predicted using experimental cooling data from GFRP samples. [ABSTRACT FROM AUTHOR]

In this study, five theoretical equations of specific characteristic peak times are proposed to predict the defect depth for step-heating thermography. These equations were derived for test samples with surfaces under adiabatic and convective heat transfer conditions, where, as demonstrated from experiments, the effect of convection on depth prediction can be significant for materials with low thermal conductivities. Two glass fiber reinforced plastic (GFRP) samples with flat-bottom holes at various depths were inspected by step-heating thermography, and the defect depths were predicted by these five methods. Based on the experimental results, the prediction accuracy and the performance of these depth prediction methods are discussed. [ABSTRACT FROM AUTHOR]

Abstract: PDE4 (phosphodiesterase-4) plays a critical role in pathogenesis of allergic asthma and chronic obstructive pulmonary disease (COPD). PDE4 inhibitors are presently under clinical development for the treatment of asthma and/or COPD. Ciclamilast, a new PDE4 inhibitor, is a piclamilast (RP 73401) structural analogue, but has a more potent inhibitory effect on PDE4 and inflammation in the airway tissues and less side effects than that of piclamilast. In this study, we elucidate primarily on the roles of compound on PDE4 enzyme in physiological and pathological processes in a mouse model of asthma. The sensitized/challenged mice were reexposed to ovalbumin and airway response to inhaled methacholine was monitored. Orally administration of ciclamilast, in a dose-dependent manner, significantly inhibited changes in lung resistance and lung dynamic compliance, as well as upregulation of cAMP-PDE activity, increase of PDE4D mRNA expression, but not PDE4B from lung tissue in the murine model. In addition, the compound dose-dependently reduced mRNA expression of eotaxin, tumor necrosis factor (TNF)-α and interleukin (IL)-4, but slightly increased mRNA expression of interferon (IFN)-γ from lung tissue. Further, levels of eotaxin, TNF-α and IL-4, and eosinophil and neutrophil accumulation in bronchoalveolar lavage fluid were also significantly reduced. Pathological examination, goblet cell hyperplasia and inflammatory cells infiltration in lung tissue were suppressed by treatment with ciclamilast. A significant correlation was observed between the increases in PDE4D mRNA expression and airway hyperresponsiveness. These studies confirm that inhibitory effect of ciclamilast on airway hyperresponsiveness includes its inhibiting PDE4D mRNA expression, down-modulating PDE4 activity, anti-inflammation and anti-mucus hypersecretion, and ciclamilast may have therapeutic potential for the treatment of asthma. [Copyright &y& Elsevier]